PURPOSE: Previous studies and our own clinical experience suggest that concurrent corticosteroid treatment for severe rickettsial disease with multiorgan failure may improve the clinical course or reduce mortality. However, the use of corticosteroids as adjunctive treatment for rickettsial diseases is controversial. We attempted to determine the influences of corticosteroid on the growth of Orientia tsutsugamushi in vitro to justify and evaluate the clinical applicability of corticosteroid in rickettsial disease. MATERIALS AND METHODS: L929 cells were infected with Orientia tsutsugamushi Gilliam. Dexamethasone was added to the cells at final concentrations of 10(1) and 10(7) pg/mL. Cultures were incubated at 35degrees C and processed for flow cytometry on the 6th day after addition of dexamethasone. RESULTS: Observation on the 6th day after treatment with dexamethasone in infected cultures revealed that there was no difference in fluorescence intensity among the treatment wells. Treatment of the cells with dexamethasone at concentrations of 10(1) and 10(7) pg/mL showed no influence on the growth of Orientia tsutsugamushi. CONCLUSION: Our results to show that isolated corticosteroid does not enhance the replication of Orientia tsutsugamushi in vitro. Concurrent use of anti-inflammatory or immunosuppressive doses of corticosteroids in conjunction with antibiotics may not have detrimental effects on the course of scrub typhus.
Animals ; Cell Line ; Cell Proliferation/drug effects ; Dexamethasone/*pharmacology ; Flow Cytometry ; Interferon-gamma/pharmacology ; Mice ; Orientia tsutsugamushi/*drug effects/growth & development ; Scrub Typhus/drug therapy/microbiology

BACKGROUND: To investigate whether chloroquine enhances the effect of antibiotics against Orientia tsutsugamushi, the causative organism of scrub typhus, we compared the effect of antibiotics in combination with chloroquine with the effect of antibiotics alone in vitro. MATERIALS AND METHODS: The Boryong or AFSC-4 strain was inoculated into ECV304 cells, and incubated in medium containing doxycycline (4 microg/mL), rifampin (4 microg/mL), azithromycin (0.5 microg/mL), chloroquine (1 microg/mL), and each of these antibiotics in combination with chloroquine for 7 d. Immunofluorescence (IF) staining for O. tsutsugamushi was performed 4 hr and 7 d after inoculation of the bacteria, and IF-positive foci were enumerated. RESULTS: Chloroquine inhibited the growth of O. tsutsugamushi by 15.5%. In combination with chloroquine, the antimicrobial effects increased by 4.4% for doxycycline (a 92.9% reduction of bacterial numbers for doxycycline versus a 97.3% reduction for doxycycline plus chloroquine), 4.6% for rifampin (90.0% versus 94.6%), and 8.3% for azithromycin (86.9% versus 95.2%). The antimicrobial effect of the antibiotics alone was significantly different compared to the combined effect of antibiotics and chloroquine (Wilcoxon signed-rank test, P = 0.001). CONCLUSIONS: The combined use of chloroquine with an antibiotic for the treatment of O. tsutsugamushi infections may be useful for increasing the efficacy of the antibiotics.
Anti-Bacterial Agents* ; Azithromycin ; Bacteria ; Chloroquine* ; Chungcheongnam-do ; Doxycycline ; Drug Synergism ; Drug Therapy, Combination ; Fluorescent Antibody Technique ; Orientia tsutsugamushi* ; Rifampin ; Scrub Typhus

Rhabdomyolysis is a rare complication that emerges in a variety of infectious diseases, such as tsutsugamushi infection. In this study, we report a 71-year-old female patient with tsutsugamushi infection who exhibiting rhabdomyolysis and acute renal failure. On admission, an eschar, which is characteristic of tsutsugamushi infection, was found on her right flank area. Moreover, her tsutsugamushi antibody titer was 1: 40960. The elevated values of serum creatinine phosphokinase (CPK), aldolase, creatinine and dark brown urine secondary to myoglobinuria are consistent with indications of rhabdomyolysis and acute renal failure due to tsutsugamushi infection. Her health improved without any residual effects after treatment with doxycyclin and hydration with normal saline.
Acute Disease ; Aged ; Creatine Kinase/blood ; Doxycycline/therapeutic use ; Female ; Human ; Kidney Failure/*etiology ; Rhabdomyolysis/*etiology ; Scrub Typhus/*complications/*diagnosis/drug therapy ; Support, Non-U.S. Gov't

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.
Anti-Bacterial Agents ; Azithromycin ; Cefotaxime ; Cell Line ; Doxycycline ; Drug Therapy, Combination ; Flow Cytometry ; Membrane Proteins ; Orientia tsutsugamushi ; Rifampin ; Scrub Typhus ; Sprains and Strains

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.
Anti-Bacterial Agents ; Azithromycin ; Cefotaxime ; Cell Line ; Doxycycline ; Drug Therapy, Combination ; Flow Cytometry ; Membrane Proteins ; Orientia tsutsugamushi ; Rifampin ; Scrub Typhus ; Sprains and Strains

Scrub typhus is a zoonosis caused by Orientia tsutsugamushi (O. tsutsugamushi) occurring mainly in autumn in Korea. The need of new antibiotics has arisen with a report on strains resistant to antibiotics and chronic infection. This study aims to identify susceptibility of tigecycline in-vitro as a new therapeutic option for O. tsutsugamushi. Antibacterial activity of tigecycline against the O. tsutsugamushi was compared with doxycycline using flow cytometry assay. The inhibitory concentration 50 (IC50) was 3.59×10(-3) µg/mL in doxycycline-treated group. Whereas in 0.71×10(-3) µg/mL tigecycline-treated group. These findings indicate that tigecycline may be a therapeutic option for the treatment of scrub typhus.
Anti-Bacterial Agents/*pharmacology/therapeutic use ; Drug Resistance, Bacterial/drug effects ; Humans ; Inhibitory Concentration 50 ; Minocycline/*analogs & derivatives/pharmacology/therapeutic use ; Orientia tsutsugamushi/*drug effects/physiology ; Scrub Typhus/drug therapy

No abstract available.
Anti-Bacterial Agents/therapeutic use ; Doxycycline/therapeutic use ; Face ; Humans ; Male ; Middle Aged ; Orientia tsutsugamushi/isolation & purification ; Scrub Typhus/drug therapy/microbiology/*pathology ; Skin/drug effects/*pathology ; Treatment Outcome

Nephrotic syndrome associated with Tsutsugamushi disease has not been previously reported. We are describing a case of Tsutsugamuchi disease presenting with nephrotic syndrome. A 72-year-old woman presented with fever and generalized edema. Laboratory studies revealed a leukocytosis, hypoalbuminemia, and hypercholesterolemia. Her urine protein excretion was 5.4 g/day. The anti-Tsutsugamushi antibody test was strongly positive (1:2,560). A renal biopsy was performed, and pathologic findings revealed membranous glomerulonephritis. The patient's clinical symptoms improved markedly after treatment with doxycycline.
Aged ; Anti-Bacterial Agents/therapeutic use ; Antibodies, Bacterial/blood ; Biopsy ; Doxycycline/therapeutic use ; Female ; Glomerulonephritis, Membranous/diagnosis/*etiology ; Humans ; Nephrotic Syndrome/diagnosis/*etiology ; Orientia tsutsugamushi/immunology ; Scrub Typhus/*complications/diagnosis/drug therapy/microbiology ; Treatment Outcome

OBJECTIVETo analyze the clinical manifestations and intervention against fulminant scrub typhus-associated hemophagocytic syndrome.

METHODThe medical records for the onset time of hemophagocytic syndrome, the clinical course, the chest radiographic findings, laboratory data, antibiotic therapy, clinical outcome and its prognosis were retrospectively reviewed.

RESULT(1) Four patients were diagnosed as scrub typhus based on clinical manifestations only, while 15 patients met the criteria of laboratory diagnosis. All 19 patients with scrub typhus had hemophagocytic syndrome. Eschar lesion was identified in 12 patients, 7 patients were described as an ulcer. A seasonal pattern (78.9% from June through September in 15 patients) was observed. Clinical misdiagnosis was common (all 19 cases). There were 9 patients with admitting diagnosis of scrub typhus, 10 patients were not diagnosed as scrub typhus after admission. In 5 cases within 3 days after admission diagnosis was corrected as scrub typhus. Until discharge from the hospital, 5 cases were not diagnosed with scrub typhus. In this study, the length of time from the illness onset (beginning of fever) to the occurrence of clinical symptoms was (9 ± 4) days. (2) All 19 patients had changed AST levels (149 ± 37) U/L, albumin levels (23 ± 4) g/L, C-reactive protein levels (103 ± 51) mg/L, and platelet count (48 ± 41) × 10⁹/L; bone marrow aspiration revealed in 16 patients marked hemophagocytosis. Weil-Felix agglutination test revealed positive results in 6 of 15 cases. Diagnostic IFA results were positive for 14 patients; 19 patients had interstitial pneumonitis and 17 patients had pleural effusion. (3) Five cases with failure to diagnose the disease had ineffective antibiotics treatment (imipenem or β-lactam-based regimens). These patients did not receive appropriate treatment with antibiotics against scrub typhus. Fourteen patients with admitting diagnosis of scrub typhus were successfully treated with appropriate antibiotics, 8 cases with chloramphenicol, 3 cases with azithromycin, and in 3 patients (2 cases of azithromycin and one case of erythromycin), therapy was then switched to chloramphenicol. Four patients were treated with methylprednisolone and 10 patients with dexamethasone. (4) During their hospitalization, the clinical course in five cases with failure to diagnose the disease rapidly developed and progressed to the life-threatening MODS, four of five cases died. However, the course in 14 patients were relieved and did not progress to MODS.

CONCLUSIONThe diagnosis of scrub typhus was frequently delayed, the early course of scrub typhus could be associated with hemophagocytic syndrome. Serious complications of MODS generally occur without antibiotic treatment. Scrub typhus-associated hemophagocytic syndrome should be taken into consideration among patients with acute systemic febrile illness, significant increases in levels of CRP, hypoalbuminemia, thrombocytopenia, splenomegaly, pneumonitis with pleural effusion, especially those with suspected exposure history. It was not easily recognized without careful observation and was present for a few days in each patient.

Anti-Bacterial Agents ; therapeutic use ; Azithromycin ; therapeutic use ; C-Reactive Protein ; analysis ; Clinical Laboratory Techniques ; Diagnosis, Differential ; Erythromycin ; therapeutic use ; Humans ; Imipenem ; therapeutic use ; Lymphohistiocytosis, Hemophagocytic ; epidemiology ; Pneumonia ; Retrospective Studies ; Scrub Typhus ; diagnosis ; drug therapy ; epidemiology

The use of quinolone for treatment of rickettsial diseases remains controversial. Recent clinical studies suggest that quinolone is not as effective as others in patients with rickettsial diseases including scrub typhus, although the mechanism is not well understood. In this study, we evaluated the mutation in gyrA associated with quinolone resistance. We prospectively enrolled scrub typhus patients, collected blood samples and clinical data from October, 2010 to November, 2011. Among the 21 patients enrolled, one initially received ciprofloxacin for 3 days but was switched to doxycycline due to clinical deterioration. We obtained the gyrA gene of Orientia tsutsugamushi from 21 samples (20 Boryong strain, 1 Kato strain) and sequenced the quinolone resistance-determining region. All of 21 samples had the Ser83Leu mutation in the gyrA gene, which is known to be associated with quinolone resistance. This suggests that quinolones may be avoided for the treatment of serious scrub typhus.
Aged ; Aged, 80 and over ; Amino Acid Sequence ; Anti-Bacterial Agents/*therapeutic use ; Bacterial Proteins/*genetics ; Ciprofloxacin/*therapeutic use ; DNA Gyrase/*genetics ; Doxycycline/therapeutic use ; Drug Resistance, Bacterial ; Female ; Genotype ; Humans ; Male ; Middle Aged ; Molecular Sequence Data ; Mutation ; Orientia tsutsugamushi/classification/enzymology/*genetics ; Phylogeny ; Prospective Studies ; Scrub Typhus/*drug therapy ; Sequence Alignment ; Sequence Analysis, DNA