국내 환자에서 분리된 Orientia tsutsugamushi에서 doxycycline 내성

김은실,김미경,이혜명,길세희,정문현,이진수,강재승 대한감염학회 2008 Infection and Chemotherapy Vol.40 No.5

Background : Doxycycline has been the drug of choice for the treatment of scrub typhus. However, scrub typhus with poor response to doxycycline was first reported in Thailand in 1996. To date, it is not known whether doxycycline resistant scrub typhus is present in Korea. To investigate the doxycycline resistance of scrub typhus in Korea, we performed an experiment to evaluate the degree of growth inhibition of Orientia tsutsugamushi at the minimal inhibitory concentration (MIC) of doxycycline. Materials and Methods : 37 isolates of Orientia tsutsugamushi were collected from Korean patients with scrub typhus during 10 year period (from 1997 to 2007). 34 isolates consisted of Boryong serotype or related serotypes. These strains were stained with FS15, a monoclonal antibody against the linear epitope on the protein located at the outer membrane of O. tsutsugamushi. Three isolates were confirmed as serotype Gilliam, which was stained by anti-Gilliam antibody. The antibody- stainable 35 isolates were incubated in media containing 0.1 and 0.2 µg/mL of doxycycline for 3 days. Then the growth indices of Orientia were measured by flow cytometry. If the growth index was greater than 10%, the isolate was tentatively classified as an isolate resistant to doxycycline and its MIC was measured. Results : Demographic and treatment data were similar to the results of previous reports. Infection was mainly observed in Inchon and the Chungcheongnam province. No patient showed delayed response to antibiotics. Of 35 hospitalized patients, 4 (11.4%) were managed at the intensive care unit, and 1 (2.9%) died of nosocomial pneumonia. All the 2 patients whose isolates were serotype Gilliam Yonchon/Ikeda-like strain were managed at the intensive care unit. Six of the 34 isolates from Korean patients exhibited growth indices greater than 10% at the MIC of doxycycline; however, the MICs of these isolates did not exceed 0.2 µg/mL. One isolate of serotype Gilliam showed an MIC of 0.0125 ug/mL, which seemed to be underestimated due to weak fluorescence of the anti-Gilliam antibody. Conclusions : Although the number of tested isolates is small, insensitivity of scrub typhus to doxycycline is not a major reason for treatment failure in Korea. Serotype Gilliam, especially Yochon/ Ikeda-like strain, may be associated with severe form of scrub typhus. More studies concerning the antibiotic susceptibility for serotype Gilliam are warranted. Background : Doxycycline has been the drug of choice for the treatment of scrub typhus. However, scrub typhus with poor response to doxycycline was first reported in Thailand in 1996. To date, it is not known whether doxycycline resistant scrub typhus is present in Korea. To investigate the doxycycline resistance of scrub typhus in Korea, we performed an experiment to evaluate the degree of growth inhibition of Orientia tsutsugamushi at the minimal inhibitory concentration (MIC) of doxycycline. Materials and Methods : 37 isolates of Orientia tsutsugamushi were collected from Korean patients with scrub typhus during 10 year period (from 1997 to 2007). 34 isolates consisted of Boryong serotype or related serotypes. These strains were stained with FS15, a monoclonal antibody against the linear epitope on the protein located at the outer membrane of O. tsutsugamushi. Three isolates were confirmed as serotype Gilliam, which was stained by anti-Gilliam antibody. The antibody- stainable 35 isolates were incubated in media containing 0.1 and 0.2 µg/mL of doxycycline for 3 days. Then the growth indices of Orientia were measured by flow cytometry. If the growth index was greater than 10%, the isolate was tentatively classified as an isolate resistant to doxycycline and its MIC was measured. Results : Demographic and treatment data were similar to the results of previous reports. Infection was mainly observed in Inchon and the Chungcheongnam province. No patient showed delayed response to antibiotics. Of 35 hospitalized patients, 4 (11.4%) were managed at the intensive care unit, and 1 (2.9%) died of nosocomial pneumonia. All the 2 patients whose isolates were serotype Gilliam Yonchon/Ikeda-like strain were managed at the intensive care unit. Six of the 34 isolates from Korean patients exhibited growth indices greater than 10% at the MIC of doxycycline; however, the MICs of these isolates did not exceed 0.2 µg/mL. One isolate of serotype Gilliam showed an MIC of 0.0125 ug/mL, which seemed to be underestimated due to weak fluorescence of the anti-Gilliam antibody. Conclusions : Although the number of tested isolates is small, insensitivity of scrub typhus to doxycycline is not a major reason for treatment failure in Korea. Serotype Gilliam, especially Yochon/ Ikeda-like strain, may be associated with severe form of scrub typhus. More studies concerning the antibiotic susceptibility for serotype Gilliam are warranted.

Orientia tsutsugamushi에 대한 항균제 병용의 실험실 효과

김은실,김미경,이혜명,정문현,이진수,강재승 대한감염학회 2008 Infection and Chemotherapy Vol.40 No.6

Background : Occasionally, combinations of antibiotics are used for the treatment of scrub typhus. However, the effectiveness of such combined therapies has rarely been evaluated. To date, no experimental studies have been performed; only 1 clinical study has assessed the efficacy of combined doxycycline and rifampin therapy. To elucidate the efficacies of other antibiotic combinations, we performed an experiment to evaluate the in vitro efficacy of antibiotic combinations against Orientia tsutsugamushi. Materials and Methods : O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were cultured in antibiotic-containing media for 3-5 days and stained with FS15, a monoclonal antibody reacting against the linear epitope on the 56-kDa major outer membrane protein of O. tsutsugamushi. Thereafter, antimicrobial susceptibility was measured by flow cytometry and expressed as a growth index (total mass of Orientia). The growth indices of doxycycline (0.1 µg/ mL), azithromycin (0.1 µg/mL), rifampin (0.0125 µg/mL), cefotaxime (2 and 20 µg/mL), and their various combinations (doxycycline+cefotaxime, doxycycline+rifampin, azithromycin+cefotaxime, and rifampin+cefotaxime) were measured. The above mentioned antibiotic concentrations, except for that of cefotaxime, represent the minimal inhibitory concentrations of each antibiotic. Results : The growth indices of doxycycline (4.67% and 0.52%), rifampin (2.35% and 0.26%), and azithromycin (7.54%) were within the range of full suppression of O. tsutsugamushi; in contrast, cefotaxime (87.60%) was in effective. The growth indices of doxycycline + rifampin were 0.10% and 0.10%, which were similar to those obtained with doxycycline or rifampin alone. The growth indices of doxycycline+cefotaxime were 3.99% and 3.65% in low-dose cefotaxime (2 µg/mL), and 3.69% and 4.40% in high-dose cefotaxime (20 µg/mL). The growth indices of rifampin + cefotaxime (2.19% and 2.19% at 2 µg/mL; 1.84% and 2.04% at 20 µg/mL cefotaxime) were similar to those obtained with rifampin alone (2.35% and 0.26%). Azithromycin+cefotaxime (11.06-14.63%) showed higher growth indices than azithromycin alone; this suggests that this combination may be antagonistic. Conclusions : The anti-Orientia efficacies of doxycycline+rifampin, doxycycline+cefotaxime, and rifampin+cefotaxime were not antagonistic. The efficacy of the azithromycin+cefotaxime combination needs to be confirmed by more sensitive methods to exclude the possibility of antagonistic interactions between the antibiotics. Background : Occasionally, combinations of antibiotics are used for the treatment of scrub typhus. However, the effectiveness of such combined therapies has rarely been evaluated. To date, no experimental studies have been performed; only 1 clinical study has assessed the efficacy of combined doxycycline and rifampin therapy. To elucidate the efficacies of other antibiotic combinations, we performed an experiment to evaluate the in vitro efficacy of antibiotic combinations against Orientia tsutsugamushi. Materials and Methods : O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were cultured in antibiotic-containing media for 3-5 days and stained with FS15, a monoclonal antibody reacting against the linear epitope on the 56-kDa major outer membrane protein of O. tsutsugamushi. Thereafter, antimicrobial susceptibility was measured by flow cytometry and expressed as a growth index (total mass of Orientia). The growth indices of doxycycline (0.1 µg/ mL), azithromycin (0.1 µg/mL), rifampin (0.0125 µg/mL), cefotaxime (2 and 20 µg/mL), and their various combinations (doxycycline+cefotaxime, doxycycline+rifampin, azithromycin+cefotaxime, and rifampin+cefotaxime) were measured. The above mentioned antibiotic concentrations, except for that of cefotaxime, represent the minimal inhibitory concentrations of each antibiotic. Results : The growth indices of doxycycline (4.67% and 0.52%), rifampin (2.35% and 0.26%), and azithromycin (7.54%) were within the range of full suppression of O. tsutsugamushi; in contrast, cefotaxime (87.60%) was in effective. The growth indices of doxycycline + rifampin were 0.10% and 0.10%, which were similar to those obtained with doxycycline or rifampin alone. The growth indices of doxycycline+cefotaxime were 3.99% and 3.65% in low-dose cefotaxime (2 µg/mL), and 3.69% and 4.40% in high-dose cefotaxime (20 µg/mL). The growth indices of rifampin + cefotaxime (2.19% and 2.19% at 2 µg/mL; 1.84% and 2.04% at 20 µg/mL cefotaxime) were similar to those obtained with rifampin alone (2.35% and 0.26%). Azithromycin+cefotaxime (11.06-14.63%) showed higher growth indices than azithromycin alone; this suggests that this combination may be antagonistic. Conclusions : The anti-Orientia efficacies of doxycycline+rifampin, doxycycline+cefotaxime, and rifampin+cefotaxime were not antagonistic. The efficacy of the azithromycin+cefotaxime combination needs to be confirmed by more sensitive methods to exclude the possibility of antagonistic interactions between the antibiotics.

쯔쯔가무시병에서의 항균요법의 종류와 그 치료기간에 따른 치료 성적의 임상적, 분자생물학적 비교연구

김양수,최선영,이미숙,정두련,김은옥,우준희,류지소 대한화학요법학회 1999 대한화학요법학회지 Vol.17 No.4

요약 : 쯔쯔가무시병은 중요한 급성열성질환으로 주로 농촌지역에 많이 발생하며 되도록 간편하고 짧은 기간의 치료로 완치될 수 있도록 하는 것이 바람직하다. 최근 doxycycline 3일 요법이 좋은 치료성적을 거두었으며 doxycycline 1일 요법으로도 효과가 있었다는 보고가 있었으며 또한 azithromycin은 반감기가 길고 실험실연구에서 doxycycline에 내성균주에 효과적이었으며 임산부에서도 보고된 부작용이 없어 저자들은 쯔쯔가무시병에 대한 doxycycline 1일 요법과 azithromycin 1회 요법의 효과를 알아보고자 하였다. 방법 : 급성열성질환을 보인 환자들 중 급성의 발열과 함께 특징적인 발진, 혹은 가피를 보인 환자를 대상으로 무작위로 세 치료군을 배정하여 A 치료군은 doxycycline 100㎎을 1일 2회 용법으로 3일간 경구 투여하고 B치료군은 doxycycline 200㎎ 1일 2회 용법으로 1일간 투여하며 C치료군은 axithromycin 1,000㎎을 1회 투여하였다. 해열 및 기타 임상소견의 소실로 치료에 대한 반응을 평가하였고 치료 개시 2주 후에 완치 및 재발에 대해 조사하였다. 결과 : Azithromycin 1회 요법과 doxycycline 1일 요법은 doxycycline 3일 요법에 비해 쯔쯔가무시병의 치료 및 재발방지에 차이가 없었으며 특히 azithromycin은 1회 투여로 간편하게 치료할 수 있고 임산부 및 어린이와 doxycycline에 내성을 보인 균주에도 사용할 수 있어 임상적으로 많은 도움이 될 것으로 생각된다. 결론 : Doxycycline 1일 요법과 azithromycin 1회 요법은 쯔쯔가무시병의 치료에 안전하고 효과적으로 사용할 수 있으리라 사료된다. Background : Tsutsugamushi disease (Scrub typus) is an acute febrile disease caused by Orientitia tsutsugamushi. Recently, effectiveness of short course doxycycline therapy was investigated. In an in vitro assay, azithromycin was more effective than doxycycline against doxycycline-susceptible and doxycycline-resistant strains of Orientitia tsutsugamushi, also can be used for the treatment of tsutsugamushi disease in children and pregnant women. Methods : To assess the clinical efficacy of one day doxycycline and one dose azithromycin in the treatment of tsutugamushi disease, we compared conventional three day doxycycline theraphy(100㎎ twice daily) with one day doxycycline (200㎎ twice) and one dose azithromycin (1,000㎎ once) in 45patients. These patients are followed for 4 weeks. Detection of O. tsutsugamushi was performed by PCR technique. Results : The three groups did not differ significantly in defervescence time or for the alleviation of symptoms. There were no relapse in each group and no significant adverse drug reaction. Conclusion : One day doxycycline therapy and once azithromycin therapy are effective as conventional three day doxycycline therapy of tsutsugamushi disease.

Doxycycline에 의한 성인 치아의 착색

김상진,강희영 대한피부과학회 2015 대한피부과학회지 Vol.53 No.10

Doxycycline은 다양한 피부 질환에 흔히 쓰이는 항생제로서 tetracycline계의 반합성, 친유성 약물이다1,2. 비록 다른 tetracycline계의 항생제보다 빈도는 매우 적으나 피부, 손톱 및 치아를 침범하는 부작용이 발생할 수 있다1,2. 환자는 29세 미국 국적의 백인 여자로 얼굴에 발생한 여드름의 치료를 위해 내원하였다. 1년 전 isotretinoin을 복용한 적 있으며 최근에는 benzoyl peroxide 2.5% 국소외용제를 사용하고 있었다. 치료를 위하여 doxycycline 100 mg과 얼굴 가려움증 조절을 위해 fexofenadine 180 mg을 하루 1회 복용하였다. 2주 후 내원했을 때 환자는 앞니와 송곳니에 발생한 착색에 대해 불평하였다(Fig. 1). 문진상 치아 착색을 일으킬만한 fluoride 또는 sulfur 계통 약물 복용력과 외상력은 없었다. 환자에게 doxycycline 복용 중단을 권고한 후 착색은 더 이상 진행하지 않았으며, 중단 3개월 후 치아 착색은 완전히 사라졌다고 하였다. Tetracycline계 항생제는 치아가 성장하는 시기에 복용했을 때 유치의 착색과 에나멜 형성부전을 유발할 수 있다3. 또한 장기간의 tetracycline과 minocycline 복용에 의한 성인 영구치의 착색도 보고된 바 있으나 doxycycline에 의한 증례는 드물다1,2. Tetracycline에 의한 치아 착색 기전은 명확히 알려지진 않았지만 칼슘 이온이 킬레이트화를 통해 치아에 침착되어 발생한다고 알려져 있다2. 반면 doxycyline은 이러한 과정에서 다른 tetracycline계 약물에 비해 적은 양의 칼슘과 결합하므로 드물게 치아 착색이 발생한다고 알려져 있다1. 또한 푸른색 내지는 회색의 착색을 보이는 minocycline과 달리 노란색 내지는 갈색의 착색을 보인다는 차이점이 있다3. Doxycycline으로 인한 치아착색은 영어 문헌 검색상 총 5예가 보고되어 있는데 모두 12세에서 29세 사이의 영구치를 가진 환자로 하루 200 mg 복용 후 4주에서 10주 사이에 발생하였고 복용 중단 후 대부분 호전 되었다(Table 1)1,2. 본 증례는 지금까지 보고된 증례들과 비교했을 때 doxycycline 저용량(100 mg/d)을 단기간 사용 했을 때에도 치아 착색이 발생할 수 있음을 제시하였다. Doxycycline은 피부과에서 자주 쓰는 약으로 성인에서 치아착색이 발생할 수 있다는 점을 인지하는 것이 필요하다고 생각된다.

국내 환자에서 분리된 Orientia tsutsugamushi에서 doxycycline 내성

김은실,김미경,이혜명,길세희,정문현,이진수,강재승 대한감염학회 2008 감염과 화학요법 Vol.40 No.5

Background : Doxycycline has been the drug of choice for the treatment of scrub typhus. However, scrub typhus with poor response to doxycycline was first reported in Thailand in 1996. To date, it is not known whether doxycycline resistant scrub typhus is present in Korea. To investigate the doxycycline resistance of scrub typhus in Korea, we performed an experiment to evaluate the degree of growth inhibition of Orientia tsutsugamushi at the minimal inhibitory concentration (MIC) of doxycycline. Materials and Methods : 37 isolates of Orientia tsutsugamushi were collected from Korean patients with scrub typhus during 10 year period (from 1997 to 2007). 34 isolates consisted of Boryong serotype or related serotypes. These strains were stained with FS15, a monoclonal antibody against the linear epitope on the protein located at the outer membrane of O. tsutsugamushi. Three isolates were confirmed as serotype Gilliam, which was stained by anti-Gilliam antibody. The antibody-stainable 35 isolates were incubated in media containing 0.1 and 0.2 ug/mL of doxycycline for 3 days. Then the growth indices of Orient/a were measured by flow cytometry. If the growth index was greater than 10%, the isolate was tentatively classified as an isolate resistant to doxycycline and its MIC was measured. Results : Demographic and treatment data were similar to the results of previous reports. Infection was mainly observed in Inchon and the Chungcheongnam province. No patient showed delayed response to antibiotics. Of 35 hospitalized patients, 4 (11.4%) were managed at the intensive care unit and 1 (2.9%) died of nosocomial pneumonia. All the 2 patients whose isolates were serotype Gilliam Yonchon/Ikeda-like strain were managed at the intensive care unit. Six of the 34 isolates from Korean patients exhibited growth indices greater than 10% at the MIC of doxycycline; however, the MICs of these isolates did not exceed 0.2 ug/mL. One isolate of serotype Gilliam showed an MIC of 0.0125 ug/mL, which seemed to be underestimated due to weak fluorescence of the anti-GiIIiam antibody. Conclusions : Although the number of tested isolates is small, insensitivity of scrub typhus to doxy-cycline is not a major reason for treatment failure in Korea. Serotype Gilliam, especially Yochon/Ikeda-like strain may be associated with severe form of scrub typhus. More studies concerning the antibiotic susceptibility for serotype Gilliam are warranted.

Evaluation of the periodontal and pulpal healing of replanted rat molars with doxycycline root conditioning

남옥형,Kyounga Cheon,김미선,이효설,최성철 대한치주과학회 2019 Journal of Periodontal & Implant Science Vol.49 No.3

Purpose: This study aimed to evaluate periodontal and pulpal healing in replanted rat teeth, preserved under different storage conditions, with or without root conditioning using doxycycline. Methods: A total of 40 maxillary first molars extracted from 20 Sprague-Dawley rats were stored for different durations under different conditions (5 minutes in dry storage and 60 minutes in Hank's balanced salt solution [HBSS]) and subsequently replanted. The rats were divided into 2 groups based on the use of root surface treatment: the doxycycline group (root surface treated with doxycycline) and the control group (no doxycycline treatment). Eight weeks after replantation, the animals were sacrificed, and the teeth were evaluated using micro-computed tomography (micro-CT) and histomorphometric analysis. Results: In the micro-CT analysis, the doxycycline group showed the same rate of occurrence of periapical radiolucency as was observed in the control group, but a lower degree of root resorption in teeth replanted after 60 minutes of storage in HBSS (P<0.05). In the histomorphometric analysis, the doxycycline group exhibited no improvement in either pulpal or periodontal healing of the replanted tooth after 5 minutes of dry storage, but showed a lower grade of surface root resorption (1.37±0.77) and inflammatory resorption in the teeth stored for 60 minutes in HBSS (1.33±0.71). Conclusions: In conclusion, doxycycline improved the periodontal healing of replanted teeth stored for 60 minutes in HBSS, whereas doxycycline did not improve periodontal healing of replanted tooth after 5 minutes of dry storage. Within the limits of this study, doxycycline showed more favorable periodontal healing despite delayed replantation.

Evaluation of the periodontal and pulpal healing of replanted rat molars with doxycycline root conditioning

Nam, Ok Hyung,Cheon, Kyounga,Kim, Mi Sun,Lee, Hyo-Seol,Choi, Sung Chul Korean Academy of Periodontology 2019 Journal of Periodontal & Implant Science Vol.49 No.3

Purpose: This study aimed to evaluate periodontal and pulpal healing in replanted rat teeth, preserved under different storage conditions, with or without root conditioning using doxycycline. Methods: A total of 40 maxillary first molars extracted from 20 Sprague-Dawley rats were stored for different durations under different conditions (5 minutes in dry storage and 60 minutes in Hank's balanced salt solution [HBSS]) and subsequently replanted. The rats were divided into 2 groups based on the use of root surface treatment: the doxycycline group (root surface treated with doxycycline) and the control group (no doxycycline treatment). Eight weeks after replantation, the animals were sacrificed, and the teeth were evaluated using micro-computed tomography (micro-CT) and histomorphometric analysis. Results: In the micro-CT analysis, the doxycycline group showed the same rate of occurrence of periapical radiolucency as was observed in the control group, but a lower degree of root resorption in teeth replanted after 60 minutes of storage in HBSS (P<0.05). In the histomorphometric analysis, the doxycycline group exhibited no improvement in either pulpal or periodontal healing of the replanted tooth after 5 minutes of dry storage, but showed a lower grade of surface root resorption ($1.37{\pm}0.77$) and inflammatory resorption in the teeth stored for 60 minutes in HBSS ($1.33{\pm}0.71$). Conclusions: In conclusion, doxycycline improved the periodontal healing of replanted teeth stored for 60 minutes in HBSS, whereas doxycycline did not improve periodontal healing of replanted tooth after 5 minutes of dry storage. Within the limits of this study, doxycycline showed more favorable periodontal healing despite delayed replantation.

백서 치주인대세포에서 Doxycycline의 Mefenamic Acid 병용사용 시 MMP-13mRNA 발현 억제 효과

서진희,최득철,김영준,Seo, Jin-Hee,Ciu, De-Zhe,Kim, Young-Joon 대한치주과학회 2005 Journal of Periodontal & Implant Science Vol.35 No.1

It has been focused on the importance of the host inflammatory response in periodontal pathogenesis and progression, treatment has been introduced to control the host response and the method, which diminishes production and activity of MMP by doxycycline, has been used in periodontal field. MMP is a proteolytic enzyme which plays a major role in tissue destruction and MMP-1 is secreted in the periodontally healthy tissue, while MMP-8, 9, 13, etc in the inflammatory state. Among these, MMP-13 has been discovered lately and reported to degrade primarily type II collagen. Periodontal ligament (PDL) cell plays a role in destruction of periodontal tissue. This study was to evaluate the effect of doxycycline and mefenamic acid, non-steroidal antiinflammatory drug on MMP-13 mRNA expression in the rat PDL cell. Doxycycline concentration of $1{\sim}100\;{\mu}g/ml$ was added rat PDL cell and cell activity was measured by MIT assay at day 1 and 3. MMP-13 gene expression was evaluated by RT-PCR after PDL cells were pre-treated for 1hour with doxycycline (50 ${\mu}g/ml$) alone or with mefenamic acid ($10^{-6}M$), then added $IL-1{\beta}$(1.0 ng/ml) and incubated for 16-18 hours. The results are as follows: 1. Cell activity decreased Significantly at 24 and 72 hours in 100 ${\mu}g/ml$ (p<0.05). 2. Level of MMP-13 mRNA was in 20.2% increase by $IL-1{\beta}$ and in pre-treating doxycycline group, expression of $IL-1{\beta}$ induced MMP-13 mRNA was inhibited by 31% than $IL-1{\beta}$ treated only. 3. Mefenamic acid did not inhibit on the expression of $IL-1{\beta}$ induced MMP-13 mRNA, while mefenamic acid in combination with doxycycline inhibited the expression by 41% compared to only $IL-1{\beta}$ stimulation. These results suggest that doxycycline synergistically inhibit the expression of $IL-1{\beta}$ induced MMP-13 mRNA in combination with mefenamic acid.

Orientia tsutsugamoshi에 대한 항균제 병용의 실험실 효과

김은실,김미경,이혜명,정문현,이진수,강재승 대한감염학회 2008 감염과 화학요법 Vol.40 No.6

Background : Occasionally, combinations of antibiotics are used for the treatment of scrub typhus. However, the effectiveness of such combined therapies has rarely been evaluated. To date, no experimental studies have been performed; only 1 clinical study has assessed the efficacy of combined doxycycline and rifampin therapy. To elucidate the efficacies of other antibiotic combinations, we performed an experiment to evaluate the in vitro efficacy of antibiotic combinations against Orientia tsutsugamushi. Materials and Methods : O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were cultured in antibiotic-containing media for 3-5 days and stained with FS15, a monoclonal antibody reacting against the linear epitope on the 56-kDa major outer membrane protein of O. tsutsugamushi. Thereafter, antimicrobial susceptibility was measured by flow cytometry and expressed as a growth index (total mass of Orientia). The growth indices of doxycycline (0.1 ug/mL), azithromycin (0.1 ug/mL), rifampin (0.0125 ug/mL), cefotaxime (2 and 20 ug/mL), and their various combinations (doxycycline+cefotaxime, doxycycline+rifampin, azithromycin+cefotaxime, and rifampin+cefotaxime) were measured. The above mentioned antibiotic concentrations, except for that of cefotaxime, represent the minimal inhibitory concentrations of each antibiotic. Results : The growth indices of doxycycline (4.67% and 0.52%), rifampin (2.35% and 0.26%), and azithromycin (7.54%) were within the range of full suppression of O. tsutsugamushi', in contrast, cefotaxime (87.60%) was in effective. The growth indices of doxycycline + rifampin were 0.10% and 0.10% which were similar to those obtained with doxycycline or rifampin alone. The growth indices of doxycycline+cefotaxime were 3.99% and 3.65% in low-dose cefotaxime (2 ug/mL), and 3.69% and 4.40% in high-dose cefotaxime (20 ug/mL). The growth indices of rifampin +cefotaxime (2.19% and 2.19% at 2 ug/mL; 1.84% and 2.04% at 20 ug/mL cefotaxime) were similar to those obtained with rifampin alone (2.35% and 0.26%). Azithromycin+cefotaxime (11.06-14.63%) showed higher growth indices than azithromycin alone; this suggests that this combination may be antagonistic. Conclusions : The anti-Orientia efficacies of doxycycline+rifampin, doxycycline+cefotaxime, and rifampin+cefotaxime were not antagonistic. The efficacy of the azithromycin+cefotaxime combination needs to be confirmed by more sensitive methods to exclude the possibility of antagonistic interactions between the antibiotics.

독시사이클린 복용 후 발생한 식도궤양형성 사례

김가연,이찬희,이정우,이정민,이모세,지은희 한국임상약학회 2019 한국임상약학회지 Vol.29 No.3

Doxycycline is frequently prescribed to treat urogenital infections or acne vulgaris. A 39-year-old man was prescribed doxycycline as a treatment for his skin infection. He took each tablet on an empty stomach in the morning, and just before going to bed with insufficient water. After taking the prescribed medication for approximately 3 weeks, he was diagnosed with esophageal ulcer. He had not experienced these symptoms before, and the drug label says that doxycycline rarely causes esophageal ulcer. After discontinuing the medication, the symptoms disappeared. Using the World Health Organization-Uppsala Monitoring Center criteria, the causality for doxycycline-induced esophageal ulcer was evaluated as “possible.” Additionally, using the Naranjo scale and Korean causality assessment algorithm (Ver. 2), the causality was evaluated as “probable.” Previous reports have stated that most patients who took doxycycline with insufficient water just before going to bed or in the supine position developed esophageal ulcer. Therefore, all patients taking doxycycline must be provided with detailed instructions about the appropriate administration methods.