Best Achievements in Clinical Medicine in Diabetes and Dyslipidemia in 2020

Over the last two decades, our understanding of diabetes and treatment strategies have evolved tremendously, from scientific, mechanistic, and human perspectives. The categories of anti-diabetic medications expanded from a few to numerous, enabling clinicians to personalize diabetes care and treatment. Thanks to rapid growth in the field of science and medical engineering, newer treatment options are coming to the market with various advantages and disadvantages to be aware of. Therefore, clinicians should rapidly adopt new trends based on guidelines and data from many clinical trials in the field of diabetes. In the treatment of dyslipidemia, trends and guidelines are changing every year, and novel therapies are being developed. In this review, we would like to summarize the major achievements in clinical medicine in 2020 in the field of diabetes mellitus and dyslipidemia.

A Model for Role Transition of Older Mothers with Preschool Children

PURPOSE: The purpose of this study was to construct a model to explain the parenting satisfaction associated with the role transition of older mothers with preschool children. METHODS: The participants of this study were mothers of 3– to 6–year–old children who gave birth after 35 years of age, and were drawn from 16 child care centers and 8 kindergartens in 4 administrative districts of B city. Data were analyzed using SPSS for Windows version 22.0 and AMOS for Windows version 22.0. RESULTS: Parental stress, mother-child interactions, parental beliefs regarding personality, and socioeconomic status(income, education, and occupation) had direct effects on parenting satisfaction. Social support also showed direct and indirect effects. Among the sub factors of child temperament, sociability had a significant effect. These variables explained 57.4% of the variation in parenting satisfaction. CONCLUSION: The results of this study will contribute to the development of effective programs to enhance the parenting satisfaction of older mothers, and will help older mothers through the role transition necessary for the growth of their children.

The Association between Pancreatic Steatosis and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients

BACKGROUND: Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). METHODS: The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis (‘P’ mean: mean attenuation of three pancreatic regions; P–S: difference between ‘P’ mean and ‘S’; P/S: the ‘P’ mean to ‘S’ ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy. RESULTS: The average P mean was 29.02 Hounsfield units (HU), P–S was −18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P–S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively. CONCLUSION: In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Differentiation of benign and malignant thyroid nodules based on the proportion of sponge-like areas on ultrasonography: imaging-pathologic correlation

PURPOSE: The purpose of this study was to determine whether it is possible to differentiate benign from malignant thyroid nodules according to the proportion of sponge-like appearance within the nodules. METHODS: A total of 201 thyroid nodules containing sponge-like appearance from 195 patients (157 women and 38 men) were included this study. Each thyroid nodule was classified into one of three grades by real-time ultrasonography (US) based on the areas with a sponge-like appearance within nodule: grade I had sponge-like areas occupying 75%. We evaluated whether a correlation existed between these grades and cytopathologic diagnoses. RESULTS: Of the 201 nodules, 196 were benign and five were malignant, and according to the US classification, 101 nodules were grade I, 45 were grade II, and 55 were grade III. Of the five malignant nodules, four were grade I, and one was grade II. No statistically significant difference was found in the rate of malignancy between grade III and grades I and II, due to insufficient statistical power. A sponge-like appearance was correlated with follicles filled with colloid and cholesterol granules in benign nodules and with papillary fronds around the dilated cystic spaces in malignant nodules. CONCLUSION: No malignancies were found in thyroid nodules with >75% sponge-like appearance. Due to the overall low incidence of malignancy and the limited number of patients, a statistically significant difference could not be found in the prevalence of malignancy depending on the proportion of sponge-like areas within the nodule.

Biological Activity and Single Oral Dose Toxicity of Dansam-samultang / 한국실험동물학회지

In this study, we investigated the in vitro antioxidative effects, antimicrobial activities and single oral dose toxicity of the extracts from Dansam-samultang to evaluate its use as a functional ingredient in cosmetics. In the antioxidative effect, the ethanol extract from Dansam-samultang (DSE) had higher antioxidant values of 92.0% at 1,000 microg/mL than that of water extract from Dansam-samultang (DSW, 86.0%) when evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. The superoxide dismutase-like activity of DSW and DSE were 16.3% and 21.3% at 1,000 microg/mL in concentration, respectively. Xanthine oxidase inhibition activity of the DSE was higher 51.5% than that of the DSW (21.4%). This study was also undertaken to test the in vitro antimicrobial activity with the extracts of Dansam-samultang. In general, the DSE showed the significant antimicrobial activity against Staphylococcus aureus, Staphylococcus epidermiders and Escherichia coli. In single oral dose toxicity study, in vivo, there were no differences between control and treated groups in clinical signs, body weight gains, and gross finding. The results indicated that DSE did not show any toxic effects at 10 mL/kg in mice, and the LD50 of DSE was found to be higher than 10 mL/kg in this experiment. In conclusion, the extracts from Dansam-samultang may act as a natural subsistence for functional cosmetics.

Investigations of Samwhang-sasimtang Extracts on Biological Activities In Vitro and Vivo / 한국실험동물학회지

In this study, we investigated the in vitro antioxidative effects, antimicrobial activities and single oral dose toxicity of the extracts from Samwhang-sasimtang to evaluate its use as a functional ingredient in cosmetics. In the antioxidative effect, the ethanol extract from Samwhang-sasimtang (SSE) had higher antioxidant values of 91.9% at 1,000 microgram/mL than that of water extract from Samwhang-sasimtang (SSW, 77.0%) when evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation decolorization of SSE was 82.2%, higher than that of the SSW (55.0%) and the antioxidant protection factors (APF) of SSW and SSE were 1.64 and 1.62 at 1,000 microgram/mL in concentration, respectively. This study was also undertaken to test the in vitro antimicrobial activity with the extracts of Samwhang-sasimtang. In general, the SSE showed the significant antimicrobial activity against Staphylococcus aureus and Staphylococcus epidermidis. In single oral dose toxicity study, there were no differences in vivo were observed between control and treated groups in clinical signs, body weight gains, and gross finding. The results indicated that SSE did not show any toxic effects at 10 mL/kg in mice, and the LD50 of SSE was found to be higher than 10 mL/kg in this experiment. In conclusion, the extracts from Samwhang-sasimtang may act as a natural subsistence for functional cosmetics.

Cholestatic Hepatitis Caused by Tongyeong Strain of Orientia tsutsugamushi / 감염과화학요법

In Korea, the clinical manifestation of scrub typhus in humans appears to be severe in the northern regions of the country and mild in the southern areas. Studies on the geographic distribution of the serotype of Orientia tsutsugamushi revealed that the Boryong serotype is predominant in the southern Korean peninsula, whereas the Gilliam, Karp, and Gilliam-Karp serotypes prevail in the northern or central peninsula. We report a case of severe scrub typhus caused by the Japanese Gilliam type of Orientia tsutsugamushi in a 66-year-old woman from Tongyeong, a city located in the southern part of Korean peninsula. The patient was admitted to the hospital with fever on August 29th, 2001. Scrub typhus complicated by shock, pneumonitis, and encephalitis was diagnosed. Additionally, markedly elevated alkaline phosphatase levels was observed, which necessitated an ultrasonographic examination, which showed an ill-defined hyperechogenic mass on the right hepatic lobe. Liver biopsy showed cholestatic hepatitis and blood culture showed growth of O. tsutsugamushi. Gene sequencing of the amplicons of a polymerase chain reaction using primers for the amplification of the gene encoding the 56-kDa protein of O. tsutsugamushi revealed a nucleotide sequence that matched Yonchon strain of O. tsutsugamushi.

Cholestatic Hepatitis Caused by Tongyeong Strain of Orientia tsutsugamushi / 감염과화학요법

In Korea, the clinical manifestation of scrub typhus in humans appears to be severe in the northern regions of the country and mild in the southern areas. Studies on the geographic distribution of the serotype of Orientia tsutsugamushi revealed that the Boryong serotype is predominant in the southern Korean peninsula, whereas the Gilliam, Karp, and Gilliam-Karp serotypes prevail in the northern or central peninsula. We report a case of severe scrub typhus caused by the Japanese Gilliam type of Orientia tsutsugamushi in a 66-year-old woman from Tongyeong, a city located in the southern part of Korean peninsula. The patient was admitted to the hospital with fever on August 29th, 2001. Scrub typhus complicated by shock, pneumonitis, and encephalitis was diagnosed. Additionally, markedly elevated alkaline phosphatase levels was observed, which necessitated an ultrasonographic examination, which showed an ill-defined hyperechogenic mass on the right hepatic lobe. Liver biopsy showed cholestatic hepatitis and blood culture showed growth of O. tsutsugamushi. Gene sequencing of the amplicons of a polymerase chain reaction using primers for the amplification of the gene encoding the 56-kDa protein of O. tsutsugamushi revealed a nucleotide sequence that matched Yonchon strain of O. tsutsugamushi.

The Classification of Diabetic Patients Presenting Diabetic Ketoacidosis: The Characteristics of Fulminant Type 1 Diabetes / 당뇨병

No abstract available.

The Classification of Diabetic Patients Presenting Diabetic Ketoacidosis: The Characteristics of Fulminant Type 1 Diabetes / 당뇨병

BACKGROUND: The aim of the study was to classify newly diagnosed diabetic patients who initially presented with diabetic ketoacidosis (DKA) into specific types of diabetes and to describe the clinical and biochemical characteristics of patients with fulminant type 1 DM in Korea. METHODS: Using data from 4 hospitals of CMC from 1 January 1999 to 1 March 2008, we identified all patients who manifested DKA when they were first diagnosed as diabetes. Clinical and laboratory data were reviewed from medical records. RESULTS: We identified 51 newly diagnosed diabetic patients manifested DKA. Among them, 14 (27.4%) patients were classified as autoimmune type 1 DM, 8 (15.7%) as antibody negative type 1 DM, 5 (9.8%) as fulminant type 1, 16 (31.4%) as type 2 DM and 8 (15.7%) as secondary DM. Five patients who fulfilled the criteria of fulminant type 1 DM were older (32.2 +/- 10.7 vs. 15.7 +/- 4.4 years, P = 0.010), had shorter duration of symptoms (4.2 +/- 2.7 vs.16.7 +/- 15.2 days, P = 0.014) and lower stimulated C-peptide levels (0.1 +/- 0.0 vs. 0.7 +/- 0.6 ng/mL, P = 0.050) compared with patients with autoimmune type 1 DM. CONCLUSION Newly diagnosed diabetic patients presenting with DKA composed of heterogenous types of diabetes. The prevalence of fulminant type 1 diabetes among them was 9.8% and the clinical and biochemical characteristics of these patients were different from those of autoimmune type 1 DM.

In Vitro Antibiotic Susceptibility of Orientia tsutsugamushi strain Boryong Measured by Flow Cytometry / 감염과화학요법

BACKGROUND: Scrub typhus, an infectious disease caused by Orientia tsutsugamushi, is endemic in Korea. With the introduction of tetracycline and chloramphenicol in clinical practice, the mortality due to scrub typhus has markedly decreased. In 1995, scrub typhus poorly responsive to doxycycline was reported in Thailand; the need for safe antibiotics for the treatment of scrub typhus acquired during pregnancy or for children is emerging; also, broader spectrum antibiotics having anti-Orientia activity may be preferred for empirical therapy of enteric fever syndrome and for complicated scrub typhus. The anti-Orientia activities of various antibiotics, including recently licensed antibiotics, were investigated by flow cytometry. MATERIALS AND METHODS: O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were stained with FS15, a monoclonal antibody reacting against a linear epitope on 56-kDa major outer membrane protein of O. tsutsugamushi. Then the antimicrobial susceptibilities were measured by flow cytometry and expressed as a growth index (total mass of Orientia). A concentration at which no further decrease in growth index occurred was defined as the minimal inhibitory concentration (MIC). Microbial susceptibilities to the following antibiotics were measured: quinupristin-dalfopristin (Synercid), levofloxacin, ciprofloxacin, moxifloxacin, metronidazole, linezolid, clindamycin, chloramphenicol, doxycycline, azithromycin, and rifampin. RESULTS: Considering the usual serum concentrations of rifampin (MIC=0.025-0.05 microg/mL), azithromycin (MIC=0.05-0.5 microg/mL) and doxycycline (MIC=0.05-0.1 microg/mL), these antibiotics exhibited very low MICs. Synercid (MIC=0.2-1.0 microg/mL), clindamycin (MIC=1.0 microg/mL) and chloramphenicol (MIC=1-2 microg/mL) exhibited moderately low MICs; moxifloxacin (MIC=8 microg/mL), ciprofloxacin (MIC=25.6 microg/mL or more) and levofloxacin (MIC=30 microg/mL) exhibited relatively high MICs; and cefotaxime (MIC>50 microg/mL), metronidazole (MIC>30 microg/mL) and linezolid (>30 microg/mL) exhibited high MICs. CONCLUSIONS: Among the new antibiotics, none was superior to doxycycline, azithromycin or rifampin with respect to anti-Orientia activity. Synercid, clindamycin, and moxifloxacin may show moderate therapeutic efficacies in human.

A Case of Scrub Typhus in Summer Presenting as Atypical Pneumonia / 감염과화학요법

Scrub typhus usually occurs in October and November in Korea. Its typical clinical manifestations are fever, rash, eschar, and lymphadenopathies. Pneumonitis may occur, however, it occurs as a complication at the late phase of scrub typhus, when it is inappropriately treated. We encountered a case of pneumonitis that was an initial manifestation of scrub typhus which was confirmed by rickettsial culture, positive seroconversion, and polymerase chain reaction. The case was a 16-year-old high school adolescent who presented with fever and headache that lasted for 1 day in July, 2007. He denied of any outdoor activities. A chest radiograph showed patchy infiltrates in the left lower lung, which improved with the administration of cefotaxime and azithromycin for empirical treatment of community-acquired pneumonia. Blood taken on the second febrile day showed a positive culture for Orientia tsutsugamushi and was also positive for O. tsutsugamushi DNA polymerase chain reaction. Immunofluorescent antibody (IFA) test for O. tsutsugamushi showed that the initial antibody was negative, but convalescent serum tested positive with an antibody titer of 1:80. IFA for Coxiella burnetii showed false positive results; the initial IgM and IgG titers were 1:128 and 1:256, respectively, and the IgM and IgG titers in convalescent serum were 1:128 and 1:128, respectively.

In vitro Study on the Dose and Duration of Doxycycline Treatment against Orientia tsutsugamushi / 감염과화학요법

BACKGROUND: Doxycycline, azithromycin, and chloramphenicol have been used for the treatment of scrub typhus; however, the duration of treatment for this disease is still controversial. Most clinical studies on the treatment of scrub typhus focus on the effectiveness of antibiotics; few studies have focused on the duration of the treatment. There has been no in vitro evaluation of the optimal duration of treatment of scrub typhus. We performed an experiment to evaluate the regrowth of Orientia tsutsugamushi after exposure to doxycycline of various concentration and exposure time. MATERIALS AND METHODS: O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were stained with FS15, a monoclonal antibody reacting against a linear epitope on the 56-kDa major outer membrane protein of O. tsutsugamushi; thereafter, the antimicrobial susceptibilities were measured by flow cytometry and expressed as a growth index (total mass of Orientia). Incubation in media containing 0.1 (the minimal inhibitory concentration of doxycycline against O. tsutsugamushi strain Boryong), 0.2, and 2 microg/mL doxycycline for 1, 3, 5, and 7 day was followed by incubation in antibiotic-free media for 5 day. Two inocula sizes were employed; low inoculum (45.18% of cells were infected) and high inoculum (87.21% of cells). RESULTS: The incubation with 0.1 microg/mL doxycycline resulted in O. tsutsugamushi regrowth irrespective of doxycycline treatment duration. When the concentration of doxycycline was increased to 0.2 or 2 microg/mL, regrowth was observed in short duration treatments (1-5 day at 0.2 microg/mL; 1 day at 2 microg/mL). Higher inoculum size of O. tsutsugamushi increased regrowth (1 day at the low inoculum; 1-5 day at the high inoculum). Conclusions: The regrowth of O. tsutsugamushi after doxycycline treatment depends on the doxycycline dose; the higher the dose, the lower the relapse rate. If this result is extrapolated to humans, higher dose of doxycycline might be preferred to lower the relapse rate. The inoculum effect in O. tsutsugamushi infection needs further investigations.

Doxycycline Resistance in Orientia tsutsugamushi Isolated from Korean Patients / 감염과화학요법

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 microg/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 microg/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.

In vitro Efficacy of Antibiotic Combinations against Orientia tsutsugamushi / 감염과화학요법

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 microg/mL), azithromycin (0.1 microg/mL), rifampin (0.0125 microg/mL), cefotaxime (2 and 20 microg/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 microg/mL), and 3.69% and 4.40% in high-dose cefotaxime (20 microg/mL). The growth indices of rifampin+cefotaxime (2.19% and 2.19% at 2 microg/mL; 1.84% and 2.04% at 20 microg/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.

In Vitro Antibiotic Susceptibility of Orientia tsutsugamushi strain Boryong Measured by Flow Cytometry / 감염과화학요법

BACKGROUND: Scrub typhus, an infectious disease caused by Orientia tsutsugamushi, is endemic in Korea. With the introduction of tetracycline and chloramphenicol in clinical practice, the mortality due to scrub typhus has markedly decreased. In 1995, scrub typhus poorly responsive to doxycycline was reported in Thailand; the need for safe antibiotics for the treatment of scrub typhus acquired during pregnancy or for children is emerging; also, broader spectrum antibiotics having anti-Orientia activity may be preferred for empirical therapy of enteric fever syndrome and for complicated scrub typhus. The anti-Orientia activities of various antibiotics, including recently licensed antibiotics, were investigated by flow cytometry. MATERIALS AND METHODS: O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were stained with FS15, a monoclonal antibody reacting against a linear epitope on 56-kDa major outer membrane protein of O. tsutsugamushi. Then the antimicrobial susceptibilities were measured by flow cytometry and expressed as a growth index (total mass of Orientia). A concentration at which no further decrease in growth index occurred was defined as the minimal inhibitory concentration (MIC). Microbial susceptibilities to the following antibiotics were measured: quinupristin-dalfopristin (Synercid), levofloxacin, ciprofloxacin, moxifloxacin, metronidazole, linezolid, clindamycin, chloramphenicol, doxycycline, azithromycin, and rifampin. RESULTS: Considering the usual serum concentrations of rifampin (MIC=0.025-0.05 microg/mL), azithromycin (MIC=0.05-0.5 microg/mL) and doxycycline (MIC=0.05-0.1 microg/mL), these antibiotics exhibited very low MICs. Synercid (MIC=0.2-1.0 microg/mL), clindamycin (MIC=1.0 microg/mL) and chloramphenicol (MIC=1-2 microg/mL) exhibited moderately low MICs; moxifloxacin (MIC=8 microg/mL), ciprofloxacin (MIC=25.6 microg/mL or more) and levofloxacin (MIC=30 microg/mL) exhibited relatively high MICs; and cefotaxime (MIC>50 microg/mL), metronidazole (MIC>30 microg/mL) and linezolid (>30 microg/mL) exhibited high MICs. CONCLUSIONS: Among the new antibiotics, none was superior to doxycycline, azithromycin or rifampin with respect to anti-Orientia activity. Synercid, clindamycin, and moxifloxacin may show moderate therapeutic efficacies in human.

A Case of Scrub Typhus in Summer Presenting as Atypical Pneumonia / 감염과화학요법

Scrub typhus usually occurs in October and November in Korea. Its typical clinical manifestations are fever, rash, eschar, and lymphadenopathies. Pneumonitis may occur, however, it occurs as a complication at the late phase of scrub typhus, when it is inappropriately treated. We encountered a case of pneumonitis that was an initial manifestation of scrub typhus which was confirmed by rickettsial culture, positive seroconversion, and polymerase chain reaction. The case was a 16-year-old high school adolescent who presented with fever and headache that lasted for 1 day in July, 2007. He denied of any outdoor activities. A chest radiograph showed patchy infiltrates in the left lower lung, which improved with the administration of cefotaxime and azithromycin for empirical treatment of community-acquired pneumonia. Blood taken on the second febrile day showed a positive culture for Orientia tsutsugamushi and was also positive for O. tsutsugamushi DNA polymerase chain reaction. Immunofluorescent antibody (IFA) test for O. tsutsugamushi showed that the initial antibody was negative, but convalescent serum tested positive with an antibody titer of 1:80. IFA for Coxiella burnetii showed false positive results; the initial IgM and IgG titers were 1:128 and 1:256, respectively, and the IgM and IgG titers in convalescent serum were 1:128 and 1:128, respectively.

In vitro Study on the Dose and Duration of Doxycycline Treatment against Orientia tsutsugamushi / 감염과화학요법

BACKGROUND: Doxycycline, azithromycin, and chloramphenicol have been used for the treatment of scrub typhus; however, the duration of treatment for this disease is still controversial. Most clinical studies on the treatment of scrub typhus focus on the effectiveness of antibiotics; few studies have focused on the duration of the treatment. There has been no in vitro evaluation of the optimal duration of treatment of scrub typhus. We performed an experiment to evaluate the regrowth of Orientia tsutsugamushi after exposure to doxycycline of various concentration and exposure time. MATERIALS AND METHODS: O. tsutsugamushi strain Boryong was inoculated into the ECV304 cell line. The infected cells were stained with FS15, a monoclonal antibody reacting against a linear epitope on the 56-kDa major outer membrane protein of O. tsutsugamushi; thereafter, the antimicrobial susceptibilities were measured by flow cytometry and expressed as a growth index (total mass of Orientia). Incubation in media containing 0.1 (the minimal inhibitory concentration of doxycycline against O. tsutsugamushi strain Boryong), 0.2, and 2 microg/mL doxycycline for 1, 3, 5, and 7 day was followed by incubation in antibiotic-free media for 5 day. Two inocula sizes were employed; low inoculum (45.18% of cells were infected) and high inoculum (87.21% of cells). RESULTS: The incubation with 0.1 microg/mL doxycycline resulted in O. tsutsugamushi regrowth irrespective of doxycycline treatment duration. When the concentration of doxycycline was increased to 0.2 or 2 microg/mL, regrowth was observed in short duration treatments (1-5 day at 0.2 microg/mL; 1 day at 2 microg/mL). Higher inoculum size of O. tsutsugamushi increased regrowth (1 day at the low inoculum; 1-5 day at the high inoculum). Conclusions: The regrowth of O. tsutsugamushi after doxycycline treatment depends on the doxycycline dose; the higher the dose, the lower the relapse rate. If this result is extrapolated to humans, higher dose of doxycycline might be preferred to lower the relapse rate. The inoculum effect in O. tsutsugamushi infection needs further investigations.

Doxycycline Resistance in Orientia tsutsugamushi Isolated from Korean Patients / 감염과화학요법

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 microg/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 microg/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.

In vitro Efficacy of Antibiotic Combinations against Orientia tsutsugamushi / 감염과화학요법

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 microg/mL), azithromycin (0.1 microg/mL), rifampin (0.0125 microg/mL), cefotaxime (2 and 20 microg/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 microg/mL), and 3.69% and 4.40% in high-dose cefotaxime (20 microg/mL). The growth indices of rifampin+cefotaxime (2.19% and 2.19% at 2 microg/mL; 1.84% and 2.04% at 20 microg/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.