Evaluation of the Therapeutic Effect of Antibiotics on Scrub Typhus: A Systematic Review and Network Meta-Analysis.

Background: To explore the efficacy and safety of drugs in patients with scrub typhus. Methods: For this systematic review and network meta-analysis, we searched PubMed, Embase, Web of Science, Cochrane Central Register of Clinical Trials, China National Knowledge Infrastructure (CNKI), and Wanfang data (WF) up to December 2021. All randomized controlled trials (RCTs) of antibiotics used to treat scrub typhus were included without language or date restrictions. The overall effectiveness was evaluated from 4 perspectives: cure rate (CR), defervescence time (DT), gastrointestinal symptoms-adverse events (GS-AD), and abnormal blood count-adverse events (ABC-AD). The quality of evidence was evaluated using the Cochrane Risk of Bias tool and GRADE system. Results: Sixteen studies involving 1,582 patients were included to evaluate 7 drugs, namely, azithromycin, doxycycline, chloramphenicol, tetracycline, rifampin, moxifloxacin, and telithromycin. In this network meta-analysis, rifampicin (82%) and chloramphenicol (65%) were more effective in terms of CR, and moxifloxacin (3%) from the quinolone family was the worst. Azithromycin caused the fewest events in terms of ABC-AD. No differences were found in this network meta-analysis (NMA) in terms of DT and GS-AD. Conclusions: Rifampicin was associated with the highest CR benefit and the lowest risk of DT when used to treat patients with scrub typhus, except in areas where tuberculosis (TB) was endemic. Azithromycin was found to be better in CR and was associated with a lower probability of GS-AD and ABC-AD; therefore, it may be considered to treat pregnant women and children. Moxifloxacin had a much lower CR than other drugs and is, therefore, not recommended for the management of scrub typhus. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42021287837.

Generation of protective immunity against Orientia tsutsugamushi infection by immunization with a zinc oxide nanoparticle combined with ScaA antigen.

BACKGROUND: Zinc oxide nanoparticle (ZNP) has been applied in various biomedical fields. Here, we investigated the usage of ZNP as an antigen carrier for vaccine development by combining a high affinity peptide to ZNP. RESULTS: A novel zinc oxide-binding peptide (ZBP), FPYPGGDA, with high affinity to ZNP (K a  = 2.26 × 106 M-1) was isolated from a random peptide library and fused with a bacterial antigen, ScaA of Orientia tsutsugamushi, the causative agent of scrub typhus. The ZNP/ZBP-ScaA complex was efficiently phagocytosed by a dendritic cell line, DC2.4, in vitro and significantly enhanced anti-ScaA antibody responses in vivo compared to control groups. In addition, immunization with the ZNP/ZBP-ScaA complex promoted the generation of IFN-γ-secreting T cells in an antigen-dependent manner. Finally, we observed that ZNP/ZBP-ScaA immunization provided protective immunity against lethal challenge of O. tsutsugamushi, indicating that ZNP can be used as a potent adjuvant when complexed with ZBP-conjugated antigen. CONCLUSIONS: ZNPs possess good adjuvant potential as a vaccine carrier when combined with an antigen having a high affinity to ZNP. When complexed with ZBP-ScaA antigen, ZNPs could induce strong antibody responses as well as protective immunity against lethal challenges of O. tsutsugamushi. Therefore, application of ZNPs combined with a specific soluble antigen could be a promising strategy as a novel vaccine carrier system.

Epstein-Barr Virus Associated Hemophagocytic Syndrome after Scrub Typhus Infection / 감염과화학요법

There have been a small number of cases of scrub typhus-associated hemophagocytic syndrome (HPS), most of which were treated successfully using adequate antibiotics. Here, we report a case of Epstein-Barr virus (EBV)-associated HPS after scrub typhus infection that was not improved using antirickettsial treatment. A 73-year-old male who had been diagnosed with scrub typhus according to an eschar and a positive serology was transferred to our institution because of a persistent fever despite 7-day doxycycline therapy. Physical and laboratory data showed hepatosplenomegaly, bicytopenia, hyperferritinemia, and hypofibrinogenemia. A bone marrow examination (BM) revealed hypercellular marrow with hemophagocytosis and histiocyte infiltration. EBV was detected in BM aspirates using polymerase chain reaction. After a diagnosis of HPS was made, the patient was treated successfully using high-dose steroids.

Inappropriateness of quinolone in scrub typhus treatment due to gyrA mutation in Orientia tsutsugamushi Boryong strain.

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.

Inappropriateness of Quinolone in Scrub Typhus Treatment Due to gyrA Mutation in Orientia tsutsugamushi Boryong Strain

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.

Efficacy of plant essential oils for the repellents against chiggers (Leptotrombidium imphalum) vector of scrub typhus.

Scrub typhus caused by the Orientia tsutsugamushi. Rodents, particularly rats, serve as principal reservoir hosts. Infection in man is transmitted by the, chigger bite. Repellents provide an effective agent of protecting individuals from chigger. In the present study 6 plant essential oils were tested for evaluation of their repellent activity against the chigger, Leptotrombidium imphalum. The results showed that Clove oil was significantly more effective than others with ED50 and EC50 of 0.420 mg and 2.3%, followed by Zingiber oil (8.458 mg and 42.3%), Vetiver oil (19.582 mg and 97.9%), Turmeric oil (24.343 mg and 121.7%), Orange oil (27.310 mg and 136.6%) and Boesenbergia oil (30.486 mg and 152.4%). These results suggested that Clove oil was the most efficient repellent against chigger which is the vector for scrub typhus.

Successful treatment of septic shock and respiratory failure due to leptospirosis and scrub typhus coinfection with penicillin, levofloxacin, and activated protein C.

Leptospirosis and scrub typhus are common zoonoses and coinfection with both diseases has been reported sporadically, particularly in tropical and subtropical areas. A 53-year-old male presented with acute hypoxemic respiratory failure and septic shock due to leptospirosis and scrub typhus coinfection confirmed by serological assessments. Antibiotics, including intravenous penicillin and levofloxacin, were administered and human recombinant activated protein C was added because of a high risk of death due to septic shock with multiple organ failure. The patient's hemodynamics and hypoxemia substantially improved 4 days later and he had a complete recovery from the disease after 10 days of hospitalization. Coinfection of leptospirosis and scrub typhus may easily go unrecognized by physicians in febrile travelers or patients in the region where both diseases are endemic. In severe and critical cases of leptospirosis, scrub typhus, or coinfection with both, the use of APC in addition to appropriate antibiotic treatment and standard critical care might provide a greater chance for survival and a favorable outcome.

Laboratory evaluation of aromatic essential oils from thirteen plant species as candidate repellents against Leptotrombidium chiggers (Acari: Trombiculidae), the vector of scrub typhus.

Scrub typhus, a rickettsial disease transmitted by several species of Leptotrombidium chiggers (larvae), is endemic in many areas of Asia. The disease is best prevented by the use of personal protective measures, including repellents. In this study commercially produced aromatic, essential oils of 13 plant species and ethanol (control) were tested in the laboratory for repellency against host-seeking chiggers of Leptotrombidium imphalum Vercammen-Grandjean and Langston (Acari: Trombiculidae). A rapid, simple and economic in vitro test method was used by exposing the chigger for up to 5 min. Repellency was based on relative percentages of chiggers attracted to test and control substances. Four of the 13 essential oils showed promise as effective repellent against L. imphalum chiggers. Syzygium aromaticum (clove) oil exhibited 100% repellency at 5% concentration (dilution with absolute ethanol), whereas Melaleuca alternifolia (tea tree) oil exhibited 100% repellency at 40% concentration. Undiluted oils of Zingiber cassamunar (plai) and Eucalyptus globules (blue gum) exhibited 100% repellency. Of the remaining nine essential oils, only 100% Pelargonium graveolens (geranium) exhibited >50% repellency (viz. 57%). Styrax torkinensis (benzoin) oil did not exhibit any repellency. These findings show that several aromatic, essential oils of plants may be useful as chigger repellent for the prevention of scrub typhus. Syzygium aromaticum oil may be safer and more economical to prevent chigger attacks than commercially available synthetic chemicals, such as DEET that may have harmful side effects.

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 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.

Travel-acquired scrub typhus: emphasis on the differential diagnosis, treatment, and prevention strategies.

Scrub typhus should be considered in any febrile patient presenting with a macular rash, a polyadenopathy, an eschar, or a history of environmental exposure in endemic areas. The differential diagnosis includes malaria, typhoid fever, leptospirosis, and arboviroses. Doxycycline 100 mg twice daily for 7 days should be initiated as soon as the disease is suspected.

Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus.

Leptospirosis and scrub typhus are important causes of acute fever in Southeast Asia. Options for empirical therapy include doxycycline and azithromycin, but it is unclear whether their efficacies are equivalent. We conducted a multicenter, open, randomized controlled trial with adult patients presenting with acute fever (<15 days), without an obvious focus of infection, at four hospitals in Thailand between July 2003 and January 2005. Patients were randomly allocated to receive either a 7-day course of doxycycline or a 3-day course of azithromycin. The cure rate, fever clearance time, and adverse drug events were compared between the two study groups. A total of 296 patients were enrolled in the study. The cause of acute fever was determined for 151 patients (51%): 69 patients (23.3%) had leptospirosis; 57 patients (19.3%) had scrub typhus; 14 patients (4.7%) had murine typhus; and 11 patients (3.7%) had evidence of both leptospirosis and a rickettsial infection. The efficacy of azithromycin was not inferior to that of doxycycline for the treatment of both leptospirosis and scrub typhus, with comparable fever clearance times in the two treatment arms. Adverse events occurred more frequently in the doxycycline group than in the azithromycin group (27.6% and 10.6%, respectively; P = 0.02). In conclusion, doxycycline is an affordable and effective choice for the treatment of both leptospirosis and scrub typhus. Azithromycin was better tolerated than doxycycline but is more expensive and less readily available.

Successful treatment of pulmonary hemorrhage associated with leptospirosis and scrub typhus coinfection by early plasma exchange.

Leptospirosis and scrub typhus coinfections have been reported in up to 41% of agricultural workers with acute leptospirosis in Thailand, but only sporadically in Taiwan. Because of the nonspecific clinical presentations, it is difficult to differentiate patients with coinfections from leptospirosis alone. However, failure to identify coinfection may lead to mortality if inappropriate antibiotics are used. We report a 31-year-old man coinfected with leptospirosis and scrub typhus, which manifested as diffuse alveolar hemorrhage and acute renal failure mimicking pulmonary-renal syndrome. The patient was treated by early plasma exchange and a 7-day course of moxifloxacin therapy. Both pulmonary hemorrhage and hypoxemia resolved substantially on the 4th day of hospitalization. He had a complete recovery from the disease after 6 weeks of hospitalization.

Scrub typhus during pregnancy and its treatment: a case series and review of the literature.

Although scrub typhus is uncommon in pregnant women, when present, it can have serious repercussions for the mother and developing fetus. Since it is uncommon, the clinical impact of scrub typhus on pregnancy has not been elucidated and an effective and safe therapeutic regimen has not been validated. The medical records of pregnant women whose scrub typhus were treated at Chungnam National University Hospital were reviewed and their clinical outcomes were evaluated. A review of the literature was also performed on pregnant women with scrub typhus and their clinical outcomes. Eight pregnant women with scrub typhus were treated successfully with a single 500-mg dose of azithromycin, and no relapses were reported. They all delivered healthy babies at term, without congenital or neonatal complications. In the reviews, azithromycin was effective against scrub typhus and had favorable pregnancy outcomes. Ciprofloxacin and cefuroxime failed to treat scrub typhus and fetal loss resulted. A single 500-mg dose of azithromycin may be a reasonable treatment regimen for pregnant women with scrub typhus. Ciprofloxacin might not be advisable for the treatment of scrub typhus during pregnancy. Scrub typhus itself seems to have serious adverse effects on pregnancy if not appropriately controlled.

Use of High-dose Steroid in a Case of Scrub Typhus with Acutely Progressive Local Neurologic Symptoms / 감염

Scrub typhus, which is caused by Orientia tsutsugamushi, is systemic illness that causes generalized vasculitis. The central nervous system (CNS) is the most crucial target in scrub typhus as in other rickettsial disease. A 54-year-old woman, who was receiving doxycycline under the diagnosis of scrub typhus, developed rapidly progressive neurologic symptoms. During the treatment, abnormal mental function, abnormal lateral gaze, paralysis in upper extremities and dysphasia occurred in the patient. To investigate CNS involvement in the patients, CSF profile (cell count and levels of protein and glucose) and brain radiologic image (brain CT, brain MRI) were concurrently examined. And ampicillin and high-dose steroid were empirically added to her treatment with doxycycline. With use of high-dose steroid, the initial neurologic symptoms such as restlessness and irritability and other disorders like abnormal lateral gaze and paralysis in upper extremities were recovered. And also any other neurologic sequelae did not appear. We could observe the clinical improvements of abnormal neurologic symptoms and signs after use of high-dose steroid in the Orientia tsutsugamushi infected patients. A further intensive study about the steroid therapy in Orientia tsutusgamushi infected patients with focal neurologic symptoms is required.

Psoralen photochemical inactivation of Orientia tsutsugamushi in platelet concentrates.

BACKGROUND: The risk of transfusion transmission of disease has been reduced by the combination of predonation questions and improved transfusion-transmitted disease assays, but the risk is still present. This study was conducted to determine if psoralen photochemistry could inactivate an obligate intracellular bacterium, with documented potential for transfusion, in PCs to further improve safety. STUDY DESIGN AND METHODS: PCs were inoculated with MNCs infected with Orientia tsutsugamushi. The concentrates were treated with amounts ranging from 0.86 to 138 micromol per L of 4'-(aminomethyl)-4,5',8-trimethylpsoralen hydrochloride (AMT) combined with a constant long-wave UVA light (320-400 nm) exposure of 5 J per cm(2). The effects of photochemical treatment were analyzed by using a mouse infectivity assay along with in vitro testing by PCR, indirect fluorescence antibody, direct fluorescence antibody, and Giemsa staining. RESULTS: AMT, at 0.86 micromol per L or more, combined with UVA light of 5 J per cm(2), inactivated O. tsutsugamushi that contaminated PCs. The PCs that did not receive the combined treatment caused infection. CONCLUSIONS: The psoralen AMT, in conjunction with UVA light exposure, effectively abolished the infectivity of PCs deliberately contaminated with the scrub typhus organism O. tsutsugamushi, as tested in a mouse infectivity assay.

Azithromycin activities against Orientia tsutsugamushi strains isolated in cases of scrub typhus in Northern Thailand.

Azithromycin was given to mice and humans infected with strains of Orientia tsutsugamushi from northern Thailand, where drug-resistant scrub typhus occurs. Azithromycin and doxycycline yielded comparable mouse survival rates (73 and 79%, respectively; P > 0.5). Symptoms, signs, and fever in two pregnant women abated rapidly with azithromycin. Prospective human trials are needed.

Chloramphenicol, gentamicin, and ciprofloxacin against murine scrub typhus.

Ciprofloxacin (120 mg/kg of body weight per day), chloramphenicol (300 mg/kg per day), and gentamicin (30 mg/kg per day) were compared with placebo in a BALB/cj mouse model of scrub typhus. All animals treated with ciprofloxacin and chloramphenicol survived. All animals treated with gentamicin or placebo died. All surviving animals showed evidence of seroconversion. Ciprofloxacin and chloramphenicol were statistically more effective in preventing death than gentamicin or placebo.