potential, e.g. lomefloxacin and sparfloxacin, than others. Cutaneous photosensitivity reactions have been routinely observed following treatment with some ...
JAC
Journal of Antimicrobial Chemotherapy (2000) 45, 503–509
A comparison of the photosensitizing potential of trovafloxacin with that of other quinolones in healthy subjects J. Fergusona*, J. McEwenb, H. Al-Ajmia, L. Purkinsc, P. J. Colmanc and S. A. Willavized a
Photobiology Unit, University of Dundee and bDrug Development (Scotland) Ltd, Ninewells Hospital and Medical School, Dundee DD1 9SY; cPfizer Central Research, Sandwich CT13 9NJ, UK; d Pfizer Central Research, Groton, CT, USA Treatment with some quinolones is associated with an abnormal skin reaction following exposure to sunlight (photosensitivity). The objective of the current study was to compare the photosensitizing potential of a new quinolone, trovafloxacin, with that of ciprofloxacin, lomefloxacin and placebo. Forty-eight healthy males (age range 19–45 years) were randomized to receive a 7 day course of treatment with: (i) trovafloxacin 200 mg od; (ii) ciprofloxacin 500 mg bd; (iii) lomefloxacin 400 mg od; or (iv) placebo bd. Minimal erythema doses (MEDs) were assessed using a monochromator at baseline and on day 5 of treatment, for wavelengths of 305 5, 335 30, 365 30, 400 30 and 430 30 nm; 335 30 and 365 30 nm are within the UVA range. Immediate reaction MEDs were similar in all treatment groups. However, between baseline and day 5, the mean decreases in delayed-reaction MED (24 h) at 335 30 nm were only 18.99% for trovafloxacin versus placebo (P 0.1267), compared with 53.77% (P < 0.0001) and 64.13% (P < 0.0001) for ciprofloxacin and lomefloxacin, respectively. Similarly, at 365 30 nm, trovafloxacin produced the smallest reduction in delayed MED versus placebo (43.66%), compared with ciprofloxacin (61.53%) and lomefloxacin (75.81%). These differences between trovafloxacin and ciprofloxacin and lomefloxacin were significant at both 335 30 and 365 30 nm (P < 0.029). All MED values returned to baseline levels within 2 days of drug cessation. These results show that trovafloxacin has significantly less photosensitizing potential than either ciprofloxacin or lomefloxacin. This photosensitivity appears to be induced only by wavelengths in the UVA region, is maximal at 24 h and is a short-term effect.
Introduction Photosensitivity is defined as a non-immunological, lightactivated irritation that occurs following exposure to a photoactive chemical. Such reactions are dose dependent and will occur in any normal individual, provided sufficient photoactive agent in the skin is subsequently exposed to sufficient radiation of the appropriate wavelength. When mild, quinolone-induced photosensitivity is characterized by the presence of erythema, oedema, desquamation and hyperpigmentation; in more severe cases, painful blistering may necessitate hospitalization. It has become evident that some of the quinolones have a greater photosensitizing potential, e.g. lomefloxacin and sparfloxacin, than others. Cutaneous photosensitivity reactions have been routinely observed following treatment with some quinolone antibiotics,1–5 although which of the structural features of this
class of antimicrobials are responsible for enhanced photosensitization has not been established. Trovafloxacin (CP-99,219) is a new-generation quinolone that acts, as other quinolones do, by inhibition of the A subunit of bacterial DNA gyrase, topoisomerase IV being the major target in Gram-positive bacteria.6 In vitro studies have demonstrated potent activity, not only against Gramnegative bacteria, but also against many Gram-positive organisms, including penicillin-susceptible and -resistant Streptococcus pneumoniae, Staphylococcus aureus, including methicillin-resistant strains,6,7 anaerobes8–11 and atypical respiratory pathogens.12–14 When compared with the activity of other quinolones, including ciprofloxacin, resistance rates are lower in staphylococci and other bacteria.15 In addition, the long elimination half-life of trovafloxacin of approximately 11 h facilitates once-daily administration.16
*Corresponding author. Tel: 44-1382-632240; Fax: 44-1382-646047.
503 © 2000 The British Society for Antimicrobial Chemotherapy
J. Ferguson et al. This study evaluates the potential for trovafloxacin, administered orally, to induce photosensitivity in healthy subjects and compares the response of the skin after exposure to ultraviolet (UV) and visible radiation following multiple dosing with trovafloxacin, ciprofloxacin, lomefloxacin or placebo.
Materials and methods Subjects Healthy male volunteers fulfilling the following criteria were eligible for inclusion in the study (Table I): age 18–45 years; body weight 50–95 kg and 15% of the permitted range for their height and frame size;17 skin type I (always burns easily, never tans), II (always burns easily, tans minimally) or III (burns moderately, tans gradually and uniformly) according to the skin type classification.18 Subjects with a history of an allergic condition (such as asthma or eczema), epilepsy, seizure, drug hypersensitivity, photosensitivity, drug or alcohol abuse, or with a condition that may influence drug absorption were excluded from the study. Additional exclusion criteria included: any clinically significant physical or laboratory abnormalities; a positive hepatitis B surface antigen or core antibody test; treatment with systemic or topical medication (except for paracetamol); administration of experimental drugs in the preceding 4 months; the presence of abnormal levels of porphyrins, antinuclear factor or lupus erythematosus autoantibodies; and the consumption of more than five cigarettes per day. Written informed consent was obtained from all subjects before enrolment, and the study design was approved by an
independent Ethics Committee before initiation. The Ethics Committee required the study to be conducted in males.
Study design This open, observer-blinded, placebo-controlled, randomized, parallel-group study was designed to investigate the photosensitizing potential of trovafloxacin and to compare any detected effects of treatment with those seen in ciprofloxacin- and lomefloxacin-treated subjects. In the 4 weeks preceding the study, subjects underwent a complete physical examination to ensure that all inclusion criteria were satisfied. This comprised a 12-lead resting electrocardiogram (ECG), measurement of vital signs, a full medical history, and blood and urine clinical laboratory analyses. Baseline minimal erythema dose (MED) measurements were also conducted. After enrolment, subjects were randomly allocated to one of four treatment regimens; the active treatment regimens reflected those used routinely in clinical practice or clinical trials: (i) trovafloxacin 200 mg once daily (a.m.) placebo once daily (p.m.); (ii) ciprofloxacin 500 mg twice daily (a.m. and p.m.); (iii) lomefloxacin 400 mg once daily (a.m.) placebo once daily (p.m.); (iv) placebo twice daily (a.m. and p.m.). Drugs were supplied by Pfizer Inc., New York, USA (trovafloxacin), Bayer plc, Newbury, UK (ciprofloxacin) and Searle Pharmaceuticals, High Wycombe, UK (lomefloxacin). There were 12 subjects in each treatment group. Treatment was administered at 08:00–09:00 h (a.m. dose) and 20:00–21:00 h (p.m. dose), at intervals of exactly 12 h, and was continued for six complete days; the morning dose on day 7 was also given. All doses were taken orally with 240 ml water, and subjects
Table I. Characteristics of subjects enrolled in the study Treatment group trovafloxacin 200 mg od Number of subjects Age (years) mean range Weight (kg) mean range Skin type I II III Number of subjects completing study
ciprofloxacin 500 mg bd
lomefloxacin 400 mg od
Placebo
12
12
14
12
27.7 20–38
29.2 19–45
30.0 19–38
30.4 19–42
75.4 64.3–91.0
69.2 56.7–85.8
70.5 58.9–92.8
77.3 54.5–99.7
0 1 11
1 4 7
0 0 12
0 1 11
12
12
12
12
504
Photosensitizing potential of quinolones were not permitted to lie down or eat for at least 1 h after drug intake. Furthermore, subjects were instructed to refrain from strenuous physical activity or exercise, and the consumption of methylxanthines, caffeine and alcohol from 48 h before the initial dose until the end of the study was not permitted. The ingestion of foods containing high concentrations of psoralens, such as carrots, celery, citrus fruit and parsnips, and the use of perfumed toiletries was also discouraged. Sunscreen (Sun E45, Boots, Nottingham, UK) was available to the subjects throughout the study. The subjects were resident in a purpose-built clinical pharmacology unit in which all windows had UV screening. A physical examination was conducted and vital signs were measured at discharge (day 7). In addition to these assessments, an ECG and clinical blood and urine tests were conducted at a follow-up visit on day 21. Subjects were confined to the clinical unit and were under medical supervision from the day before dosing (day 0) until MED evaluation on day 7 (or day 9, if found to have an abnormal MED response on day 7).
9 and 11. Although these subjects were permitted to leave the clinical unit after MED evaluation on day 11, at the discretion of the investigator, they were instructed to avoid subsequent exposure to sunlight.
Pharmacokinetic sampling Blood samples (7 ml) were drawn from all subjects in the trovafloxacin treatment group on day 5 immediately before dosing and at 90 min post-dose to confirm compliance with dosing. The blood was allowed to clot for 45 min at room temperature, and serum was extracted by centrifugation (1500g, 10 min, 4ºC) within 60 min of blood collection. Serum was then stored at –20ºC. Serum concentrations of trovafloxacin were determined, for correlation with MEDs, by a validated HPLC method using UV detection at 275 nm.22 The dynamic range of this assay was 0.1–16.0 mg/L.
Safety Photosensitivity testing 19–21
Controlled monochromator phototesting, designed to reveal the clinical characteristics, wavelength dependence and severity of cutaneous reactions, was conducted at specified times. Baseline measurements of MED were assessed on each subject over 3 days during the 2 weeks before study initiation. A standard diffraction grating monochromator with a 1.6 kW xenon arc source was used for this purpose. The MED is defined as the minimum dose of irradiation (mJ/cm2) that produced perceptible erythema. It consists of two components: immediate and delayed reactions, which occur 5–30 min and 24–48 h, respectively, after irradiation. On the first screening day, a preliminary and approximate MED was evaluated by applying a series of graded, large-step skin exposures. A more precise MED for each subject was determined on the subsequent screening days using small-step exposures that ranged between the preliminary MED and the no-response dose. Baseline tests were performed on the right mid– upper back and were mapped to prevent repeat testing of any given area. The MEDs were determined for wavelengths in the UVB (305 5 nm), UVA (335 30 and 365 30 nm) and visible light (400 30 and 430 30 nm) ranges. Photosensitivity testing was performed on study days 5–7, on the left mid–upper back. Using an unexposed skin site as a control, irradiated sites were examined for the presence of erythema immediately before irradiation, 5–30 min post-irradiation (to detect an immediate reaction), and 24 and 48 h after irradiation (to detect a delayed reaction). Any subject with an MED reduction of 40% was discharged from the clinical unit on day 7. If the decrease in MED was 40% during study drug administration, photosensitivity measurements were repeated on days
The following clinical laboratory tests were conducted during the 4 week baseline period, before dosing on day 1 and at follow-up (day 21): urinalysis, routine blood chemistry and haematology. In addition, vital signs were recorded at baseline, and on days 1, 7 and 21, and a 12-lead ECG was obtained at baseline and at follow-up. Median changes between baseline and the last on-treatment observation (day 7) were calculated for each laboratory parameter according to treatment group. The severity, duration and causal association with study drug of all adverse events observed by the investigator or reported spontaneously by the subject were recorded. Serious adverse events occurring within 30 days, and all other adverse events occurring within 7 days of the last dose, were recorded.
Statistical analysis A sample size of 48 subjects (12 per treatment group) was estimated to allow detection of a change from baseline values of approximately 40% in MED at a wavelength of 335 nm, or 30% at 365 nm, with a probability of 80% at the 5% significance level. For each subject, the ratios of the MED at day 5:baseline were calculated for each wavelength and log-transformed for the immediate and the delayed reaction. Mean differences in ratios between treatment groups were analysed using analysis of variance. Pairwise comparisons were performed to test differences between placebo and active treatments. In addition, contrasts were estimated to test for differences between the trovafloxacin treatment group and the ciprofloxacin and lomefloxacin treatment groups. The geometric mean (G) of the day 5:baseline MED ratios was calculated for each treatment group and was converted to percentage change using the formula 100 (1 – G).
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J. Ferguson et al.
Results Study population A total of 50 healthy, white males, age range 19–45 years, were recruited into the study. However, two subjects (both of whom were in the lomefloxacin treatment group) withdrew consent after 1 day of treatment. There were no significant differences between subjects in the trovafloxacin, ciprofloxacin, lomefloxacin and placebo treatment groups with respect to age and weight (Table I). None of the subjects had a pre-existing condition expected to influence study outcome, and the majority had skin type III (n 11, 7, 12 and 11 in the trovafloxacin, ciprofloxacin, lomefloxacin and placebo groups, respectively). All 50 subjects were evaluable for safety, and the photosensitivity analyses were performed on data from the 48 subjects who completed the study. Serum concentrations of trovafloxacin confirmed its absorption following oral administration.
A comparison of delayed-reaction MED ratios at both 335 30 nm and 365 30 nm indicated that trovafloxacin has significantly less photosensitizing potential than ciprofloxacin (P 0.0012 and P 0.029, respectively) and lomefloxacin (P 0.0001 and P 0.0001, respectively) at these wavelengths. The delayed-reaction MEDs for 365 30 nm at baseline and day 5 for each individual in the four treatment groups are shown in Figure 1, and the 95% confidence intervals around the mean percentage decreases in delayedreaction MED at 335 30 nm and 365 30 nm are presented in Figure 2. Some individuals experienced a decrease of 40% in delayed-reaction MED at 335 30 nm or 365 30 nm between baseline and day 5, and therefore required further photosensitivity testing. However, in the majority of these subjects, MED values normalized by day 9, 2 days after the administration of the final dose. Serum trovafloxacin concentrations were consistent with previous data, and broadly representative of concentrations observed in the healthy volunteer population.16
Photosensitivity Photosensitivity was manifested as mild erythema (maximal at 24 h) in those subjects who experienced a reaction. No abnormal immediate reactions were observed. The geometric means of the percentage decrease in delayed reaction MED between baseline and day 5 are shown in Table II. At 335 30 nm, the mean reductions in delayedreaction MED for the ciprofloxacin and lomefloxacin treatment groups were 54% and 64%, respectively; and at 365 30 nm, the corresponding mean percentage decreases in delayed-reaction MED were 62 and 76%, respectively. These changes were all statistically significantly compared with those observed in the placebo group (P 0.0001 for all four comparisons). In contrast, the mean percentage reduction in delayed-reaction MED between baseline and day 5 for trovafloxacin was not significantly different from placebo at 335 30 nm (19%; P 0.126), but only at 365 30 nm (44%; P 0.0046).
Safety assessments A total of 39 adverse events were reported in the study, 8–12 per treatment group. All were of mild to moderate intensity and did not result in study discontinuation by any subject. Five adverse events were considered to be treatment related. These occurred in two subjects receiving trovafloxacin (two cases of headache, one of dizziness and one of impaired concentration) and in one subject receiving ciprofloxacin (one case of fatigue). The non-treatmentrelated adverse events reported most frequently were headache (in the trovafloxacin and lomefloxacin treatment groups) and toothache (in the placebo group). No serious adverse events occurred during the study. However, 14 days after study completion, one subject in the ciprofloxacin treatment group sustained a severe fracture of the right talus during a fight. This fracture was not judged to be treatment related by the investigator.
Table II. Geometric means of the percentage change in delayed-reaction minimal erythema dose (MED) between baseline and day 5 Trovafloxacin 200 mg od
Ciprofloxacin 500 mg bd
Lomefloxacin 400 mg od
Wavelength (nm)
change (%)a
P valueb
change (%)a
P valueb
change (%)a
P valueb
Placebo change (%)a
305 5 335 30 365 30 400 30 430 30
–2.32 18.99 43.66 2.85 –2.93
0.8288 0.1267 0.0046 0.8724 1.0000
3.13 53.77 61.53 15.08 5.61
0.4905 0.0001 0.0001 0.2243 0.0597
7.93 64.13 75.81 17.53 2.85
0.2606 0.0001 0.0001 0.1319 0.2043
–4.90 –4.24 6.65 4.35 –2.93
a
A negative value indicates an increase in MED compared with baseline. P value compared with placebo using an ANOVA with contrasts on the log-transformed data.
b
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Photosensitizing potential of quinolones
Figure 1. Delayed reaction minimal erythema dose (MED) values for 365 30 nm at baseline and after 5 days of treatment with trovafloxacin, ciprofloxacin, lomefloxacin or placebo.
Figure 2. Percentage change between baseline and treatment day 5 in delayed-reaction minimal erythema dose (MED) at 335 30 nm and 365 30 nm with 95% confidence intervals.
No clinically significant changes from baseline were observed during the study in vital signs or in clinical laboratory parameters.
Discussion Cutaneous photosensitivity reactions are an uncommon, but consistent feature of treatment with quinolones. The photosensitivity of this class of antimicrobial drugs, how-
ever, varies according to the individual agent. For example, severe photosensitivity reactions have been observed in studies with pefloxacin,23 fleroxacin24 and lomefloxacin,25 whereas ciprofloxacin and norfloxacin26 have been associated with mild photosensitizing effects.27 Wagai et al.27 compared the relative photosensitizing potential of quinolones in mice by administering a single oral dose followed by irradiation for 4 h. They established that, of the six quinolones tested, lomefloxacin had the greatest photosensitizing potential and ciprofloxacin the least. In the current study, the photosensitizing potential of a new quinolone, trovafloxacin, was investigated and was compared with that of ciprofloxacin (positive control), lomefloxacin (positive control) and placebo (negative control) using a validated monochromator test technique. At baseline and after 5 days of treatment, phototesting was conducted at wavelengths within the UVA, UVB and visible regions of the solar spectrum. Drug photosensitization was apparent only in some subjects and only at wavelengths tested within the UVA waveband (335 30 nm and 365 30 nm); i.e. photosensitivity was UVA dependent. In all cases, photosensitization resulted in asymptomatic erythema, which was maximal at 24 h after irradiation; no abnormal immediate erythema or urticarial reactions were seen. Furthermore, the photosensitizing potential of each of the quinolones tested was short lived, resolving within 2 days of drug cessation. Ciprofloxacin and lomefloxacin demonstrated statistically significant photosensitivity, compared with placebo at both 335 30 nm and 365 30 nm (P 0.0001); a statistically significant difference between trovafloxacin and placebo was observed only at 365 30 nm (P 0.0046).
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J. Ferguson et al. Trovafloxacin was also shown to possess significantly less photosensitizing potential than either ciprofloxacin or lomefloxacin at 335 30 nm and 365 30 nm (P 0.029), a finding consistent with a previous animal study.27 The subjects in the trovafloxacin, lomefloxacin and placebo groups, with the exception of one placebo subject and one in the trovafloxacin group, were exclusively classed as skin type III. By contrast, within the ciprofloxacin group, subjects with skin types I and II were included, and hence would burn more easily. The assessment of skin type, however, is subjective rather than quantitative, with considerable overlap between types I and II, and types II and III. The difference in the distribution of skin types between the trovafloxacin and ciprofloxacin study groups is minimized, as MEDs were determined at baseline and after quinolone administration, and by expressing the results as a ratio, a within-subject control was introduced. Model systems have demonstrated that photosensitivity is dependent on drug concentration. In addition, dosedependent cutaneous photosensitivity may occur following the oral administration of potent photosensitizing agents, such as 8-methoxypsoralen. Any variations in the potential of different quinolones to cause photosensitivity is important, as it may influence the choice of agent in patients in whom effective broadspectrum quinolone therapy is indicated, but who may be particularly susceptible to photosensitization by being exposed to high levels of UVA irradiation (e.g. outdoor workers, sports enthusiasts or sunbed users). Data from the current study suggest that the photosensitizing effects of trovafloxacin, at commonly used therapeutic doses, are unlikely to be clinically significant. Nevertheless, patients should be advised that abnormal cutaneous reactions may occur on exposure to UVA radiation, and appropriate precautions, such as the use of a broad-spectrum sunscreen and avoidance of sunbed exposure, should be encouraged.
6. Fromtling, R. A. & Castañer, J. (1996). Trovafloxacin mesylate. Drugs of the Future 21, 496–505. 7. Jones, R. N. (1995). In vitro antimicrobial activity of CP-99,219, a new 7-azabicyclonaphthyridone. Drugs 49, Suppl. 2, 205–7. 8. Bowker, K. E., Wootton, M., Holt, H. A., Reeves, D. S. & MacGowan, A. P. (1996). The in-vitro activity of trovafloxacin and nine other antimicrobials against 413 anaerobic bacteria. Journal of Antimicrobial Chemotherapy 38, 271–81. 9. Gooding, B. B. & Jones, R. N. (1993). In vitro antimicrobial activity of CP-99,219, a novel azabicyclo-naphthyridone. Antimicrobial Agents and Chemotherapy 37, 349–53. 10. Snydman, D. R. & McDermott, L. (1996). Analysis of the in vitro activity of trovafloxacin (CP-99,219) against Bacteroides species. Infectious Diseases in Clinical Practice 5, Suppl. 3, 96–100. 11. Spangler, S. K., Jacobs, M. R. & Appelbaum, P. C. (1994). Activity of CP-99,219 compared with those of ciprofloxacin, grepafloxacin, metronidazole, cefoxitin, piperacillin and piperacillin/ tazobactam against 489 anaerobes. Antimicrobial Agents and Chemotherapy 38, 2471–6. 12. Child, J., Andrews, J., Boswell, F., Brenwald, N. & Wise, R. (1995). The in-vitro activity of CP-99,219, a new naphthyridone antimicrobial agent: a comparison with fluoroquinolone agents. Journal of Antimicrobial Chemotherapy 35, 869–76. 13. Edelstein, P. H., Edelstein, M. A., Ren, J., Polzer, R. & Gladue, R. P. (1996). Activity of trovafloxacin (CP-99,219) against Legionella isolates: in vitro activity, intracellular accumulation and killing in macrophages, and pharmacokinetics and treatment of guinea pigs with L. pneumophila pneumonia. Antimicrobial Agents and Chemotherapy 40, 314–9. 14. Kenny, G. E. & Cartwright, F. D. (1996). Susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum to a new quinolone, trovafloxacin (CP-99,219). Antimicrobial Agents and Chemotherapy 40, 1048–9. 15. Thomson, K. S., Moland, E. S. & Sanders, C. C. (1999). Activity of trovafloxacin against antibiotic resistant bacterial pathogens. Infectious Diseases in Clinical Practice 8, Suppl. 1, 5–16.
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Received 2 June 1999; returned 31 August 1999; revised 14 October 1999; accepted 13 December 1999
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