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Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose
International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose夽 Dieter Boy a , Michaela Well a , Martina Kinzig-Schippers b , Fritz Sörgel b , Dorothe Ankel-Fuchs c , Kurt G. Naber a,∗ a b
Department of Urology, Hospital St. Elisabeth, St. Elisabeth-Str. 23, D-94315 Straubing, Germany Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany c Grünenthal GmbH, Aachen, Germany
Abstract In an open randomised double-crossover study 12 volunteers (six men, six women) received a single oral dose of gatifloxacin (400 mg) or ciprofloxacin (500 mg) to assess urinary bactericidal activity (in eight intervals up to 120 h) and pharmacokinetic (PK) parameters (up to 36 h). Plasma concentrations and urinary excretion were determined by HPLC with fluorescence detection, and urinary bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35 mg/l and that of ciprofloxacin 2.12 mg/l. The mean (median) cumulative renal excretion of the parent drug was for gatifloxacin 81 (83)% of the administered dose within 120 h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two-fold dilution (antibiotic-free urine as diluent) of urine still being bactericidal, were determined for an Escherichia coli ATCC reference strain and nine clinical uropathogens with the following MICs (mg/l) for gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922 (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016); Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125); Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The median UBTs measured within the first 6 h for gatifloxacin were between 1:16 and 1:≥1024 for the Gram-negative strains including P. aeruginosa and between 1:8 and 1:≥1024 for the five Gram-positive strains. The median UBTs for ciprofloxacin were between 1:64 and 1:≥1024 for the Gram-negative strains (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive strains. The UBTs up to 12 h showed no difference (P < 0.05) for both E. coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin against all Gram-positive strains. For the UBTs at 12–24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference in the Proteus and Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120 h showed statistically significant (P < 0.05) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. In conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary bactericidal activity with some differences for specific pathogens, some times in favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually Gram-negatives), suggesting that for empiric therapy a single oral dose of gatifloxacin (400 mg) would be clinically equivalent to ciprofloxacin (500 mg) twice daily—in agreement with the results of a clinical study in complicated UTI performed previously [Int. J. Antimicrob. Agents (2004)]. © 2003 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Urinary bactericidal activity; Urinary excretion; Plasma concentration; Gatifloxacin; Ciprofloxacin; Single oral dose
1. Introduction
夽 Part of this study was presented at the 4th European Congress of Chemotherapy and Infection, Paris, 4–7 May 2002 (Poster PM 199). ∗ Corresponding author. Tel.: +49-9421-710-1700; fax: +49-9421-710-1717. E-mail address: [email protected] (K.G. Naber).
Urinary tract infections (UTI) are usually caused by Escherichia coli and other Enterobacteriaceae, such as Proteus, Klebsiella, Enterobacter spp., but also by non-fermenters, such as Pseudomonas aeruginosa, and Gram-positive cocci, such as enterococci and staphylococci, and especially Staphylococcus saprophyticus. For empiric antimicrobial
0924-8579/$ – see front matter © 2003 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2003.09.006
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
therapy an antibiotic agent should be chosen which includes most of the uropathogens in its antibacterial spectrum and displays mainly renal excretion. In this regard, ciprofloxacin, with clinical experience over two decades, can still be considered a drug of choice and was therefore chosen as the comparator. Since the fluoroquinolones differ mainly in their pharmacokinetic properties, and in addition, their antibacterial activity in urine is reduced significantly depending on urine pH and contents [2], newer quinolones, such as gatifloxacin, should be investigated with regard to these issues. To obtain comparable dosages of gatifloxacin and ciprofloxacin (both have different pharmacokinetic properties) for the treatment of UTI and to approximate more closely the antibacterial activities at the site of infection, an ex vivo clinical study was performed to determine the concentrations in plasma and urine and the urinary bactericidal activity against clinical isolates of common uropathogens in healthy volunteers after administration of a single oral dose [3,4]. This pharmacodynamic (PD) model combines the pharmacokinetic and antibacterial properties in a human system and therefore exhibits the biological variations which have to be considered. According to animal and human studies [5], the efficacy of fluoroquinolones can be considered comparable if peak concentrations and area of concentration time curves above minimal inhibitory/bactericidal activity, which corresponds to the urinary bactericidal titers (UBT), are in the same range. 2. Materials and methods 2.1. Study design and demographic data of volunteers The study was approved by the ethics committee of the Landesärztekammer Bayern, Germany. It was an ex vivo, open, randomised, double-crossover, clinical trial in 12 healthy volunteers (six men, six women). Mean age was 30 years (median 30 years; range, 19–43 years), mean body weight was 74.8 kg (median 72.1 kg; range, 63–91 kg), and mean height was 172.4 cm (median 171.5 cm; range, 162–187 cm). The volunteers were considered to be healthy, based on medical history, physical examination and ECG, haematologic parameters (haemoglobin concentration, erythrocyte, leukocyte and platelet counts), serum chemistry parameters (glucose, creatinine, AST, ALT, ␥-glutamyl transferase, alkaline phosphatase, total protein and total bilirubine levels, HIV, Hbs-Ag, anti-HBs, anti-HBc) and urinalysis (glucose and protein levels, white and red blood cell counts). Lack of antibacterial activity in urine was tested by inhibition of Bacillus subtilis. 2.2. Drug administration After giving written informed consent to participate in the study, each volunteer successively received one oral dose of 400 mg gatifloxacin (Grünenthal GmbH, Aachen, Germany)
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or 500 mg ciprofloxacin (Bayer AG, Wuppertal, Germany) in a double-crossover design at an interval of 7 days according to the randomisation schedule. Study drugs were administered after an overnight fasting state. Alcohol- and xanthine-containing beverages and meals were not allowed 12 h before and 24 h after drug administration. The volunteers were asked to drink sufficient and comparable amounts of water to ensure sufficient urine production through both collection periods. Before and after each study phase, a physical examination, electrocardiography and laboratory tests were performed. Adverse events were recorded continuously throughout the trial period. The volunteers were monitored and urine collection was controlled in the study centre for the first 48 h and thereafter at the end of each sampling period for up to 120 h. 2.3. Sample collection Plasma samples were first taken before drug administration (H0), then after 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36 h and (gatifloxacin group only) 48 h. All urine voided was collected over a 12 h interval prior to drug administration and at the following time intervals thereafter: 0–6, 6–12, 12–24, 24–36, 36–48, 48–72, 72–96, and 96–120 h. All samples were stored at −20 ◦ C until assayed. 2.4. Determination of gatifloxacin and ciprofloxacin Gatifloxacin and ciprofloxacin concentrations in serum and urine were determined by HPLC using fluorescence detection. All sample handling was done under protection from daylight. Plasma samples were thawed and vigorously mixed, then precipitated with an acetonitrile mixture containing the internal standard. After centrifugation, for gatifloxacin (ciprofloxacin) 5 (10) l of the supernatant were analyzed. Urine samples were thawed and vigorously mixed and then diluted 1:100 with buffer containing the internal standard. Five or ten microlitres of the diluted sample were then analyzed. Chromatographic separation was performed using a reversed-phase column (250 mm × 4.6 mm), eluted with an isocratic solvent system consisting of an acetonitrile/water mixture and monitored by fluorescence detection (for gatifloxacin: excitation: 293 nm, emission: 490 nm; for ciprofloxacin: excitation: 278 nm, emission: 460 nm). Under these conditions, gatifloxacin and the internal standard were eluted after approximately 5.5 and 3.8 min, respectively, and ciprofloxacin and the internal standard were eluted after approximately 7.7 and 3.6 min, respectively. Turbochrom 3 software (version 3.2, PE Nelson, Cupertino, CA, 1991) was used for evaluation of chromatograms. Plasma and urine samples were measured against a plasma and urine calibration series, respectively. Calibration standards were prepared by adding the appropriate volumes of standard solution of gatifloxacin and ciprofloxacin, respectively, to drug-free human plasma or urine. Concentrations of gatifloxacin were obtained down to 0.0101 mg/l for plasma
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D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
and 0.444 mg/l for urine and that of ciprofloxacin down to 0.005 mg/l for plasma and 0.5 mg/l for urine. Spiked quality controls were prepared for inter-assay variation by adding the appropriate volumes of standard solution of gatifloxacin drug-free human plasma or urine. There was no interference observed, either in plasma or urine, for gatifloxacin, for ciprofloxacin or for their internal standards. Weighted linear regression (1/peak height ratio) was performed for calibration. Linearity of the calibration could be proven for gatifloxacin between 0.0101 and 10.3 mg/l in plasma and between 0.444 and 888.9 mg/l in urine, and for ciprofloxacin between 0.005 and 10.0 mg/l in plasma and between 0.500 and 1000 mg/l in urine. Quantification levels were identical with the lowest calibration levels. For gatifloxacin inter-assay precisions of the SQC in plasma were 4.6% (8.13 mg/l), 2.4% (0.993 mg/l), and 4.2% (0.0767 mg/l). The accuracy of the standards in plasma ranged from 91.1 to 95.2%. In urine, inter-assay precisions of the SQC were 7.4% (800 mg/l), 8.2% (80 mg/l), 7.9% (6.4 mg/l) and 10.5% (1 mg/l), and the accuracy of the standards ranged from 87.9 to 100.9%. For ciprofloxacin inter-assay precisions of the SQC in plasma were 3.8% (8 mg/l), 3.1% (0.8 mg/l), 2.1% (0.640 mg/l) and 6.6% (0.01 mg/l). The accuracy of the standards in plasma ranged from 95.5 to 97.4%. In urine, inter-assay precisions of the SQC were 0.4% (800 mg/l), 8.5% (80 mg/l), 3.8% (6.4 mg/l) and 1.6% (1 mg/l), and the accuracy of the standards ranged from 92.2 to 114.3%. 2.5. Pharmacokinetic parameters The pharmacokinetic parameters were estimated by standard non-compartmental methods. All parameters were determined from true (actual) sample collection times and assayed concentrations at these times. Concentration values below the lower limit of quantification were set to zero. The pharmacokinetic calculations were performed on a Pentium II 333 MHz Computer using the program Microsoft Excel 97 (Microsoft Co., Redmond, WA, USA, 1985–1998). The equations were entered into the program manually and checked by recalculation of pharmacokinetic parameters for randomly selected data sets using the pharmacokinetic program WinNonlinTM Professional (Version 2.0, Pharsight Corporation, © 1994–1998, Palo Alto, USA). The following parameters were estimated: maximal plasma concentration (Cmax ); time to maximal plasma concentration (Tmax ); plasma half life (T1/2 ); mean transit time (MRT); area under the plasma concentration time curve (AUC); total plasma clearance (Cltot ); renal clearance (Clren ); non-renal clearance (Clnren ); apparent distribution volume at final () phase (Vd ); apparent distribution volume at steady state (Vdss ). 2.6. Determination of minimal inhibitory (MICs) and bactericidal (MBCs) concentrations MICs were determined by both an agar dilution (AD) test with Isosensitest agar (CM 471; Oxoid, Wesel, Germany) us-
ing a multipointer (Dynatech, Nürtingen, Germany) with an inoculum of 104 colony forming units (CFU) per point, and MICs and MBCs were determined by a microdilution test using Mueller–Hinton–Broth (MHB) (Oxoid, Wesel, Germany) with an inoculum of (1.5–10.7) × 105 CFU/ml. The MIC was defined as the lowest concentration inhibiting visible growth (<10 CFU/ml) after incubation at 37 ◦ C for 18 h in ambient air, while the MBC was defined in a second step by counting the numbers of CFU on antimicrobial-free Columbia agar (Merck, Darmstadt, Germany) supplemented with 5% blood, after additional incubation at 37 ◦ C for 18 h. Bactericidal activity was defined as a >99.9% (>3 log) reduction in the numbers of CFU/ml. 2.7. Determination of urinary bactericidal titers (UBTs) A logarithmic serial dilution (dilution range, 1:2–1:1024) was prepared by taking a 1:1 mixture of the urine sample and the individual’s antimicrobial-free urine collected prior to drug administration [3,6]. UBTs were then determined by microdilution, with each well of the microplates containing 100 l of the prepared dilution. The final inoculum was 105 CFU/ml, and the bactericidal activity was determined according to the recommended guidelines by NCCLS [7]. A UBT of 0 was defined as no bactericidal activity, and a UBT of 1 was used for bactericidal activity of undiluted urine. UBTs were transformed into ordinal data by using a scale from 1 for UBTs of 0 up to 12 for UBTs of 1:≥1024. The area under the UBT-time-curve (AUBT) was calculated by the trapezoidal rule by using the UBT steps (ordinal data) for each test organism and for each drug phase. 2.8. Minimal urinary bactericidal concentrations (MUBCs) The division of the antimicrobial concentrations in the urine samples by the corresponding UBTs yielded the respective minimal urinary bactericidal concentrations (MUBCs). For this calculation, UBTs of 0 and 1:≥1024 were not appropriate. 2.9. Test organisms The reference strain E. coli ATCC 25922 and nine typical uropathogens cultured from the urine of patients with UTI were used as test organisms. The pathogens included one strain each of E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, and S. saprophyticus, and two strains of both S. aureus and Enterococcus faecalis. S. aureus ATCC 29278 and E. faecalis ATCC 28243 were used in addition for internal quality control. 2.10. Statistical analyses The results of the two drug phases were compared by the paired t-test. An α value equal to 0.05 was chosen to determine statistical significance.
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
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Table 1 Median (range) urinary pH, volume, parent drug concentration, and cumulative excretion in volunteersa Collection period
Urinary pH median (range)
Volume (ml) median (range)
Concentration (mg/l) median (range)
Cumulative excretion (%) median (range); mean ± S.D.
Gatifloxacin 0–6 h 6–12 h 12–24 h 24–36 h 36–48 h 48–72 h 72–96 h 96–120 h
6.7b (5.2–8.9) 7.3 (6.1–8.6) 5.9b (5.4–6.4) 6.9 (5.1–7.6) 6.1 (5.0–7.1) 6.2 (5.3–7.1) 6.2 (5.5–8.3) 6.6 (5.3–8.4)
408.1 (162–885) 537.8b (254–1100) 705.8 (373–1398) 961.3 (589–1931) 606.0 (128–1529) 1655.2 (478–2671) 1458.4 (1077–2494) 1441.7 (959–2299)
309.2 (163.3–804.4) 141.5b (67.4–331.8) 106.1b (54.2–215.9) 22.2b (10.0–42.1) 11.3b (3.4–25.5) 2.2b (0.5–7.3) 0.8c (BQL–1.5) BQLc (BQL–0.5)
32.8 (22.8–42.3); 32.7 ± 5.3 55.1b (35.9–61.4); 53.4 ± 6.8 74.1b (53.0–80.7); 72.2 ± 7.2 79.8b (59.7–87.2); 78.0 ± 7.4 81.7b (61.7–89.5); 79.8 ± 7.6 82.7b (62.0–90.8); 80.7 ± 7.9 82.9b (62.2–91.2); 81.0 ± 8.0 83.0b (62.2–91.4); 81.0 ± 8.0
Ciprofloxacin 0–6 h 6–12 h 12–24 h 24–36 h 36–48 h 48–72 h 72–96 h 96–120 h
6.1b (5.1–8.8) 7.2 (5.5–8.4) 6.2b (4.9–7.1) 6.9 (5.6–8.5) 6.0 (5.6–7.0) 6.3 (5.7–8.0) 6.1 (5.5–8.5) 6.5 (5.3–8.3)
442.7 (174–811) 423.3b (230–773) 729.3 (373–1677) 1474.3 (692–3226) 595.0 (359–1733) 1439.6 (867–3036) 1413.4 (697–2622) 1402.1 (953–1883)
367.9 (100.2–1000.5) 76.6b (30.4–179.4) 20.1b (2.6–41.7) 3.3b (BQL–5.5) 1.5b (BQL–3.0) 0.3b (BQL–1.1) BQLc (BQL–BQL) BQLc (BQL–BQL)
32.2 (13.3–58.6); 32.4 ± 10.4 40.6b (17.7–60.0); 39.3 ± 10.6 43.9b (19.3–60.4); 42.2 ± 10.8 44.9b (19.6–61.8); 43.0 ± 11.2 45.1b (19.7–61.8); 43.1 ± 11.2 45.2b (19.7–62.0); 43.2 ± 11.2 45.2b (19.7–62.0); 43.2 ± 11.2 45.2b (19.7–62.0); 43.2 ± 11.2
BQL, below quantification limit: 0.444 mg/l for gatifloxacin; 0.500 mg/l for ciprofloxacin. a A total of 12 volunteers were tested. b Significantly different (P < 0.05) for gatifloxacin vs. ciprofloxacin. c Calculation not applicable.
3. Results 3.1. Safety and laboratory test results Gatifloxacin and ciprofloxacin were well tolerated by all volunteers. No serious adverse effects were considered to be related to a study medication. No change in ECG and no clinical significant change in routine blood and serum tests by either drug was found. 3.2. Urinary pHs, volumes and drug concentrations The median (range) values for urinary pHs, volumes, urinary drug concentrations and cumulative renal excretion obtained in the two study phases are given in Table 1. Additionally the mean ± S.D. data for cumulative excretion
are presented. The data for the corresponding collection periods of the respective study phases showed significant but small differences in urinary pHs for the first (0–6 h) and third (12–24 h) collection period and in volumes for the second interval (6–12 h). In both study phases however, the median pH for the collection period 6–12 h (afternoon) was higher than for the other collection periods. The median urinary concentrations are shown in Fig. 1. All urine samples collected prior to drug administration had no detectable drug. The first collection period (0–6 h) showed no statistically significant difference between gatifloxacin (309.2 mg/l) and ciprofloxacin (367.9 mg/l). Thereafter, up to the collecting period 48–72 h, the median urinary concentrations of gatifloxacin were significantly higher than those of ciprofloxacin, and later on ciprofloxacin was below the quantification limit in urine of all volunteers. The cumu-
Fig. 1. Median (n = 12) concentrations of gatifloxacin (400 mg) and ciprofloxacin (500 mg) in urine (see Table 1 for concentration ranges).
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Time of sample (h)
0.0 0.5 1.0 1.5 2.0 3.0 4.0 6.0 8.0 12 24 30 36 a ∗
Plasma concentration (mg/l) of gatifloxacin 400 (mg p.o.)
Plasma concentration (mg/l) of ciprofloxacin 500 (mg p.o.)
Significantly different (yes/no) t = 1.7959
N
Mean (mg/l)
S.D. (mg/l)
Median (mg/l)
Min (mg/l)
Max (mg/l)
N
Mean (mg/l)
S.D. (mg/l)
Median (mg/l)
Min (mg/l)
Max (mg/l)
12 11 11 12 12 12 12 12 12 12 12 12 12
BQLa 1.99 2.87 2.78 2.62 2.67 2.54 2.03 1.65 1.06 0.30 0.16 0.086
BQL 1.55 1.13 1.09 0.96 0.57 0.57 0.43 0.35 0.26 0.08 0.05 0.026
BQL 2.0 2.6 2.9 2.6 2.7 2.5 2.0 1.6 0.9 0.3 0.2 0.1
BQL 0.17 0.79 0.06 0.40 1.87 1.88 1.49 1.18 0.82 0.17 0.07 0.032
BQL 5.28 4.31 4.03 3.99 3.59 3.41 2.71 2.17 1.59 0.47 0.25 0.13
12 12 12 12 12 12 12 12 12 12 12 12 10
BQL 1.48 1.90 1.77 1.51 1.14 0.89 0.59 0.39 0.20 0.03 0.01 0.009
BQL 0.83 0.40 0.35 0.28 0.22 0.21 0.15 0.12 0.06 0.01 0.00 0.002
BQL 1.1 1.9 1.7 1.4 1.1 0.9 0.6 0.4 0.2 0.034 0.015 0.009
BQL 0.50 1.28 1.16 1.00 0.67 0.48 0.29 0.17 0.07 0.016 0.008 0.006
BQL 2.98 2.64 2.45 2.03 1.47 1.28 0.83 0.59 0.31 0.053 0.022 0.011
BQL, below quantification limit: 0.010 mg/l for gatifloxacin; 0.005 mg/l for ciprofloxacin. Not applicable.
t
Yes/no
∗
∗
1.3 3.0 3.2 4.1 9.4 10.2 11.6 12.1 11.8 11.5 10.8 12.7
No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
Table 2 Mean, standard deviation (S.D.), median, minimum and maximum of plasma concentrations
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
lative urinary excretion (mean, median, range) of the parent drug up to 120 h was for gatifloxacin 81% (83, 62–91%) and for ciprofloxacin 43% (45, 20–62%) of the administered dose (Table 1). 3.3. Plasma concentrations and pharmacokinetic parameters The plasma concentrations (mean, median, range) of both drugs (Table 2) showed no difference at 0.5 h; all the other samples, up to 36 h, showed significantly higher plasma concentrations of gatifloxacin versus ciprofloxacin. The mean (median) maximum plasma concentration of gatifloxacin was 3.35 (3.19) mg/l and that of ciprofloxacin 2.12 (2.07) mg/l (Table 3). The mean (median) half life of gatifloxacin was 6.69 (6.61) h and that of ciprofloxacin was 5.69 (5.58) h. Further pharmacokinetic parameters, such as time to maximum plasma concentration (Tmax ), 0–36 h and 0-undefinite area under the plasma concentration curve (AUC), total clearance (Cltot ), renal clearance (Clren ), non-renal clearance (Clnren ), and distribution volume at steady state (Vdss ) and at -phase (Vd ) are also shown in Table 3.
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3.5. UBTs and AUBTs The UBTs and AUBTs for both study drugs for the test organisms are given in Table 5 and Fig. 2. The UBTs of gatifloxacin and ciprofloxacin measured within the first 12 h for the five Gram-negative strains were between 1:≥1024 and 1:8, and showed identical bactericidal activity against both E. coli strains but higher activity of ciprofloxacin against Klebsiella, Proteus and Pseudomonas. The UBTs within the first 12 h for the five tested Gram-positive strains were between 1:≥1024 and 1:0.5 and showed significantly higher bactericidal activity of gatifloxacin against all the strains of S. saprophyticus, S. aureus and E. faecalis. Thereafter, the median UBTs of both drugs for the susceptible strains decreased, but was much quicker for ciprofloxacin than for gatifloxacin. The difference was due to differences in urinary excretion. Therefore the areas under the UBT-time-curve showed statistically significant (P < 0.05) higher activity of gatifloxacin than ciprofloxacin against 8 of 10 strains tested; no difference was seen for P. mirabilis but there was a significantly higher activity of ciprofloxacin against P. aeruginosa.
3.4. MICs and MBCs 3.6. MUBCs The MICs (microdilution in Mueller–Hinton–broth) of gatifloxacin and ciprofloxacin for each of the ATCC test strains (E. coli, S. aureus, E. faecalis), which were in accepted ranges, and for the isolates for which UBTs were determined ranging from ≤0.008 to 8 mg/l for gatifloxacin and ≤0.008 to 32 mg/l for ciprofloxacin, are given in Table 4.
The median (range) MUBCs of both study drugs for the test organisms are given in Table 6. They showed wide interindividual ranges. For gatifloxacin they were between 2.9 and 31.7 times of corresponding MIC (microdilution), for ciprofloxacin between 3.3 and 39.
Table 3 Pharmacokinetic parameters of gatifloxacin (400 mg) vs. ciprofloxacin (500 mg) after single oral dose in 12 healthy volunteers Parameter Tmax (h)
T1/2 (h)
MRT (h)
AUC 0–>36 h (mg h/l)
AUC 0–>∞ (mg h/l)
Gatifloxacin Mean 3.35 S.D. 0.94 CV(%) 28.0 Min 2.09 Max 5.28 Median 3.19
1.67 1.11 66.6 0.50 4.00 1.25
6.69 0.69 10.4 5.02 7.65 6.61
9.92 1.02 10.3 7.28 11.0 9.99
33.3 6.94 20.9 25.2 48.3 32.9
34.1 7.05 20.7 25.8 49.6 33.4
203 38.2 18.9 135 258 200
163 40.4 24.8 113 224 159
Ciprofloxacin Mean 2.12 S.D. 0.50 CV(%) 23.7 Min 1.28 Max 2.98 Median 2.07
1.04 0.45 43.2 0.50 2.00 1.00
5.69 0.62 10.9 4.76 7.09 5.58
5.88 0.58 9.90 4.50 6.64 5.96
10.5 2.30 21.9 5.54 13.9 10.2
10.6 2.31 21.8 5.61 14.0 10.3
814 231 28.4 594 1486 782
343 75.7 22.1 265 523 312
Cmax (mg/l)
Ctot (ml/min)
Clren (ml/min)
Clnren (ml/min)
Vd (l)
Vdss (l)
39.5 14.2 35.9 21.6 73.9 37.6
118 28.9 24.5 76.1 155 115
121 27.3 22.6 80.8 155 122
471 247 52.3 284 1192 381
401 121 30.1 265 721 368
284 69.7 24.5 209 470 266
Cmax : maximal plasma concentration; Tmax : time to maximal plasma concentration; T1/2 : plasma half life; MRT: mean transit time; AUC: area under the plasma concentration time curve to last 36 h or to undefinite, respectively; Cltot : total plasma clearance; Clren : renal clearance; Clnren : non-renal clearance; Vd : apparent distribution volume at final () phase; Vdss : apparent distribution volume at steady state; S.D.: standard deviation; min: minimal value; max: maximal value; ∞: indefinate.
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Table 4 MICs and MBCs of gatifloxacin and ciprofloxacin for an E. coli test strain (ATCC 25922) and nine uropathogens cultured from the urine of patients with complicated and uncomplicated UTIs [inoculum for agar dilution (AD)-test 104 per point, for Mueller–Hinton–Broth (MHB) 1.5–6.7 × 105 CFU/ml] No.
Test strain and laboratory number
MIC or MBC (mg/l) Gatifloxacin
1 2 3 4 5 6 7 7a 8 8a 9 10 11a 12a
E. coli ATCC 25922 E. coli 523 K. pneumoniae 1058 P. mirabilis 524 P. aeruginosa 568 S. saprophyticus Ho94 S. aureus 248 S. aureus 248 S. aureus 596 S. aureus 596 E. faecalis 60 E. faecalis 55 S. aureus ATCC 29278 E. faecalis ATCC 28243
Ciprofloxacin
MIC AD
MIC MHB
MBC MHB
MIC AD
MIC MHB
MBC MHB
– 0.25 0.06 0.25 4 0.125 0.125 – 0.06 – 0.5 8 – –
0.008 0.06 0.03 0.125 1 0.125 0.03 0.06 0.03 0.03 0.5 8 0.06 0.25
0.008 0.06 0.03 0.25 2 0.125 0.03 0.06 0.03 0.06 0.5 8 0.06 0.25
– 0.25 0.06 0.06 1 0.25 0.5 – 0.5 – 2 64 – –
0.008 0.06 0.016 0.016 0.125 0.25 0.125 0.25 0.125 0.125 1 32 0.25 0.5
0.008 0.06 0.016 0.03 0.25 0.25 0.125 0.25 0.125 0.25 1 32 0.25 0.5
Inoculum MHB (CFU/ml) 1.5 2.4 3.2 2.3 5.9 4.9 4.5 5.2 5.1 6.7 3.6 4.7 10.7 5.3
× × × × × × × × × × × × × ×
105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml
Date of test 28 January 2002. a Date of control 23 January 2003.
4. Discussion It is quite difficult to predict the impact of the chemical structure of a new fluoroquinolone on metabolic stability, renal excretion and bactericidal activity. Gatifloxacin and ciprofloxacin both have a cyclopropyl-substituent in position 1 and a piperazinyl-substituent in position 7. Gatifloxacin has an additional methyl-group in position 3 of the piperazinyl-substituent and the new unique 8-methoxy-group [8–10]. So far, gatifloxacin has been shown to be clinically effective in infections of the skin and soft tissue [11], in the respiratory system, and also in UTI [1,12,13]. However, no comparative pharmacodynamic study is yet published [14]. The incidence of UTIs differs with age and sex and affects up to 40–50% adult women with an anatomically normal urinary tract [15]. UTIs are usually caused by E. coli, Enterobacteriaceae such as Klebsiella and Proteus spp., and non-fermenters such as P. aeruginosa and by Gram-positive bacteria. There are several new fuoroquinolones that potentially target this spectrum of pathogens but only a few are sufficiently excreted unchanged in the urine to make them suitable for the treatment of UTI [16,17]. In the present study, we investigated both the pharmacokinetics in plasma, and urine and the urinary bactericidal activity (as urinary bactericidal titers) after single oral doses of gatifloxacin (400 mg) and ciprofloxacin (500 mg); the latter having been in clinical use for two decades and can still be considered as a drug of choice for the treatment of uncomplicated and complicated UTI [18]. We found several marked differences between the pharmacokinetics in plasma and urine of the two drugs. The mean maximum plasma concentration after an oral dose of 400 mg gatifloxacin (3.35 mg/l) was 1.5 times higher than that af-
ter an oral dose of 500 mg ciprofloxacin (2.12 mg/l). Plasma concentrations at 1 h post-medication up to 36 h were significantly (P < 0.05) higher for gatifloxacin while the median urinary concentrations within the first 6 h were comparable (gatifloxacin 309.2 mg/l versus ciprofloxacin 367.9 mg/l). In all subsequent intervalls up to 72 h gatifloxacin showed significantly higher urinary concentrations than ciprofloxacin (e.g. 6–12 h; gatifloxacin 141.5 mg/l versus ciprofloxacin 76.6 mg/l). The mean (median) cumulative renal excretion rate of gatifloxacin of 81% (83%) was almost twice of that of ciprofloxacin with 43% (45%). The UBTs and AUBTs in fact showed statistically significant (P < 0.05) differences. While the UBTs of both drugs displayed an overall comparable bactericidal activity in urine within the first 12 h after medication, statistically significant differences are present for Gram-negative (in favour of ciprofloxacin) and Gram-positive (in favour of gatifloxacin) uropathogens. Differences in subsequent intervals were statistically in favour of gatifloxacin. The total AUBT (up to 120 h) after one single oral dose of gatifloxacin demonstrates its favourable pharmacokinetic properties, arising from its high cumulative excretion of parent drug, for the treatment of UTIs. Based on considerations of the UBTs and AUBTs the clinical equivalence of 400 mg gatifloxacin once daily versus 500 mg ciprofloxacin twice daily may be assumed; and this has been demonstrated in a clinical study in complicated UTI performed previously [1]. The MUBCs show a wide interindividual variability. For gatifloxacin they were between 2.9 and 31.7 times of the corresponding MIC, and for ciprofloxacin between 3.3 and 39, indicating the need for MIC-testing with both drugs. The MUBCs calculated from the UBTs and the urinary concentrations demonstrate that the bactericidal activity of fluoroquinolones are reduced in urine compared to broth and
Drug and strain
AUBT (h−1 )
UBT for the following collection period (h) 0–6
6–12
12–24
24–36
36–48
48–72
72–96
96–120
Gatifloxacin E. coli ATCC 25922 E. coli 523 K. pneumoniae 1058 P. mirabilis 524 P. aeruginosa 568 S. saprophyticus Ho94 S. aureus 248 S. aureus 596 E. faecalis 60 E. faecalis 55
≥1024 (256 ≥ 1024) 256 (32 ≥ 1024) 512a (64 ≥ 1024) 384a (64 ≥ 1024) 16a (4–64) 768a (256 ≥ 1024) ≥1024a (≥1024) ≥1024a (512 ≥ 1024) 256a (64 ≥ 1024) 8a (2–64)
768 (128 ≥ 1024) 96 (32 ≥ 1024) 192a (64 ≥ 1024) 128a (32 ≥ 1024) 8a (2–64) 256a (128 ≥ 1024) ≥1024a (256 ≥ 1024) ≥1024a (512 ≥ 1024) 64a (32 ≥ 1024) 4a (2–64)
768a (64 ≥ 1024) 48a (8 ≥ 1024) 128a (16 ≥ 1024) 128 (32–512) 2 (0–32) 256a (64–512) 512a (64 ≥ 1024) ≥1024a (128 ≥ 1024) 64a (4–512) 3a (0–64)
128a (16 ≥ 1024) 12a (2–256) 32a (4–512) 32a (16–128) 1a (0–8) 48a (16–128) 128a (8–512) 96a (16–512) 16a (2–128) 0.5a (0–4)
64a (8 ≥ 1024) 4a (0–128) 12a (1–256) 16a (8–64) 0a (0–4) 24a (8–64) 64a (4–256) 64a (16–256) 4a (0–32) 0 (0–1)
8a (8–256) 1a (0–32) 2a (0–64) 3 (1–16) 0 (0–1) 4a (1–8) 12a (2–64) 12a (8–64) 1a (0–16) 0 (0–0)
3a (0–32) 0 (0–4) 0 (0–8) 1 (0–2) 0 (0–0) 1a (0–2) 4a (1–8) 4a (1–8) 0a (0–2) 0 (0–0)
0.5a (0–16) 0a (0–1) 0 (0–4) 0 (0–1) 0 (0–0) 0 (0–2) 1a (0–8) 1a (0–8) 0 (0–0) 0 (0–0)
606a (342–1008) 312a (144–708) 396a (192–828) 408 (330–624) 96a (42–240) 456a (384–588) 636a (432–804) 666a (504–792) 288a (180–588) 84a (30–216)
Ciprofloxacin E. coli ATCC 25922 E. coli 523 K. pneumoniae 1058 P. mirabilis 524 P. aeruginosa 568 S. saprophyticus Ho94 S. aureus 248 S. aureus 596 E. faecalis 60 E. faecalis 55
≥1024 (256 ≥ 1024) 192 (32 ≥ 1024) ≥1024a (128 ≥ 1024) ≥1024a (256 ≥ 1024) 64a (8–256) 256a (128 ≥ 1024) 768a (256 ≥ 1024) 512a (128 ≥ 1024) 64a (16–256) 1.5a (1–4)
768 (64 ≥ 1024) 64 (8 ≥ 1024) 384a (32 ≥ 1024) 256a (32 ≥ 1024) 24a (2–128) 128a (8–512) 256a (64 ≥ 1024) 256a (32 ≥ 1024) 16a (4–128) 0.5a (0–2)
128a (16 ≥ 1024) 8a (2–128) 48a (4 ≥ 1024) 96 (16 ≥ 1024) 4 (1–64) 24a (2–64) 48a (16–128) 64a (8–128) 4a (1–32) 0a
16a (2–512) 2a (0–32) 6a (1–256) 16a (4–128) 0a (0–4) 4a (0–16) 6a (1–16) 8a (2–16) 1a (0–2) 0a
8 (1–256) 0a (0–16) 3a (1–128) 8a (2–64) 0a (0–2) 0a (0–4) 2a (1–8) 2a (2–8) 0a 0
4a (1–64) 0a (0–4) 0.5a (0–64) 2 (0–32) 0 0a (0–2) 0.5a (0–4) 1a (0–4) 0a 0
0a (0–32) 0 (0–2) 0 (0–16) 0.5 (0–8) 0 0a 0a (0–1) 0a (0–2) 0a 0
0a (0–8) 0a (0–0) 0 (0–4) 0 (0–4) 0 0 0a (0–2) 0a (0–2) 0 0
426a (216–900) 177a (84–480) 300a (144–828) 342 (312–756) 117a (48–246) 222a (120–294) 279a (192–444) 297a (180–463) 111a (60–192) 12a (6–24)
a
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Table 5 Median (range) reciprocal UBTs for gatifloxacin (400 mg) and ciprofloxacin (500 mg) after single dose administration in 12 volunteers
Significantly different (paired t-test; P < 0.05) for gatifloxacin vs. ciprofloxacin.
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Fig. 2. Median reciprocal UBTs of gatifloxacin (400 mg) and ciprofloxacin (500 mg) for E. coli ATCC 25922 and nine clinical uropathogens in 12 volunteers tested (see Tables 2 and 3 for ranges).
that considerable interindiviual variation has to be taken in account. Therefore the estimation of the urinary bactericidal activity by use of dilutions with the individual’s antimicrobial-free urine may be considered more appropri-
ate for approximation of the expected in vivo activity of an antimicrobial agent in the treatment of complicated UTI. The pharmacokinetic/pharmacodynamic (PK/PD) index, which is most closely associated with the bacteriological ef-
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
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Table 6 Median (range) of minimum urinary batericidal concentrations (mg/l) of gatifloxacin (400 mg) and ciprofloxacin (500 mg) after single dose administration in volunteers Strains Species
No.
E. coli E. coli K. pneumoniae P. mirabilis P. aeruginosa S. saprophyticus S. aureus S. aureus E. faecalis E. faecalis
ATCC 25922 523 1058 524 568 HO94 248 596 60 55
a
MUBC for gatifloxacin (mg/l)
MUBC for ciprofloxacin (mg/l)
0.25 (0.03–2.31) 1.75 (0.16–17.51) 0.71 (0.08–11.85) 0.88 (0.27–3.45) 16.01 (4.49–119.10) 0.50 (0.12–1.29) 0.18 (0.00a –2.65) 0.18 (0.04–1.29) 1.54 (0.33–13.54) 22.85 (3.37–173.25)
0.18 (0.01–1.59) 1.12 (0.16–11.09) 0.40 (0.02–3.22) 0.23 (0.01–1.55) 4.88 (0.33–27.51) 0.83 (0.08–6.20) 0.55 (0.04–3.08) 0.46 (0.02–1.61) 4.33 (0.65–13.76) 137.03 (30.39–581.20)
Calculation not applicable.
ficacy of fluoroquinolones, is the 24 h area under the plasma concentration curve in relation to the MIC (AUC/MIC (AUIC)) [19,20]. This ratio is independent of the dosing interval, the fluoroquinolone used and the site of infection [5,21]. Gunderson et al. [22] have recently summarised the PK/PD data available from animal models and from human studies for fluoroquinolones. The optimum AUIC against Gram-negative pathogens seems to be >125 whereas 30–50 may be sufficient for Gram-positives such as S. pneumoniae and anaerobes like Bacteriodes fragilis. Particularly against Gram-negative bacilli (e.g. E. coli) which can cause nosocomial infections the AUIC needs to reach or exceed 100; that is, serum levels need to average around four times the MIC over a 24 h period [5]. Against Gram-positive pathogens fluoroquinolones such as sitafloxacin, gatifloxacin and gemifloxacin retain full activity at AUICs as low as 30–50 [23–25]. In studies of pneumonia, peritonitis and sepsis in mice, rats and guinea pigs, in general, 24 h AUIC ratios of <30 for fluoroquinolones were associated with >50% mortality, whereas AUIC values of ≥100 were associated with almost no mortality when animals were infected with various strains of Gram-positive and Gram-negative bacteria [5]. Since gatifloxacin is prescribed once daily and ciprofloxacin twice daily the time segments of the AUC which need to be considered are 0–24 h for gatifloxacin and two times 0–12 h for ciprofloxacin (with a cumulative factor of about 1.2 calculated from previous studies) [unpublished data]. Using the results of the present study for gatifloxacin, AUC (mean ± S.D.; median, range) of 31.2 ± 6.6 (30.8, 23.6–45.0) mg h/l and for ciprofloxacin of 21.5 ± 4.5 (21.0, 11.8–28.5) mg h/l can be calculated. The mean gatifloxacin AUC0–24 value is in agreement with published values for AUC0–∞ of 33.8 ± 3.11 mg h/l in healthy volunteers [26]; the mean ciprofloxacin AUC0–36 of 10.5 ± 2.3 mg h/l (Table 3) corresponds to a recently published geometric mean AUC0–∞ value of 11.81 mg h/l [27]. If the minimal AUCs observed in this study are used, a MIC of ≤0.25 mg/l for gatifloxacin and a MIC of ≤0.125 mg/l for ciprofloxacin result in AUIC ratios of ≥100. These MICs should therefore be considered as the PK/PD
breakpoints for the optimal treatment of systemic infections with Gram-negative uropathogens such as Enterobacteriaceae using the above dosage regimens. For gatifloxacin, P. aeruginosa (MIC 1 mg/l) and the Gram-positive two enterococcal strains (MIC 0.5 and 8 mg/l), for ciprofloxacin S. saprophyticus (MIC 0.25 mg/l) and the two enterococcal strains (MIC 1 and 32 mg/l) would be outside these limits. It is not known whether the same criteria apply for the treatment of complicated UTI, but in the case of complicated pyelonephritis with systemic infectious reactions and most likely in urosepsis such conditions might be very relevant. Since the area under the UBT-time-curve takes into consideration urinary concentration and bactericidal activity against a specific strain, these areas can be used for comparison of two antimicrobials. The data indicate that for Gram-negative uropathogens the AUBTs for ciprofloxacin and for Gram-positive uropathogens the AUBTs for gatifloxacin appear in favour and suggest use will result in successful treatment. Although the absolute AUBT necessary for effective therapy of complicated UTI is not known—it is not known whether it follows the same criteria as the plasma AUC for systemic infections—the AUBT of gatifloxacin 400 mg once daily for the treatment of a complicated UTI due to P. aeruginosa, which per se is usually difficult to treat, appears borderline compared to that of ciprofloxacin 500 mg twice daily.
5. Conclusion In particular, the following conclusions may be drawn from the present study: (i) The mean/median cumulative renal excretion (parent drug) of gatifloxacin (81.0%/83.0%) was almost twice that of ciprofloxacin (43.2%/45.2%). (ii) After an oral dose of 400 mg gatifloxacin the mean maximum plasma concentration (3.35 mg/l) was about 1.5 times higher than that after an oral dose of 500 mg ciprofloxacin (2.12 mg/l).
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(iii) If an AUC/MIC (AUIC) >100 is taken for optimal therapy of a systemic infection, then for gatifloxacin a MIC of ≤0.25 mg/l and for ciprofloxacin that of ≤0.125 mg/l would fulfil this criterion. (iv) The UBTs up to 12 h showed no difference (P < 0.05) for both E. coli strains, but ciprofloxacin was superior to Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to all Gram-positive strains. For the UBTs at 12–24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference for the Proteus and Pseudomonas strains. (v) The areas under the UBT-time-curve up to 120 h showed statistically significant (P < 0.05) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. (vi) According to the UBTs within the first 24 h, a dosage of 400 mg gatifloxacin once daily should be overall clinically equivalent to a dosage of 500 mg ciprofloxacin twice daily. This has also been demonstrated in a clinical study in complicated UTI performed previously. References [1] Naber KG, Bartnicki A, Bishoff W, et al. Gatifloxacin 200 mg or 400 mg once daily is as effective as ciprofloxacin 500 mg twice daily for the treatment of patients with acute pyelonepliritis or complicated urinary tract infections. Int J Antimicrob Agent 2004;2351:41–53. [2] Naber KG, Antibacterial activity of antibacterial agents in urine: an overview of applied methods. In: Bergan T, editor. Infectiology, Urinary Tract Infections. Basel: Karger; 1997. p. 74–83. [3] Naber KG, Theuretzbacher U, Kinzig M, Savov O, Sörgel F. Urinary excretion and bactericidal activities of a single oral dose of 400 milligrams of fleroxacin versus a single oral dose of 800 milligrams of pefloxacin in healthy volunteers. Antimicrob Agents Chemother 1998;42:1659–65. [4] Naber CK, Hammer M, Kinzig-Schippers M, Sauber C, Sörgel F, Bygate EA, et al. Urinary excretion and bactericidal activities of gemifloxacin and ofloxacin after a single oral dose in healthy volunteers. Antimicrob Agents Chemother 2001;45:3524–30. [5] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1– 12. [6] Edberg SC. The measurement of antibiotics in human body fluids: techniques and significance. In: Lorian V, editor. Antibiotics in Laboratory Medicine. Baltimore, MD: The Williams & Wilkins Co.; 1986. p. 466–7. [7] National Committee of Clinical and Laboratory Standards (NCCLS). Methods of determining bactericidal activity of antimicrobial agents. Tentative Guideline, September 1992. NCCLS document M26-T, vol. 12. 1992. p. 1–36. [8] Appelbaum PC, Hunter PA. The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents 2000;16:5– 15.
[9] Bryskier A, Chantot JF. Classification and structure-activity relationships of fluoroquinolones. Drugs 1995;49:16–28. [10] Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials [Erratum in: J Antimicrob Chemother 1994;34:851] J Antimicrob Chemother 1994;33:685–706. [11] Tarshis GA, Miskin BM, Jones TM, Champlin J, Wingert KJ, Breen JD, et al. Once daily oral gatifloxacin vs. oral levofloxacin in the treatment of uncomplicated skin and soft tissue infections: double-blind, multicenter, randomized study. Antimicrob Agents Chemother 2001;45:2358–62. [12] Cox CE, Marbury TC, Pittman WG, Brown GL, Auerbach SM, Fox BC, et al. A randomized, double-blind, multicenter comparison of gatifloxacin versus ciprofloxacin in the treatment of complicated urinary tract infection and pyelonephritis. Clin Ther 2002;24:223–36. [13] Richard GA, Mathew CP, Kirstein J, Orchard D, Young J, Fox B. Single (400 mg) and multiple (200 mg QD) dose oral gatifloxacin (GAT) vs. multiple (100 mg BID) dose oral ciprofloxacin (CIP) in the treatment of acute, uncomplicated urinary tract infection (UTI) in women [Abstract # 152]. Clin Infect Dis 1999;29:988. [14] Perry CM, Ormrod D, Hurst M, Onrust SV. Gatifloxacin, a review of its use in the management of bacterial infections. Drugs 2002;62:169– 207. [15] Kunin CM. Urinary tract infections in females. Clin Infect Dis 1994;18:1–12. [16] Naber KG. Which fluoroquinolones are suitable for the treatment of urinary tract infections. Int J Antimicrob Agents 2001;17:331– 41. [17] Naber KG, Bergman B, Bishop MC, Bjerklund-Johansen TE, Botto H, Lobel B, et al. EAU Guidelines for the management of urinary and male genital tract infections. Eur Urol 2001;40:576–88. [18] Nicolle LE. Use of Quinolones in urinary tract infection and prostatitis. In: Andriole VT, editor. The Quinolones. 2nd ed. San Diego, London, Boston, New York, Sydney, Tokyo, Toronto: Academic Press; 1998. p. 417–29. [19] Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 2002;19:261–8. [20] MacGowan A, Bowker K. Developments in PK/PD: optimising efficacy and prevention of resistance. A critical review of PK/PD in in vitro models. Int J Antimicrob Agents 2002;19:291–8. [21] Craig WA. Re-evaluating current antibiotic therapy. Resp Med 2001;95:S12–9. [22] Gunderson BW, Ross GH, Ibrahim KH, Rotschafer JC. What do we really know about antibiotic pharmacodynamics. Pharmacotherapy 2001;21:302S–18S. [23] Andes DR, Craig WA. In vivo pharmacodynamic activity of gemifloxacin (GEM) against multiple bacterial pathogens. 39th ICAAC, San Francisco, 26–29 September 1999. Abstract 27. [24] Andes DR, Craig WA. In vivo pharmacodynamic activity of sitafloxacin (SIT) against multiple bacterial pathogens. 39th ICAAC, San Francisco, 26–29 September 1999. Abstract 28. [25] Andes DR, Craig WA. In vivo pharmacodynamic activity of gatifloxacin (GAT) against multiple bacterial pathogens. 39th ICAAC, San Francisco, 26–29 September 1999. Abstract 191. [26] Stahlberg HJ, Goehler K, Guillaume M, Mignot A. Single dose pharmacokinetics of the R- and S-enantiomers of gatifloxacin in volunteers. Drugs 1999;58:222–4. [27] Shah A, Liu MC, Vaughan D, Heller AH. Oral bioequivalence of three ciprofloxacin formulations following single-dose administration: 500 mg tablet compared with 500 mg/10 ml or 500 mg/5 ml suspension and the effect of food on the absorption of ciprofloxacin oral suspension. J Antimicrob Chemother 1999;43:49–54.
Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose夽 Dieter Boy a , Michaela Well a , Martina Kinzig-Schippers b , Fritz Sörgel b , Dorothe Ankel-Fuchs c , Kurt G. Naber a,∗ a b
Department of Urology, Hospital St. Elisabeth, St. Elisabeth-Str. 23, D-94315 Straubing, Germany Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany c Grünenthal GmbH, Aachen, Germany
Abstract In an open randomised double-crossover study 12 volunteers (six men, six women) received a single oral dose of gatifloxacin (400 mg) or ciprofloxacin (500 mg) to assess urinary bactericidal activity (in eight intervals up to 120 h) and pharmacokinetic (PK) parameters (up to 36 h). Plasma concentrations and urinary excretion were determined by HPLC with fluorescence detection, and urinary bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35 mg/l and that of ciprofloxacin 2.12 mg/l. The mean (median) cumulative renal excretion of the parent drug was for gatifloxacin 81 (83)% of the administered dose within 120 h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two-fold dilution (antibiotic-free urine as diluent) of urine still being bactericidal, were determined for an Escherichia coli ATCC reference strain and nine clinical uropathogens with the following MICs (mg/l) for gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922 (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016); Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125); Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The median UBTs measured within the first 6 h for gatifloxacin were between 1:16 and 1:≥1024 for the Gram-negative strains including P. aeruginosa and between 1:8 and 1:≥1024 for the five Gram-positive strains. The median UBTs for ciprofloxacin were between 1:64 and 1:≥1024 for the Gram-negative strains (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive strains. The UBTs up to 12 h showed no difference (P < 0.05) for both E. coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin against all Gram-positive strains. For the UBTs at 12–24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference in the Proteus and Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120 h showed statistically significant (P < 0.05) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. In conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary bactericidal activity with some differences for specific pathogens, some times in favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually Gram-negatives), suggesting that for empiric therapy a single oral dose of gatifloxacin (400 mg) would be clinically equivalent to ciprofloxacin (500 mg) twice daily—in agreement with the results of a clinical study in complicated UTI performed previously [Int. J. Antimicrob. Agents (2004)]. © 2003 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Urinary bactericidal activity; Urinary excretion; Plasma concentration; Gatifloxacin; Ciprofloxacin; Single oral dose
1. Introduction
夽 Part of this study was presented at the 4th European Congress of Chemotherapy and Infection, Paris, 4–7 May 2002 (Poster PM 199). ∗ Corresponding author. Tel.: +49-9421-710-1700; fax: +49-9421-710-1717. E-mail address: [email protected] (K.G. Naber).
Urinary tract infections (UTI) are usually caused by Escherichia coli and other Enterobacteriaceae, such as Proteus, Klebsiella, Enterobacter spp., but also by non-fermenters, such as Pseudomonas aeruginosa, and Gram-positive cocci, such as enterococci and staphylococci, and especially Staphylococcus saprophyticus. For empiric antimicrobial
0924-8579/$ – see front matter © 2003 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2003.09.006
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
therapy an antibiotic agent should be chosen which includes most of the uropathogens in its antibacterial spectrum and displays mainly renal excretion. In this regard, ciprofloxacin, with clinical experience over two decades, can still be considered a drug of choice and was therefore chosen as the comparator. Since the fluoroquinolones differ mainly in their pharmacokinetic properties, and in addition, their antibacterial activity in urine is reduced significantly depending on urine pH and contents [2], newer quinolones, such as gatifloxacin, should be investigated with regard to these issues. To obtain comparable dosages of gatifloxacin and ciprofloxacin (both have different pharmacokinetic properties) for the treatment of UTI and to approximate more closely the antibacterial activities at the site of infection, an ex vivo clinical study was performed to determine the concentrations in plasma and urine and the urinary bactericidal activity against clinical isolates of common uropathogens in healthy volunteers after administration of a single oral dose [3,4]. This pharmacodynamic (PD) model combines the pharmacokinetic and antibacterial properties in a human system and therefore exhibits the biological variations which have to be considered. According to animal and human studies [5], the efficacy of fluoroquinolones can be considered comparable if peak concentrations and area of concentration time curves above minimal inhibitory/bactericidal activity, which corresponds to the urinary bactericidal titers (UBT), are in the same range. 2. Materials and methods 2.1. Study design and demographic data of volunteers The study was approved by the ethics committee of the Landesärztekammer Bayern, Germany. It was an ex vivo, open, randomised, double-crossover, clinical trial in 12 healthy volunteers (six men, six women). Mean age was 30 years (median 30 years; range, 19–43 years), mean body weight was 74.8 kg (median 72.1 kg; range, 63–91 kg), and mean height was 172.4 cm (median 171.5 cm; range, 162–187 cm). The volunteers were considered to be healthy, based on medical history, physical examination and ECG, haematologic parameters (haemoglobin concentration, erythrocyte, leukocyte and platelet counts), serum chemistry parameters (glucose, creatinine, AST, ALT, ␥-glutamyl transferase, alkaline phosphatase, total protein and total bilirubine levels, HIV, Hbs-Ag, anti-HBs, anti-HBc) and urinalysis (glucose and protein levels, white and red blood cell counts). Lack of antibacterial activity in urine was tested by inhibition of Bacillus subtilis. 2.2. Drug administration After giving written informed consent to participate in the study, each volunteer successively received one oral dose of 400 mg gatifloxacin (Grünenthal GmbH, Aachen, Germany)
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or 500 mg ciprofloxacin (Bayer AG, Wuppertal, Germany) in a double-crossover design at an interval of 7 days according to the randomisation schedule. Study drugs were administered after an overnight fasting state. Alcohol- and xanthine-containing beverages and meals were not allowed 12 h before and 24 h after drug administration. The volunteers were asked to drink sufficient and comparable amounts of water to ensure sufficient urine production through both collection periods. Before and after each study phase, a physical examination, electrocardiography and laboratory tests were performed. Adverse events were recorded continuously throughout the trial period. The volunteers were monitored and urine collection was controlled in the study centre for the first 48 h and thereafter at the end of each sampling period for up to 120 h. 2.3. Sample collection Plasma samples were first taken before drug administration (H0), then after 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36 h and (gatifloxacin group only) 48 h. All urine voided was collected over a 12 h interval prior to drug administration and at the following time intervals thereafter: 0–6, 6–12, 12–24, 24–36, 36–48, 48–72, 72–96, and 96–120 h. All samples were stored at −20 ◦ C until assayed. 2.4. Determination of gatifloxacin and ciprofloxacin Gatifloxacin and ciprofloxacin concentrations in serum and urine were determined by HPLC using fluorescence detection. All sample handling was done under protection from daylight. Plasma samples were thawed and vigorously mixed, then precipitated with an acetonitrile mixture containing the internal standard. After centrifugation, for gatifloxacin (ciprofloxacin) 5 (10) l of the supernatant were analyzed. Urine samples were thawed and vigorously mixed and then diluted 1:100 with buffer containing the internal standard. Five or ten microlitres of the diluted sample were then analyzed. Chromatographic separation was performed using a reversed-phase column (250 mm × 4.6 mm), eluted with an isocratic solvent system consisting of an acetonitrile/water mixture and monitored by fluorescence detection (for gatifloxacin: excitation: 293 nm, emission: 490 nm; for ciprofloxacin: excitation: 278 nm, emission: 460 nm). Under these conditions, gatifloxacin and the internal standard were eluted after approximately 5.5 and 3.8 min, respectively, and ciprofloxacin and the internal standard were eluted after approximately 7.7 and 3.6 min, respectively. Turbochrom 3 software (version 3.2, PE Nelson, Cupertino, CA, 1991) was used for evaluation of chromatograms. Plasma and urine samples were measured against a plasma and urine calibration series, respectively. Calibration standards were prepared by adding the appropriate volumes of standard solution of gatifloxacin and ciprofloxacin, respectively, to drug-free human plasma or urine. Concentrations of gatifloxacin were obtained down to 0.0101 mg/l for plasma
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D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
and 0.444 mg/l for urine and that of ciprofloxacin down to 0.005 mg/l for plasma and 0.5 mg/l for urine. Spiked quality controls were prepared for inter-assay variation by adding the appropriate volumes of standard solution of gatifloxacin drug-free human plasma or urine. There was no interference observed, either in plasma or urine, for gatifloxacin, for ciprofloxacin or for their internal standards. Weighted linear regression (1/peak height ratio) was performed for calibration. Linearity of the calibration could be proven for gatifloxacin between 0.0101 and 10.3 mg/l in plasma and between 0.444 and 888.9 mg/l in urine, and for ciprofloxacin between 0.005 and 10.0 mg/l in plasma and between 0.500 and 1000 mg/l in urine. Quantification levels were identical with the lowest calibration levels. For gatifloxacin inter-assay precisions of the SQC in plasma were 4.6% (8.13 mg/l), 2.4% (0.993 mg/l), and 4.2% (0.0767 mg/l). The accuracy of the standards in plasma ranged from 91.1 to 95.2%. In urine, inter-assay precisions of the SQC were 7.4% (800 mg/l), 8.2% (80 mg/l), 7.9% (6.4 mg/l) and 10.5% (1 mg/l), and the accuracy of the standards ranged from 87.9 to 100.9%. For ciprofloxacin inter-assay precisions of the SQC in plasma were 3.8% (8 mg/l), 3.1% (0.8 mg/l), 2.1% (0.640 mg/l) and 6.6% (0.01 mg/l). The accuracy of the standards in plasma ranged from 95.5 to 97.4%. In urine, inter-assay precisions of the SQC were 0.4% (800 mg/l), 8.5% (80 mg/l), 3.8% (6.4 mg/l) and 1.6% (1 mg/l), and the accuracy of the standards ranged from 92.2 to 114.3%. 2.5. Pharmacokinetic parameters The pharmacokinetic parameters were estimated by standard non-compartmental methods. All parameters were determined from true (actual) sample collection times and assayed concentrations at these times. Concentration values below the lower limit of quantification were set to zero. The pharmacokinetic calculations were performed on a Pentium II 333 MHz Computer using the program Microsoft Excel 97 (Microsoft Co., Redmond, WA, USA, 1985–1998). The equations were entered into the program manually and checked by recalculation of pharmacokinetic parameters for randomly selected data sets using the pharmacokinetic program WinNonlinTM Professional (Version 2.0, Pharsight Corporation, © 1994–1998, Palo Alto, USA). The following parameters were estimated: maximal plasma concentration (Cmax ); time to maximal plasma concentration (Tmax ); plasma half life (T1/2 ); mean transit time (MRT); area under the plasma concentration time curve (AUC); total plasma clearance (Cltot ); renal clearance (Clren ); non-renal clearance (Clnren ); apparent distribution volume at final () phase (Vd ); apparent distribution volume at steady state (Vdss ). 2.6. Determination of minimal inhibitory (MICs) and bactericidal (MBCs) concentrations MICs were determined by both an agar dilution (AD) test with Isosensitest agar (CM 471; Oxoid, Wesel, Germany) us-
ing a multipointer (Dynatech, Nürtingen, Germany) with an inoculum of 104 colony forming units (CFU) per point, and MICs and MBCs were determined by a microdilution test using Mueller–Hinton–Broth (MHB) (Oxoid, Wesel, Germany) with an inoculum of (1.5–10.7) × 105 CFU/ml. The MIC was defined as the lowest concentration inhibiting visible growth (<10 CFU/ml) after incubation at 37 ◦ C for 18 h in ambient air, while the MBC was defined in a second step by counting the numbers of CFU on antimicrobial-free Columbia agar (Merck, Darmstadt, Germany) supplemented with 5% blood, after additional incubation at 37 ◦ C for 18 h. Bactericidal activity was defined as a >99.9% (>3 log) reduction in the numbers of CFU/ml. 2.7. Determination of urinary bactericidal titers (UBTs) A logarithmic serial dilution (dilution range, 1:2–1:1024) was prepared by taking a 1:1 mixture of the urine sample and the individual’s antimicrobial-free urine collected prior to drug administration [3,6]. UBTs were then determined by microdilution, with each well of the microplates containing 100 l of the prepared dilution. The final inoculum was 105 CFU/ml, and the bactericidal activity was determined according to the recommended guidelines by NCCLS [7]. A UBT of 0 was defined as no bactericidal activity, and a UBT of 1 was used for bactericidal activity of undiluted urine. UBTs were transformed into ordinal data by using a scale from 1 for UBTs of 0 up to 12 for UBTs of 1:≥1024. The area under the UBT-time-curve (AUBT) was calculated by the trapezoidal rule by using the UBT steps (ordinal data) for each test organism and for each drug phase. 2.8. Minimal urinary bactericidal concentrations (MUBCs) The division of the antimicrobial concentrations in the urine samples by the corresponding UBTs yielded the respective minimal urinary bactericidal concentrations (MUBCs). For this calculation, UBTs of 0 and 1:≥1024 were not appropriate. 2.9. Test organisms The reference strain E. coli ATCC 25922 and nine typical uropathogens cultured from the urine of patients with UTI were used as test organisms. The pathogens included one strain each of E. coli, K. pneumoniae, P. mirabilis, P. aeruginosa, and S. saprophyticus, and two strains of both S. aureus and Enterococcus faecalis. S. aureus ATCC 29278 and E. faecalis ATCC 28243 were used in addition for internal quality control. 2.10. Statistical analyses The results of the two drug phases were compared by the paired t-test. An α value equal to 0.05 was chosen to determine statistical significance.
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
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Table 1 Median (range) urinary pH, volume, parent drug concentration, and cumulative excretion in volunteersa Collection period
Urinary pH median (range)
Volume (ml) median (range)
Concentration (mg/l) median (range)
Cumulative excretion (%) median (range); mean ± S.D.
Gatifloxacin 0–6 h 6–12 h 12–24 h 24–36 h 36–48 h 48–72 h 72–96 h 96–120 h
6.7b (5.2–8.9) 7.3 (6.1–8.6) 5.9b (5.4–6.4) 6.9 (5.1–7.6) 6.1 (5.0–7.1) 6.2 (5.3–7.1) 6.2 (5.5–8.3) 6.6 (5.3–8.4)
408.1 (162–885) 537.8b (254–1100) 705.8 (373–1398) 961.3 (589–1931) 606.0 (128–1529) 1655.2 (478–2671) 1458.4 (1077–2494) 1441.7 (959–2299)
309.2 (163.3–804.4) 141.5b (67.4–331.8) 106.1b (54.2–215.9) 22.2b (10.0–42.1) 11.3b (3.4–25.5) 2.2b (0.5–7.3) 0.8c (BQL–1.5) BQLc (BQL–0.5)
32.8 (22.8–42.3); 32.7 ± 5.3 55.1b (35.9–61.4); 53.4 ± 6.8 74.1b (53.0–80.7); 72.2 ± 7.2 79.8b (59.7–87.2); 78.0 ± 7.4 81.7b (61.7–89.5); 79.8 ± 7.6 82.7b (62.0–90.8); 80.7 ± 7.9 82.9b (62.2–91.2); 81.0 ± 8.0 83.0b (62.2–91.4); 81.0 ± 8.0
Ciprofloxacin 0–6 h 6–12 h 12–24 h 24–36 h 36–48 h 48–72 h 72–96 h 96–120 h
6.1b (5.1–8.8) 7.2 (5.5–8.4) 6.2b (4.9–7.1) 6.9 (5.6–8.5) 6.0 (5.6–7.0) 6.3 (5.7–8.0) 6.1 (5.5–8.5) 6.5 (5.3–8.3)
442.7 (174–811) 423.3b (230–773) 729.3 (373–1677) 1474.3 (692–3226) 595.0 (359–1733) 1439.6 (867–3036) 1413.4 (697–2622) 1402.1 (953–1883)
367.9 (100.2–1000.5) 76.6b (30.4–179.4) 20.1b (2.6–41.7) 3.3b (BQL–5.5) 1.5b (BQL–3.0) 0.3b (BQL–1.1) BQLc (BQL–BQL) BQLc (BQL–BQL)
32.2 (13.3–58.6); 32.4 ± 10.4 40.6b (17.7–60.0); 39.3 ± 10.6 43.9b (19.3–60.4); 42.2 ± 10.8 44.9b (19.6–61.8); 43.0 ± 11.2 45.1b (19.7–61.8); 43.1 ± 11.2 45.2b (19.7–62.0); 43.2 ± 11.2 45.2b (19.7–62.0); 43.2 ± 11.2 45.2b (19.7–62.0); 43.2 ± 11.2
BQL, below quantification limit: 0.444 mg/l for gatifloxacin; 0.500 mg/l for ciprofloxacin. a A total of 12 volunteers were tested. b Significantly different (P < 0.05) for gatifloxacin vs. ciprofloxacin. c Calculation not applicable.
3. Results 3.1. Safety and laboratory test results Gatifloxacin and ciprofloxacin were well tolerated by all volunteers. No serious adverse effects were considered to be related to a study medication. No change in ECG and no clinical significant change in routine blood and serum tests by either drug was found. 3.2. Urinary pHs, volumes and drug concentrations The median (range) values for urinary pHs, volumes, urinary drug concentrations and cumulative renal excretion obtained in the two study phases are given in Table 1. Additionally the mean ± S.D. data for cumulative excretion
are presented. The data for the corresponding collection periods of the respective study phases showed significant but small differences in urinary pHs for the first (0–6 h) and third (12–24 h) collection period and in volumes for the second interval (6–12 h). In both study phases however, the median pH for the collection period 6–12 h (afternoon) was higher than for the other collection periods. The median urinary concentrations are shown in Fig. 1. All urine samples collected prior to drug administration had no detectable drug. The first collection period (0–6 h) showed no statistically significant difference between gatifloxacin (309.2 mg/l) and ciprofloxacin (367.9 mg/l). Thereafter, up to the collecting period 48–72 h, the median urinary concentrations of gatifloxacin were significantly higher than those of ciprofloxacin, and later on ciprofloxacin was below the quantification limit in urine of all volunteers. The cumu-
Fig. 1. Median (n = 12) concentrations of gatifloxacin (400 mg) and ciprofloxacin (500 mg) in urine (see Table 1 for concentration ranges).
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Time of sample (h)
0.0 0.5 1.0 1.5 2.0 3.0 4.0 6.0 8.0 12 24 30 36 a ∗
Plasma concentration (mg/l) of gatifloxacin 400 (mg p.o.)
Plasma concentration (mg/l) of ciprofloxacin 500 (mg p.o.)
Significantly different (yes/no) t = 1.7959
N
Mean (mg/l)
S.D. (mg/l)
Median (mg/l)
Min (mg/l)
Max (mg/l)
N
Mean (mg/l)
S.D. (mg/l)
Median (mg/l)
Min (mg/l)
Max (mg/l)
12 11 11 12 12 12 12 12 12 12 12 12 12
BQLa 1.99 2.87 2.78 2.62 2.67 2.54 2.03 1.65 1.06 0.30 0.16 0.086
BQL 1.55 1.13 1.09 0.96 0.57 0.57 0.43 0.35 0.26 0.08 0.05 0.026
BQL 2.0 2.6 2.9 2.6 2.7 2.5 2.0 1.6 0.9 0.3 0.2 0.1
BQL 0.17 0.79 0.06 0.40 1.87 1.88 1.49 1.18 0.82 0.17 0.07 0.032
BQL 5.28 4.31 4.03 3.99 3.59 3.41 2.71 2.17 1.59 0.47 0.25 0.13
12 12 12 12 12 12 12 12 12 12 12 12 10
BQL 1.48 1.90 1.77 1.51 1.14 0.89 0.59 0.39 0.20 0.03 0.01 0.009
BQL 0.83 0.40 0.35 0.28 0.22 0.21 0.15 0.12 0.06 0.01 0.00 0.002
BQL 1.1 1.9 1.7 1.4 1.1 0.9 0.6 0.4 0.2 0.034 0.015 0.009
BQL 0.50 1.28 1.16 1.00 0.67 0.48 0.29 0.17 0.07 0.016 0.008 0.006
BQL 2.98 2.64 2.45 2.03 1.47 1.28 0.83 0.59 0.31 0.053 0.022 0.011
BQL, below quantification limit: 0.010 mg/l for gatifloxacin; 0.005 mg/l for ciprofloxacin. Not applicable.
t
Yes/no
∗
∗
1.3 3.0 3.2 4.1 9.4 10.2 11.6 12.1 11.8 11.5 10.8 12.7
No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
Table 2 Mean, standard deviation (S.D.), median, minimum and maximum of plasma concentrations
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
lative urinary excretion (mean, median, range) of the parent drug up to 120 h was for gatifloxacin 81% (83, 62–91%) and for ciprofloxacin 43% (45, 20–62%) of the administered dose (Table 1). 3.3. Plasma concentrations and pharmacokinetic parameters The plasma concentrations (mean, median, range) of both drugs (Table 2) showed no difference at 0.5 h; all the other samples, up to 36 h, showed significantly higher plasma concentrations of gatifloxacin versus ciprofloxacin. The mean (median) maximum plasma concentration of gatifloxacin was 3.35 (3.19) mg/l and that of ciprofloxacin 2.12 (2.07) mg/l (Table 3). The mean (median) half life of gatifloxacin was 6.69 (6.61) h and that of ciprofloxacin was 5.69 (5.58) h. Further pharmacokinetic parameters, such as time to maximum plasma concentration (Tmax ), 0–36 h and 0-undefinite area under the plasma concentration curve (AUC), total clearance (Cltot ), renal clearance (Clren ), non-renal clearance (Clnren ), and distribution volume at steady state (Vdss ) and at -phase (Vd ) are also shown in Table 3.
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3.5. UBTs and AUBTs The UBTs and AUBTs for both study drugs for the test organisms are given in Table 5 and Fig. 2. The UBTs of gatifloxacin and ciprofloxacin measured within the first 12 h for the five Gram-negative strains were between 1:≥1024 and 1:8, and showed identical bactericidal activity against both E. coli strains but higher activity of ciprofloxacin against Klebsiella, Proteus and Pseudomonas. The UBTs within the first 12 h for the five tested Gram-positive strains were between 1:≥1024 and 1:0.5 and showed significantly higher bactericidal activity of gatifloxacin against all the strains of S. saprophyticus, S. aureus and E. faecalis. Thereafter, the median UBTs of both drugs for the susceptible strains decreased, but was much quicker for ciprofloxacin than for gatifloxacin. The difference was due to differences in urinary excretion. Therefore the areas under the UBT-time-curve showed statistically significant (P < 0.05) higher activity of gatifloxacin than ciprofloxacin against 8 of 10 strains tested; no difference was seen for P. mirabilis but there was a significantly higher activity of ciprofloxacin against P. aeruginosa.
3.4. MICs and MBCs 3.6. MUBCs The MICs (microdilution in Mueller–Hinton–broth) of gatifloxacin and ciprofloxacin for each of the ATCC test strains (E. coli, S. aureus, E. faecalis), which were in accepted ranges, and for the isolates for which UBTs were determined ranging from ≤0.008 to 8 mg/l for gatifloxacin and ≤0.008 to 32 mg/l for ciprofloxacin, are given in Table 4.
The median (range) MUBCs of both study drugs for the test organisms are given in Table 6. They showed wide interindividual ranges. For gatifloxacin they were between 2.9 and 31.7 times of corresponding MIC (microdilution), for ciprofloxacin between 3.3 and 39.
Table 3 Pharmacokinetic parameters of gatifloxacin (400 mg) vs. ciprofloxacin (500 mg) after single oral dose in 12 healthy volunteers Parameter Tmax (h)
T1/2 (h)
MRT (h)
AUC 0–>36 h (mg h/l)
AUC 0–>∞ (mg h/l)
Gatifloxacin Mean 3.35 S.D. 0.94 CV(%) 28.0 Min 2.09 Max 5.28 Median 3.19
1.67 1.11 66.6 0.50 4.00 1.25
6.69 0.69 10.4 5.02 7.65 6.61
9.92 1.02 10.3 7.28 11.0 9.99
33.3 6.94 20.9 25.2 48.3 32.9
34.1 7.05 20.7 25.8 49.6 33.4
203 38.2 18.9 135 258 200
163 40.4 24.8 113 224 159
Ciprofloxacin Mean 2.12 S.D. 0.50 CV(%) 23.7 Min 1.28 Max 2.98 Median 2.07
1.04 0.45 43.2 0.50 2.00 1.00
5.69 0.62 10.9 4.76 7.09 5.58
5.88 0.58 9.90 4.50 6.64 5.96
10.5 2.30 21.9 5.54 13.9 10.2
10.6 2.31 21.8 5.61 14.0 10.3
814 231 28.4 594 1486 782
343 75.7 22.1 265 523 312
Cmax (mg/l)
Ctot (ml/min)
Clren (ml/min)
Clnren (ml/min)
Vd (l)
Vdss (l)
39.5 14.2 35.9 21.6 73.9 37.6
118 28.9 24.5 76.1 155 115
121 27.3 22.6 80.8 155 122
471 247 52.3 284 1192 381
401 121 30.1 265 721 368
284 69.7 24.5 209 470 266
Cmax : maximal plasma concentration; Tmax : time to maximal plasma concentration; T1/2 : plasma half life; MRT: mean transit time; AUC: area under the plasma concentration time curve to last 36 h or to undefinite, respectively; Cltot : total plasma clearance; Clren : renal clearance; Clnren : non-renal clearance; Vd : apparent distribution volume at final () phase; Vdss : apparent distribution volume at steady state; S.D.: standard deviation; min: minimal value; max: maximal value; ∞: indefinate.
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D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
Table 4 MICs and MBCs of gatifloxacin and ciprofloxacin for an E. coli test strain (ATCC 25922) and nine uropathogens cultured from the urine of patients with complicated and uncomplicated UTIs [inoculum for agar dilution (AD)-test 104 per point, for Mueller–Hinton–Broth (MHB) 1.5–6.7 × 105 CFU/ml] No.
Test strain and laboratory number
MIC or MBC (mg/l) Gatifloxacin
1 2 3 4 5 6 7 7a 8 8a 9 10 11a 12a
E. coli ATCC 25922 E. coli 523 K. pneumoniae 1058 P. mirabilis 524 P. aeruginosa 568 S. saprophyticus Ho94 S. aureus 248 S. aureus 248 S. aureus 596 S. aureus 596 E. faecalis 60 E. faecalis 55 S. aureus ATCC 29278 E. faecalis ATCC 28243
Ciprofloxacin
MIC AD
MIC MHB
MBC MHB
MIC AD
MIC MHB
MBC MHB
– 0.25 0.06 0.25 4 0.125 0.125 – 0.06 – 0.5 8 – –
0.008 0.06 0.03 0.125 1 0.125 0.03 0.06 0.03 0.03 0.5 8 0.06 0.25
0.008 0.06 0.03 0.25 2 0.125 0.03 0.06 0.03 0.06 0.5 8 0.06 0.25
– 0.25 0.06 0.06 1 0.25 0.5 – 0.5 – 2 64 – –
0.008 0.06 0.016 0.016 0.125 0.25 0.125 0.25 0.125 0.125 1 32 0.25 0.5
0.008 0.06 0.016 0.03 0.25 0.25 0.125 0.25 0.125 0.25 1 32 0.25 0.5
Inoculum MHB (CFU/ml) 1.5 2.4 3.2 2.3 5.9 4.9 4.5 5.2 5.1 6.7 3.6 4.7 10.7 5.3
× × × × × × × × × × × × × ×
105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml 105 /ml
Date of test 28 January 2002. a Date of control 23 January 2003.
4. Discussion It is quite difficult to predict the impact of the chemical structure of a new fluoroquinolone on metabolic stability, renal excretion and bactericidal activity. Gatifloxacin and ciprofloxacin both have a cyclopropyl-substituent in position 1 and a piperazinyl-substituent in position 7. Gatifloxacin has an additional methyl-group in position 3 of the piperazinyl-substituent and the new unique 8-methoxy-group [8–10]. So far, gatifloxacin has been shown to be clinically effective in infections of the skin and soft tissue [11], in the respiratory system, and also in UTI [1,12,13]. However, no comparative pharmacodynamic study is yet published [14]. The incidence of UTIs differs with age and sex and affects up to 40–50% adult women with an anatomically normal urinary tract [15]. UTIs are usually caused by E. coli, Enterobacteriaceae such as Klebsiella and Proteus spp., and non-fermenters such as P. aeruginosa and by Gram-positive bacteria. There are several new fuoroquinolones that potentially target this spectrum of pathogens but only a few are sufficiently excreted unchanged in the urine to make them suitable for the treatment of UTI [16,17]. In the present study, we investigated both the pharmacokinetics in plasma, and urine and the urinary bactericidal activity (as urinary bactericidal titers) after single oral doses of gatifloxacin (400 mg) and ciprofloxacin (500 mg); the latter having been in clinical use for two decades and can still be considered as a drug of choice for the treatment of uncomplicated and complicated UTI [18]. We found several marked differences between the pharmacokinetics in plasma and urine of the two drugs. The mean maximum plasma concentration after an oral dose of 400 mg gatifloxacin (3.35 mg/l) was 1.5 times higher than that af-
ter an oral dose of 500 mg ciprofloxacin (2.12 mg/l). Plasma concentrations at 1 h post-medication up to 36 h were significantly (P < 0.05) higher for gatifloxacin while the median urinary concentrations within the first 6 h were comparable (gatifloxacin 309.2 mg/l versus ciprofloxacin 367.9 mg/l). In all subsequent intervalls up to 72 h gatifloxacin showed significantly higher urinary concentrations than ciprofloxacin (e.g. 6–12 h; gatifloxacin 141.5 mg/l versus ciprofloxacin 76.6 mg/l). The mean (median) cumulative renal excretion rate of gatifloxacin of 81% (83%) was almost twice of that of ciprofloxacin with 43% (45%). The UBTs and AUBTs in fact showed statistically significant (P < 0.05) differences. While the UBTs of both drugs displayed an overall comparable bactericidal activity in urine within the first 12 h after medication, statistically significant differences are present for Gram-negative (in favour of ciprofloxacin) and Gram-positive (in favour of gatifloxacin) uropathogens. Differences in subsequent intervals were statistically in favour of gatifloxacin. The total AUBT (up to 120 h) after one single oral dose of gatifloxacin demonstrates its favourable pharmacokinetic properties, arising from its high cumulative excretion of parent drug, for the treatment of UTIs. Based on considerations of the UBTs and AUBTs the clinical equivalence of 400 mg gatifloxacin once daily versus 500 mg ciprofloxacin twice daily may be assumed; and this has been demonstrated in a clinical study in complicated UTI performed previously [1]. The MUBCs show a wide interindividual variability. For gatifloxacin they were between 2.9 and 31.7 times of the corresponding MIC, and for ciprofloxacin between 3.3 and 39, indicating the need for MIC-testing with both drugs. The MUBCs calculated from the UBTs and the urinary concentrations demonstrate that the bactericidal activity of fluoroquinolones are reduced in urine compared to broth and
Drug and strain
AUBT (h−1 )
UBT for the following collection period (h) 0–6
6–12
12–24
24–36
36–48
48–72
72–96
96–120
Gatifloxacin E. coli ATCC 25922 E. coli 523 K. pneumoniae 1058 P. mirabilis 524 P. aeruginosa 568 S. saprophyticus Ho94 S. aureus 248 S. aureus 596 E. faecalis 60 E. faecalis 55
≥1024 (256 ≥ 1024) 256 (32 ≥ 1024) 512a (64 ≥ 1024) 384a (64 ≥ 1024) 16a (4–64) 768a (256 ≥ 1024) ≥1024a (≥1024) ≥1024a (512 ≥ 1024) 256a (64 ≥ 1024) 8a (2–64)
768 (128 ≥ 1024) 96 (32 ≥ 1024) 192a (64 ≥ 1024) 128a (32 ≥ 1024) 8a (2–64) 256a (128 ≥ 1024) ≥1024a (256 ≥ 1024) ≥1024a (512 ≥ 1024) 64a (32 ≥ 1024) 4a (2–64)
768a (64 ≥ 1024) 48a (8 ≥ 1024) 128a (16 ≥ 1024) 128 (32–512) 2 (0–32) 256a (64–512) 512a (64 ≥ 1024) ≥1024a (128 ≥ 1024) 64a (4–512) 3a (0–64)
128a (16 ≥ 1024) 12a (2–256) 32a (4–512) 32a (16–128) 1a (0–8) 48a (16–128) 128a (8–512) 96a (16–512) 16a (2–128) 0.5a (0–4)
64a (8 ≥ 1024) 4a (0–128) 12a (1–256) 16a (8–64) 0a (0–4) 24a (8–64) 64a (4–256) 64a (16–256) 4a (0–32) 0 (0–1)
8a (8–256) 1a (0–32) 2a (0–64) 3 (1–16) 0 (0–1) 4a (1–8) 12a (2–64) 12a (8–64) 1a (0–16) 0 (0–0)
3a (0–32) 0 (0–4) 0 (0–8) 1 (0–2) 0 (0–0) 1a (0–2) 4a (1–8) 4a (1–8) 0a (0–2) 0 (0–0)
0.5a (0–16) 0a (0–1) 0 (0–4) 0 (0–1) 0 (0–0) 0 (0–2) 1a (0–8) 1a (0–8) 0 (0–0) 0 (0–0)
606a (342–1008) 312a (144–708) 396a (192–828) 408 (330–624) 96a (42–240) 456a (384–588) 636a (432–804) 666a (504–792) 288a (180–588) 84a (30–216)
Ciprofloxacin E. coli ATCC 25922 E. coli 523 K. pneumoniae 1058 P. mirabilis 524 P. aeruginosa 568 S. saprophyticus Ho94 S. aureus 248 S. aureus 596 E. faecalis 60 E. faecalis 55
≥1024 (256 ≥ 1024) 192 (32 ≥ 1024) ≥1024a (128 ≥ 1024) ≥1024a (256 ≥ 1024) 64a (8–256) 256a (128 ≥ 1024) 768a (256 ≥ 1024) 512a (128 ≥ 1024) 64a (16–256) 1.5a (1–4)
768 (64 ≥ 1024) 64 (8 ≥ 1024) 384a (32 ≥ 1024) 256a (32 ≥ 1024) 24a (2–128) 128a (8–512) 256a (64 ≥ 1024) 256a (32 ≥ 1024) 16a (4–128) 0.5a (0–2)
128a (16 ≥ 1024) 8a (2–128) 48a (4 ≥ 1024) 96 (16 ≥ 1024) 4 (1–64) 24a (2–64) 48a (16–128) 64a (8–128) 4a (1–32) 0a
16a (2–512) 2a (0–32) 6a (1–256) 16a (4–128) 0a (0–4) 4a (0–16) 6a (1–16) 8a (2–16) 1a (0–2) 0a
8 (1–256) 0a (0–16) 3a (1–128) 8a (2–64) 0a (0–2) 0a (0–4) 2a (1–8) 2a (2–8) 0a 0
4a (1–64) 0a (0–4) 0.5a (0–64) 2 (0–32) 0 0a (0–2) 0.5a (0–4) 1a (0–4) 0a 0
0a (0–32) 0 (0–2) 0 (0–16) 0.5 (0–8) 0 0a 0a (0–1) 0a (0–2) 0a 0
0a (0–8) 0a (0–0) 0 (0–4) 0 (0–4) 0 0 0a (0–2) 0a (0–2) 0 0
426a (216–900) 177a (84–480) 300a (144–828) 342 (312–756) 117a (48–246) 222a (120–294) 279a (192–444) 297a (180–463) 111a (60–192) 12a (6–24)
a
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Table 5 Median (range) reciprocal UBTs for gatifloxacin (400 mg) and ciprofloxacin (500 mg) after single dose administration in 12 volunteers
Significantly different (paired t-test; P < 0.05) for gatifloxacin vs. ciprofloxacin.
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Fig. 2. Median reciprocal UBTs of gatifloxacin (400 mg) and ciprofloxacin (500 mg) for E. coli ATCC 25922 and nine clinical uropathogens in 12 volunteers tested (see Tables 2 and 3 for ranges).
that considerable interindiviual variation has to be taken in account. Therefore the estimation of the urinary bactericidal activity by use of dilutions with the individual’s antimicrobial-free urine may be considered more appropri-
ate for approximation of the expected in vivo activity of an antimicrobial agent in the treatment of complicated UTI. The pharmacokinetic/pharmacodynamic (PK/PD) index, which is most closely associated with the bacteriological ef-
D. Boy et al. / International Journal of Antimicrobial Agents 23S1 (2004) S6–S16
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Table 6 Median (range) of minimum urinary batericidal concentrations (mg/l) of gatifloxacin (400 mg) and ciprofloxacin (500 mg) after single dose administration in volunteers Strains Species
No.
E. coli E. coli K. pneumoniae P. mirabilis P. aeruginosa S. saprophyticus S. aureus S. aureus E. faecalis E. faecalis
ATCC 25922 523 1058 524 568 HO94 248 596 60 55
a
MUBC for gatifloxacin (mg/l)
MUBC for ciprofloxacin (mg/l)
0.25 (0.03–2.31) 1.75 (0.16–17.51) 0.71 (0.08–11.85) 0.88 (0.27–3.45) 16.01 (4.49–119.10) 0.50 (0.12–1.29) 0.18 (0.00a –2.65) 0.18 (0.04–1.29) 1.54 (0.33–13.54) 22.85 (3.37–173.25)
0.18 (0.01–1.59) 1.12 (0.16–11.09) 0.40 (0.02–3.22) 0.23 (0.01–1.55) 4.88 (0.33–27.51) 0.83 (0.08–6.20) 0.55 (0.04–3.08) 0.46 (0.02–1.61) 4.33 (0.65–13.76) 137.03 (30.39–581.20)
Calculation not applicable.
ficacy of fluoroquinolones, is the 24 h area under the plasma concentration curve in relation to the MIC (AUC/MIC (AUIC)) [19,20]. This ratio is independent of the dosing interval, the fluoroquinolone used and the site of infection [5,21]. Gunderson et al. [22] have recently summarised the PK/PD data available from animal models and from human studies for fluoroquinolones. The optimum AUIC against Gram-negative pathogens seems to be >125 whereas 30–50 may be sufficient for Gram-positives such as S. pneumoniae and anaerobes like Bacteriodes fragilis. Particularly against Gram-negative bacilli (e.g. E. coli) which can cause nosocomial infections the AUIC needs to reach or exceed 100; that is, serum levels need to average around four times the MIC over a 24 h period [5]. Against Gram-positive pathogens fluoroquinolones such as sitafloxacin, gatifloxacin and gemifloxacin retain full activity at AUICs as low as 30–50 [23–25]. In studies of pneumonia, peritonitis and sepsis in mice, rats and guinea pigs, in general, 24 h AUIC ratios of <30 for fluoroquinolones were associated with >50% mortality, whereas AUIC values of ≥100 were associated with almost no mortality when animals were infected with various strains of Gram-positive and Gram-negative bacteria [5]. Since gatifloxacin is prescribed once daily and ciprofloxacin twice daily the time segments of the AUC which need to be considered are 0–24 h for gatifloxacin and two times 0–12 h for ciprofloxacin (with a cumulative factor of about 1.2 calculated from previous studies) [unpublished data]. Using the results of the present study for gatifloxacin, AUC (mean ± S.D.; median, range) of 31.2 ± 6.6 (30.8, 23.6–45.0) mg h/l and for ciprofloxacin of 21.5 ± 4.5 (21.0, 11.8–28.5) mg h/l can be calculated. The mean gatifloxacin AUC0–24 value is in agreement with published values for AUC0–∞ of 33.8 ± 3.11 mg h/l in healthy volunteers [26]; the mean ciprofloxacin AUC0–36 of 10.5 ± 2.3 mg h/l (Table 3) corresponds to a recently published geometric mean AUC0–∞ value of 11.81 mg h/l [27]. If the minimal AUCs observed in this study are used, a MIC of ≤0.25 mg/l for gatifloxacin and a MIC of ≤0.125 mg/l for ciprofloxacin result in AUIC ratios of ≥100. These MICs should therefore be considered as the PK/PD
breakpoints for the optimal treatment of systemic infections with Gram-negative uropathogens such as Enterobacteriaceae using the above dosage regimens. For gatifloxacin, P. aeruginosa (MIC 1 mg/l) and the Gram-positive two enterococcal strains (MIC 0.5 and 8 mg/l), for ciprofloxacin S. saprophyticus (MIC 0.25 mg/l) and the two enterococcal strains (MIC 1 and 32 mg/l) would be outside these limits. It is not known whether the same criteria apply for the treatment of complicated UTI, but in the case of complicated pyelonephritis with systemic infectious reactions and most likely in urosepsis such conditions might be very relevant. Since the area under the UBT-time-curve takes into consideration urinary concentration and bactericidal activity against a specific strain, these areas can be used for comparison of two antimicrobials. The data indicate that for Gram-negative uropathogens the AUBTs for ciprofloxacin and for Gram-positive uropathogens the AUBTs for gatifloxacin appear in favour and suggest use will result in successful treatment. Although the absolute AUBT necessary for effective therapy of complicated UTI is not known—it is not known whether it follows the same criteria as the plasma AUC for systemic infections—the AUBT of gatifloxacin 400 mg once daily for the treatment of a complicated UTI due to P. aeruginosa, which per se is usually difficult to treat, appears borderline compared to that of ciprofloxacin 500 mg twice daily.
5. Conclusion In particular, the following conclusions may be drawn from the present study: (i) The mean/median cumulative renal excretion (parent drug) of gatifloxacin (81.0%/83.0%) was almost twice that of ciprofloxacin (43.2%/45.2%). (ii) After an oral dose of 400 mg gatifloxacin the mean maximum plasma concentration (3.35 mg/l) was about 1.5 times higher than that after an oral dose of 500 mg ciprofloxacin (2.12 mg/l).
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(iii) If an AUC/MIC (AUIC) >100 is taken for optimal therapy of a systemic infection, then for gatifloxacin a MIC of ≤0.25 mg/l and for ciprofloxacin that of ≤0.125 mg/l would fulfil this criterion. (iv) The UBTs up to 12 h showed no difference (P < 0.05) for both E. coli strains, but ciprofloxacin was superior to Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to all Gram-positive strains. For the UBTs at 12–24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference for the Proteus and Pseudomonas strains. (v) The areas under the UBT-time-curve up to 120 h showed statistically significant (P < 0.05) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. (vi) According to the UBTs within the first 24 h, a dosage of 400 mg gatifloxacin once daily should be overall clinically equivalent to a dosage of 500 mg ciprofloxacin twice daily. This has also been demonstrated in a clinical study in complicated UTI performed previously. References [1] Naber KG, Bartnicki A, Bishoff W, et al. Gatifloxacin 200 mg or 400 mg once daily is as effective as ciprofloxacin 500 mg twice daily for the treatment of patients with acute pyelonepliritis or complicated urinary tract infections. Int J Antimicrob Agent 2004;2351:41–53. [2] Naber KG, Antibacterial activity of antibacterial agents in urine: an overview of applied methods. In: Bergan T, editor. Infectiology, Urinary Tract Infections. Basel: Karger; 1997. p. 74–83. [3] Naber KG, Theuretzbacher U, Kinzig M, Savov O, Sörgel F. Urinary excretion and bactericidal activities of a single oral dose of 400 milligrams of fleroxacin versus a single oral dose of 800 milligrams of pefloxacin in healthy volunteers. Antimicrob Agents Chemother 1998;42:1659–65. [4] Naber CK, Hammer M, Kinzig-Schippers M, Sauber C, Sörgel F, Bygate EA, et al. Urinary excretion and bactericidal activities of gemifloxacin and ofloxacin after a single oral dose in healthy volunteers. Antimicrob Agents Chemother 2001;45:3524–30. [5] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1– 12. [6] Edberg SC. The measurement of antibiotics in human body fluids: techniques and significance. In: Lorian V, editor. Antibiotics in Laboratory Medicine. Baltimore, MD: The Williams & Wilkins Co.; 1986. p. 466–7. [7] National Committee of Clinical and Laboratory Standards (NCCLS). Methods of determining bactericidal activity of antimicrobial agents. Tentative Guideline, September 1992. NCCLS document M26-T, vol. 12. 1992. p. 1–36. [8] Appelbaum PC, Hunter PA. The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents 2000;16:5– 15.
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