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Concentration of orally administered antimicrobial agent in burn scar tissue, granulation tissue, normal skin and serum
Bums (1993) 19, (6), 529-530
Printed in Great Britain
529
Concentration of orally administered antimicrobial agent in burn scar tissue, granulation tissue, normal skin and serum Y. Sawadal, T. Ohkuboz, M. Kudo2 and K. SugawaraZ ‘Department of Plastic and Reconstructive Medicine, Hirosaki, Japan
Surgery, and 2Department
Tissue and serum concentration5of orally administered oflomcin were measured using high pe+rmance liquid chromatography. From 56 pafienfs who recekd 200 mg ofofloxacinprior to surgey, 103 specimens including 48 of serum, 32 of scar fissue, 18 of normal skin and five of granulation tissue were harvested between 2 and .?h after adminisfrafion. The ofloxacin values were 1798.6 f 1125.5 rig/g in fhegranulation tissue followed by 1525.5 f 1002.7nglml in the serum, 1450.0f 1011.3 nglg in the scar fissue and 1092.8f 593.3 rig/g in normal skin. There was no sfafisficdly signijicanf diflerence between the ofixacin concenfrafions in those four specimens by ANOVA test.
Introduction Although there have been many reports concerning the concentration of orally administered antimicrobial agents in various tissues, we could find few reports on drug concentrations in scar tissue. However, recurrent abscess formation sometimes occurs on the dense scar after bum injury. We therefore studied the concentration of orally administered ofloxacin in scar tissue, granulation tissue, normal skin and serum.
Materials and methods Fifty-six patients who underwent surgery in our hospital were entered into this study. They included 29 males and 27 females, with ages that ranged from 13 to 75 years (average 37.5 f 16.6 years). These patients had scars from bums of various sizes and after varying periods following injury. The period after injury was from I to 70 months (average 17.7f 15.6 months). Four of the 56 patients were studied within I month after injury. A dose of 200 mg of ofloxacin was administered to each patient before surgery, and a normal skin specimen was harvested from those patients who needed full thickness skin grafts. Samples of both scar tissue and granulation tissue were also obtained at this time. Immediately after the tissue specimens were excised, they were wiped gently with dry absorbent gauze. They were then weighed and stored at - 85°C until assayed for their content of ofloxacin. For the blood specimens, the samples were centrifuged at 3000 r.p.m. for 5 min, and the separated serum was stored at - 85°C until evaluation. 0 1993 Butterworth-Heinemann 0305-4179/93/060529-02
Ltd
of Pharmacy, Hirosaki University
School of
Estimations of ofloxacin levels were carried out using the technique described by Sugawara et al. (1992). After homogenizing and filtration of the tissue samples to remove proteins, the filtrate was concentrated on a pre-column using a phenyl-stationary phase and introduced to an analytical column by means of a column-switching technique. Ofloxatin was detected by ultraviolet ray absorbance at 3000 M-I. By using this method, determination of ofloxacin is possible in the range of 25&3000 rig/g.. The limit of detection was 100 rig/g.. The absolute recovery of ofloxacin added to skin tissue homogenate was over 72 per cent, with a coefficient of variation of less than 4.1 per cent (Sugawara et al., 1992).
Results From these 56 patients, 103 specimens consisting of 48 sera, 32 scar tissue, 18 normal skin and five granulation tissue were obtained between 2 and 3 h after administration (mean 2.3 h). Furthermore, from five patients, serum, scar tissue, granulation tissue and normal skin specimens were obtained simultaneously during surgery. The observed levels of ofloxacin detected in this study are shown in Figures 1 and 2. The highest ofloxacin value was found in the granulation tissue, followed in descending order by serum, scar tissue and normal skin. There was no statistically significant difference among the ofloxacin concentrations of all four specimens using the ANOVA test. Although the drug concentrations in the five sets of specimens harvested simultaneously after drug administration also showed the highest levels in granulation tissue, followed in descending order by scar tissue, serum and normal skin samples, there was no statistically significant difference among those four specimens.
Discussion Ofloxacin is said to have a broad spectrum of antibacterial activity against both Gram-negative and Gram-positive bacteria (Monk and Campoli-Richards, 1984). Tomizawa et al. (1984) reported that among 16 patients, the skin and serum concentrations at about 2 h after oral administration of 200mg of ofloxacin were from 1.15 to 6.10 pg/g in the former and from 1.59 to 4.20l.rg/ml in the latter. The
530
Sawada et al.: Concentration of orally administered ofloxacin
3000
3000
2500
2500
I
=_ E 2000 P $ g1500 c
Z?
E 2000 F 6 9 1500 P x
1
0
0 500
500
= 10000 I
i Normal skin
I
I
Scar tissue
G;anulation tissue
Serum
2 10000 :
1
I
Normal skin
Specimens
Scar tissue
Granulation tissue
Serum
Specimens
Figure 1. Ofloxacin concentration in serum and tissue specimens between 2 and 3 h after oral administration among 56 patients.
Figure 2. In five of the 56 patients, tissue and serum samples were harvested simultaneously. This figure shows the ofloxacin values among these five patients.
minimum inhibition concentration was from 0.39 to 1.56 pg/ml against clinically isolated Stuphylococnrs aureus and from 0.78 to 1.56 pg/d against Psardomonas uemginma (Tomizawa et al., 1984). It has been shown that ofloxacin reaches its highest concentration in serum approximately 2-3 h after administration (Tomizawa et al., 1984; Monk and Campoli-Richards, 1987). The elimination half-life of ofloxatin after doses of more than 200mg has generally been reported to be about 6 h or longer when the resultant tissue concentrations were at least as high as the serum concentration for most tissues (Monk and Campoli-Richards, 1987). The results of our present study, with regard to the levels in serum and normal skin are quite similar to those reported by Tomizawa et al. (1984) and Monk and Campoli-Richards, (1987). Rather higher ofloxacin values, however, were detected in the scar and granulation tissues compared with normal skin. In the field of plastic surgery, surface infection is frequently caused by S. aureus or other Gram-positive bacteria. Ofloxacin appears to be a more potent inhibitor against both such Gram-positive organisms and against Gram-negative organisms (Monk and Campoli-Richards, 1987). In the patients with scars resulting from bums, infection will sometimes develop in the scar tissue, initially occurring at the deeply seated follicles beneath a dense scar. Such an infection is one of the causes of the growth of hypertrophic scar in some instances. Treatment of such a patient is carried out on an outpatient basis, and routine administration of an antimicrobial agent is sometimes necessary. Our present study showed that orally administered ofloxacin would appear to be effective in both
preventing and treating such infections. Our present study also suggested that oral administration of ofloxacin seems to be effective for treating an infected granulation wound.
Acknowledgements The authors wish to thank Dr Koichi Ohtani for his helpful advice during the preparation of this manuscript.
References Monk J. P. and Campoli-Richards D. M. (1987) Ofloxacin, a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drup 33,347. Sugawara K., Okubo T., Kudo M. et al. (1992) Correlation between skin tissue levels and serum levels of ofloxacin administered in patients with scars. Jup. J. Phmmacol. 58, 159. Tomizawa T., Yamaguchi J. and Kinoshita M. (1984) Laboratory and clinical studies on DL-8280 in the treatment of bacterial skin infection. Chemotherapy 32, 980 (in Japanese). Paper accepted 10 June 1993.
Correspondenceshould be addressedto: Dr Yukimasa Sawada, Department of Plastic and Reconstructive Surgery, Hirosaki University School of Medicine, 53 Hon-cho, Hirosaki City, Aomori Prefecture 036, Japan.
Printed in Great Britain
529
Concentration of orally administered antimicrobial agent in burn scar tissue, granulation tissue, normal skin and serum Y. Sawadal, T. Ohkuboz, M. Kudo2 and K. SugawaraZ ‘Department of Plastic and Reconstructive Medicine, Hirosaki, Japan
Surgery, and 2Department
Tissue and serum concentration5of orally administered oflomcin were measured using high pe+rmance liquid chromatography. From 56 pafienfs who recekd 200 mg ofofloxacinprior to surgey, 103 specimens including 48 of serum, 32 of scar fissue, 18 of normal skin and five of granulation tissue were harvested between 2 and .?h after adminisfrafion. The ofloxacin values were 1798.6 f 1125.5 rig/g in fhegranulation tissue followed by 1525.5 f 1002.7nglml in the serum, 1450.0f 1011.3 nglg in the scar fissue and 1092.8f 593.3 rig/g in normal skin. There was no sfafisficdly signijicanf diflerence between the ofixacin concenfrafions in those four specimens by ANOVA test.
Introduction Although there have been many reports concerning the concentration of orally administered antimicrobial agents in various tissues, we could find few reports on drug concentrations in scar tissue. However, recurrent abscess formation sometimes occurs on the dense scar after bum injury. We therefore studied the concentration of orally administered ofloxacin in scar tissue, granulation tissue, normal skin and serum.
Materials and methods Fifty-six patients who underwent surgery in our hospital were entered into this study. They included 29 males and 27 females, with ages that ranged from 13 to 75 years (average 37.5 f 16.6 years). These patients had scars from bums of various sizes and after varying periods following injury. The period after injury was from I to 70 months (average 17.7f 15.6 months). Four of the 56 patients were studied within I month after injury. A dose of 200 mg of ofloxacin was administered to each patient before surgery, and a normal skin specimen was harvested from those patients who needed full thickness skin grafts. Samples of both scar tissue and granulation tissue were also obtained at this time. Immediately after the tissue specimens were excised, they were wiped gently with dry absorbent gauze. They were then weighed and stored at - 85°C until assayed for their content of ofloxacin. For the blood specimens, the samples were centrifuged at 3000 r.p.m. for 5 min, and the separated serum was stored at - 85°C until evaluation. 0 1993 Butterworth-Heinemann 0305-4179/93/060529-02
Ltd
of Pharmacy, Hirosaki University
School of
Estimations of ofloxacin levels were carried out using the technique described by Sugawara et al. (1992). After homogenizing and filtration of the tissue samples to remove proteins, the filtrate was concentrated on a pre-column using a phenyl-stationary phase and introduced to an analytical column by means of a column-switching technique. Ofloxatin was detected by ultraviolet ray absorbance at 3000 M-I. By using this method, determination of ofloxacin is possible in the range of 25&3000 rig/g.. The limit of detection was 100 rig/g.. The absolute recovery of ofloxacin added to skin tissue homogenate was over 72 per cent, with a coefficient of variation of less than 4.1 per cent (Sugawara et al., 1992).
Results From these 56 patients, 103 specimens consisting of 48 sera, 32 scar tissue, 18 normal skin and five granulation tissue were obtained between 2 and 3 h after administration (mean 2.3 h). Furthermore, from five patients, serum, scar tissue, granulation tissue and normal skin specimens were obtained simultaneously during surgery. The observed levels of ofloxacin detected in this study are shown in Figures 1 and 2. The highest ofloxacin value was found in the granulation tissue, followed in descending order by serum, scar tissue and normal skin. There was no statistically significant difference among the ofloxacin concentrations of all four specimens using the ANOVA test. Although the drug concentrations in the five sets of specimens harvested simultaneously after drug administration also showed the highest levels in granulation tissue, followed in descending order by scar tissue, serum and normal skin samples, there was no statistically significant difference among those four specimens.
Discussion Ofloxacin is said to have a broad spectrum of antibacterial activity against both Gram-negative and Gram-positive bacteria (Monk and Campoli-Richards, 1984). Tomizawa et al. (1984) reported that among 16 patients, the skin and serum concentrations at about 2 h after oral administration of 200mg of ofloxacin were from 1.15 to 6.10 pg/g in the former and from 1.59 to 4.20l.rg/ml in the latter. The
530
Sawada et al.: Concentration of orally administered ofloxacin
3000
3000
2500
2500
I
=_ E 2000 P $ g1500 c
Z?
E 2000 F 6 9 1500 P x
1
0
0 500
500
= 10000 I
i Normal skin
I
I
Scar tissue
G;anulation tissue
Serum
2 10000 :
1
I
Normal skin
Specimens
Scar tissue
Granulation tissue
Serum
Specimens
Figure 1. Ofloxacin concentration in serum and tissue specimens between 2 and 3 h after oral administration among 56 patients.
Figure 2. In five of the 56 patients, tissue and serum samples were harvested simultaneously. This figure shows the ofloxacin values among these five patients.
minimum inhibition concentration was from 0.39 to 1.56 pg/ml against clinically isolated Stuphylococnrs aureus and from 0.78 to 1.56 pg/d against Psardomonas uemginma (Tomizawa et al., 1984). It has been shown that ofloxacin reaches its highest concentration in serum approximately 2-3 h after administration (Tomizawa et al., 1984; Monk and Campoli-Richards, 1987). The elimination half-life of ofloxatin after doses of more than 200mg has generally been reported to be about 6 h or longer when the resultant tissue concentrations were at least as high as the serum concentration for most tissues (Monk and Campoli-Richards, 1987). The results of our present study, with regard to the levels in serum and normal skin are quite similar to those reported by Tomizawa et al. (1984) and Monk and Campoli-Richards, (1987). Rather higher ofloxacin values, however, were detected in the scar and granulation tissues compared with normal skin. In the field of plastic surgery, surface infection is frequently caused by S. aureus or other Gram-positive bacteria. Ofloxacin appears to be a more potent inhibitor against both such Gram-positive organisms and against Gram-negative organisms (Monk and Campoli-Richards, 1987). In the patients with scars resulting from bums, infection will sometimes develop in the scar tissue, initially occurring at the deeply seated follicles beneath a dense scar. Such an infection is one of the causes of the growth of hypertrophic scar in some instances. Treatment of such a patient is carried out on an outpatient basis, and routine administration of an antimicrobial agent is sometimes necessary. Our present study showed that orally administered ofloxacin would appear to be effective in both
preventing and treating such infections. Our present study also suggested that oral administration of ofloxacin seems to be effective for treating an infected granulation wound.
Acknowledgements The authors wish to thank Dr Koichi Ohtani for his helpful advice during the preparation of this manuscript.
References Monk J. P. and Campoli-Richards D. M. (1987) Ofloxacin, a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drup 33,347. Sugawara K., Okubo T., Kudo M. et al. (1992) Correlation between skin tissue levels and serum levels of ofloxacin administered in patients with scars. Jup. J. Phmmacol. 58, 159. Tomizawa T., Yamaguchi J. and Kinoshita M. (1984) Laboratory and clinical studies on DL-8280 in the treatment of bacterial skin infection. Chemotherapy 32, 980 (in Japanese). Paper accepted 10 June 1993.
Correspondenceshould be addressedto: Dr Yukimasa Sawada, Department of Plastic and Reconstructive Surgery, Hirosaki University School of Medicine, 53 Hon-cho, Hirosaki City, Aomori Prefecture 036, Japan.