Oral Azithromycin Versus Doxycycline in the Treatment of Children With Uncomplicated Scrub Typhus: A Randomized Controlled Trial.

OBJECTIVES: To compare the efficacy of azithromycin versus doxycycline in treatment of children with uncomplicated scrub typhus in terms of percentage of children who attained remission of fever after 72 hours of administration of first dose of the study drug, mean time taken to attain fever defervescence, normalization of laboratory parameters, resolution of hepatosplenomegaly and lymphadenopathy. DESIGN: Interventional, open-labeled randomized controlled trial. STUDY METHODS: Patients admitted with undifferentiated fever in the In-Patient Department (IPD), Department of Paediatrics, All India Institute of Medical Sciences, Bhubaneswar, India, as per the inclusion criteria were randomized and was treated with azithromycin at 10 mg/kg/d in one group and doxycycline at 4.4 mg/kg/d for 5 days in the other group and was assessed based on the primary and secondary objectives. RESULTS: There was no statistically significant difference between the percentage of children who attained remission of fever after 72 hours of administration of azithromycin (98.2%) and doxycycline (96.5%) (P value 0.47) and the average time taken for fever defervescence (azithromycin: 24.53 hours; doxycycline: 25.82 hours; P value 0.36). The odds of attaining fever remission in the doxycycline group as compared with the azithromycin group was 1.01 (95% confidence interval -0.60 to -1.71), which was also statistically not significant. There was less incidence of adverse drug events in the azithromycin group (1.78%) as compared with the doxycycline group (8.6%), which was statistically significant (P value 0.02). CONCLUSION: Azithromycin is equally efficacious in terms of fever defervescence, resolution of clinical signs and laboratory parameters as doxycycline, is safer and better tolerated in children.

Rickettsiosis, un caso de TIBOLA / Rickettsia, a case of TIBOLA

Las rickettsiosis están cobrando especial protagonismo a raíz de nuevas especies descritas en los últimos años. La más frecuente en nuestro medio es la infección por Rickettsia conorii, que produce la fiebre botonosa mediterránea. Recientemente se incluye con más frecuencia en el diagnóstico diferencial la denominada TIBOLA (tick-borne lymphadenopathy) o DEBONEL (dermacentor-borne necrosis eritema lymphadenopathy), cuya primera confirmación serológica data de 1997 en Francia y que es transmitida por la garrapata Dermacentor marginatus, producida por R. slovaca, entre otras, y con similares características clínicas a las de la fiebre botonosa mediterránea. Se presenta el caso de una niña de ocho años de edad que acude al Servicio de Urgencias con la presencia de fiebre y una lesión costrosa, de aspecto necrótico, en el cuero cabelludo, así como adenopatías de localización cérvico-occipital y retroauricular, refiriendo la picadura de una garrapata hace 15 días. El diagnóstico se confirma mediante la presentación clínica y serologías cruzadas con Rickettsia conorii. Tras pauta de eritromicina a dosis de 40 mg/kg/día durante ocho días se evidencia la desaparición progresiva de las lesiones a lo largo de un mes (AU)

Rickettsia are gaining special importance following new species discovered in recent years. The most common in our environment is Rickettsia conorii infection, which produces the so-called Mediterranean fever boutonneuse. Recently are included more often in the differential diagnosis the called TIBOLA (tick-borne lymphadenopathy) or also known as DEBONEL (dermacentor-borne necrosis lymphadenopathy erythema), whose first serologic confirmation dates back to 1997 in France and is transmitted by the tick Dermacentor marginatus, produced by R. slovaca among others and has similar clinical features as the Mediterranean spotted fever. The case of an 8 year-old who came to the Emergency Services with the presence of fever and scabby lesion, necrotic scalp and cervical lymphadenopathy of occipital and retroauricular location is presented, referring tick bite 15 days ago. The diagnosis is confirmed by clinical and serological tests Rickettsia conorii cross-presentation. After erythromycin dose regimen of 40 mg/kg/day for 8 days, progressive disappearance of lesions was evident after a month (AU)

Arthropod-borne bacterial diseases in pregnancy.

Arthropod-borne bacterial diseases affect more than 25,000 Americans every year and thousands more around the world. These infections present a diagnostic dilemma for clinicians because they mimic many other pathologic conditions and are often low on or absent from the differential diagnosis list. Diagnosis is particularly challenging during pregnancy, as these infections may mimic common pregnancy-specific conditions, such as typical and atypical preeclampsia, or symptoms of pregnancy itself. Concerns regarding the safety in pregnancy of some indicated antibiotics add a therapeutic challenge for the prescriber, requiring knowledge of alternative therapeutic options for many arthropod-borne bacterial diseases. Physicians, especially those in endemic areas, must keep this class of infections in mind, particularly when the presentation does not appear classic for more commonly seen conditions. This article discusses presentation, diagnosis, and treatment of the most common of these arthropod-borne bacterial diseases, including Lyme disease, Rocky Mountain spotted fever, tick-borne relapsing fever, typhus, plague, cat-scratch disease, and Carrión disease.

[Rickettsial diseases in Switzerland, update for the general practitioner]. / Rickettsioses d'importation.

Rickettsial diseases are arthropod-borne zoonosis. They are still misdiagnosed in Switzerland. Since development in molecular genetics, number of pathogenic species increased dramatically. In recent years, the incidence rise worldwide. Climatic conditions and development of tropical travels could explain it. In a near future, the Swiss general practitioner may face an increase of cases. Clinical presentation is unspecified. The eschar is the key diagnostic element but can be easily overlooked. Serology, the indirect immunofluorescence assay is the reference method. PCR can give the diagnosis in acute phase. However empirical treatment should be prescribed as soon as diagnosis is suspected. No vaccine is currently available and use of repellent is still the best way of prevention.

Systemic treatment with CpG-B after sublethal rickettsial infection induces mouse death through indoleamine 2,3-dioxygenase (IDO).

Due to its strong immune stimulatory effects through TLR9, CpG-containing oligodeoxynucleotides (CpG ODN) have been tested in multiple clinical trials as vaccine adjuvant for infectious diseases and cancer. However, immune suppression induced by systemic administration of CpGs has been reported recently. In this study, we evaluated the impact of CpGs in an acute rickettsiosis model. We found that systemic treatment with type B CpG (CpG-B), but not type A CpG (CpG-A), at 2 days after sublethal R. australis infection induced mouse death. Although wild-type (WT) B6 and IDO(-/-) mice showed similar survival rates with three different doses of R. australis infection, treatment with CpG-B after sublethal infection consistently induced higher mortality with greater tissue bacterial loads in WT but not IDO(-/-) mice. Also, CpG-B treatment promoted the development of higher serum concentrations of proinflammatory cytokines/chemokines through IDO. Furthermore, while T cell-mediated immune responses enhanced by CpG-B were independent of IDO, treatment with CpG-B promoted T cell activation, PD-1 expression and cell apoptosis partially through IDO. A depletion study using anti-mPDCA-1 mAb indicated that plasmacytoid dendritic cells (pDC) were not required for CpG-B-induced death of R. australis-infected mice. Additionally, the results in iNOS(-/-) mice suggested that nitric oxide (NO) was partially involved in CpG-B-induced death of R. australis-infected mice. Surprisingly, pre-treatment with CpG-B before administration of a lethal dose of R. australis provided effective immunity in WT, IDO(-/-) and iNOS(-/-) mice. Taken together, our study provides evidence that CpGs exert complex immunological effects by both IDO-dependent and -independent mechanisms, and that systemic treatment with CpGs before or after infection has a significant and distinct impact on disease outcomes.

New insight into immunity and immunopathology of Rickettsial diseases.

Human rickettsial diseases comprise a variety of clinical entities caused by microorganisms belonging to the genera Rickettsia, Orientia, Ehrlichia, and Anaplasma. These microorganisms are characterized by a strictly intracellular location which has, for long, impaired their detailed study. In this paper, the critical steps taken by these microorganisms to play their pathogenic roles are discussed in detail on the basis of recent advances in our understanding of molecular Rickettsia-host interactions, preferential target cells, virulence mechanisms, three-dimensional structures of bacteria effector proteins, upstream signalling pathways and signal transduction systems, and modulation of gene expression. The roles of innate and adaptive immune responses are discussed, and potential new targets for therapies to block host-pathogen interactions and pathogen virulence mechanisms are considered.

Rickettsiosis Variceliforme o Viruela Rickettsiósica / Varicelliform Rickettsiosis or Rickettsial pox

El género de las Rickettsias tiene como característica ser bacterias gramnegativas intracelulares que precisan de un vector para su transmisión. Las fiebres exantemáticas producidas por Rickettsias son endémicas en nuestra región (Albacete), sobre todo en áreas rurales. Se presenta el caso de un paciente con una variedad inusual de enfermedad producida por Rickettsias, caracterizada por lesiones papulovesiculosas (AU)

Rickettsia is a genus of intracellular, gram-negative bacteria that requires a vector for transmission. Spotted fever caused by Rickettsia is endemic in our region (Albacete), especially in rural areas. We present a patient with an unusual variety of Rickettsial disease, characterised by papulovesicular lesions (AU)

A randomized trial of doxycycline for Mansonella perstans infection.

BACKGROUND: Mansonella perstans infection is common in areas of Africa where Wuchereria bancrofti, a causative agent of lymphatic filariasis, is endemic. M. perstans is refractory to standard antifilarial therapies. The recent discovery of bacterial endosymbionts (e.g., wolbachia) in most filarial species, including M. perstans, provides new therapeutic options for reducing microfilaremia. METHODS: In an open-label, randomized trial, we recruited subjects with M. perstans microfilaremia, with or without concomitant W. bancrofti infection, from four villages in Mali and randomly assigned them to receive doxycycline, at a dose of 200 mg daily for 6 weeks (106 subjects), or no treatment (110). At 6 months, subjects who were coinfected with W. bancrofti underwent a second random assignment, to treatment with a single dose of albendazole (400 mg) and ivermectin (150 microg per kilogram of body weight) or no treatment. Subjects were monitored daily during the first 6-week study period for adverse events. M. perstans and W. bancrofti microfilarial levels were assessed at 6, 12, and 36 months. RESULTS: At 12 months, 67 of 69 subjects who had received treatment with doxycycline only (97%) had no detectable M. perstans microfilariae per 60 microl of blood, as compared with 10 of 63 subjects who had received no treatment (16%) (relative risk, 6.18; 95% confidence interval, 3.63 to 11.89; P<0.001). At 36 months, M. perstans microfilaremia remained suppressed in 48 of 64 subjects who had received treatment with doxycycline only (75%), a finding that was consistent with a macrofilaricidal effect of doxycycline. Vomiting was more frequent in the doxycycline-treated group than in the untreated group (17% vs. 4%). CONCLUSIONS: These results are consistent with previous findings that M. perstans harbors the intracellular endosymbiont, wolbachia, and suggest that doxycycline is an effective therapy for M. perstans infection. (ClinicalTrials.gov number, NCT00340691.)

Human rickettsialpox, southeastern Mexico.

The detection of Rickettsia akari in 2 human patients increased the diversity of rickettsioses affecting the public health in the southeast of Mexico. Rickettsialpox should be considered in the differential diagnosis with other febrile illnesses for the correct diagnosis and accurate treatment of this potential threat to human health.

Fever of unknown origin due to rickettsioses.

Most common rickettsioses do not fill the criteria for fever of unknown origin, with fever often inferior to lasting less than 1 week. Q fever, scrub typhus, murine typhus, human monocytic ehrlichiosis, and Bartonellosis could fill these criteria, however, notably in uncommon presentations. Moreover, in patients returning from tropical areas or from geographic endemic areas for rickettsiosis, or in patients in contact with animals or ticks, theses etiologies should be kept in mind by physicians challenged to diagnose cause of fever. In this context, even without confirmation of diagnosis, treatment with doxycycline should be used.

Rickettsioses in Japan and the far East.

Three rickettsial diseases are known to exist in Japan currently: Japanese spotted fever (JSF), Tsutsugamushi disease (TD; scrub typhus), and Q fever. Since April 1999, the system for infection control and prevention in Japan has changed drastically. JSF, Q fever, and TD, as emerging infectious diseases, are designated as national notifiable diseases.The geographic distribution of JSF patients is along the coast of central and southwestern Japan, whereas TD and Q fever occur almost all over the country. The number of JSF patients reported was 216 cases during 1984-1998 and 268 cases, under the revised law, in 1999-2004. About 300-1000 cases of TD occur every year, and 7-46 cases of Q fever in 1999-2004. The number of cases of JSF and its endemic area are gradually increasing. There was only one fatality due to JSF until 2003, whereas two patients died of JSF in 2004, so JSF is still a life-threatening disease in Japan. Treatment of fulminant JSF consists of prompt administration of a combination of tetracycline and quinolone. Recent tick surveys revealed that the most probable vectors of JSF are Haemophysalis flava and Haemophysalis hystericis. In addition to R. japonica, two serotypes or species of spotted fever group rickettsiae have been isolated from ticks in Japan; one is closely related to R. helvetica and the other is a new genotype of unknown genotype AT, which is closely related to a Slovakian genotype. These serotypes are of uncertain clinical significance. Epidemiology of rickettsioses in the Far East is mentioned briefly.

Infección por Rickettsia slovaca tras la picadura de una garrapata / Rickettsia slovaca infection alter a tick bite

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Rickettsial skin disease: uncommon presentations.

Rickettsioses occurring worldwide show a significant morbidity and mortality when not properly treated. Early diagnosis is mandatory for better outcome. Clinical symptoms and patient's history are essential, but uncommon presentation of these arthropod-borne diseases may be a challenge.

Rickettsialpox: report of three cases and a review.

Rickettsialpox is a rare mite-borne rickettsiosis that is encountered in urban populations in the eastern United States and throughout the world. It is characterized clinically by an eschar, fever, and a papulovesicular eruption. Both of these cutaneous manifestations may be mimicked by infectious diseases that have been designated as bioterrorist agents by the United States Centers for Diseases Control and Prevention: the former by anthrax, and the latter by smallpox. It is thus important for clinicians to be familiar with rickettsialpox. We report 3 cases and review the epidemiology, clinical and laboratory findings, differential diagnosis, and management of this disease.

Scrub typhus and tropical rickettsioses.

PURPOSE OF REVIEW: Recent developments in molecular taxonomic methods have led to a reclassification of rickettsial diseases. The agent responsible for scrub typhus (Orientia tsutsugamushi ) has been removed from the genus Rickettsia and a bewildering array of new rickettsial pathogens have been described. An update of recent research findings is therefore particularly timely for the nonspecialist physician. RECENT FINDINGS: An estimated one billion people are at risk for scrub typhus and an estimated one million cases occur annually. The disease appears to be re-emerging in Japan, with seasonal transmission. O. tsutsugamushi has evolved a variety of mechanisms to remain viable in its intracellular habitat. Slowing the release of intracellular calcium inhibits apoptosis of macrophages. Subsets of chemokine genes are induced in infected cells, some in response to transcription factor activator protein 1. Cardiac involvement is uncommon and clinical complications are predominantly pulmonary. Serious pneumonitis occurred in 22% of Chinese patients. Dual infections with leptospirosis have been reported. Standardized diagnostic tests are being developed and attempts to improve treatment of women and children are being made. Of the numerous tick-borne rickettsioses identified in recent years, African tick-bite fever appears to be of particular importance to travellers. The newly described flea-borne spotted fever caused by Rickettsia felis may be global in distribution. SUMMARY: Rash and fever in a returning traveler could be rickettsial and presumptive doxycycline treatment can be curative. Recent research findings raise more questions than answers and should stimulate much needed research.

Wolbachia infection and the expression of cytoplasmic incompatibility in sandflies (Diptera: Psychodidae) from Egypt.

A PCR-based method was used to screen four laboratory colonies of sandflies for Wolbachia infection. The colonies - one of Phlebotomus langeroni, one of P. bergeroti and two of P. papatasi - were all derived from sandflies collected in Egypt. Only one of the colonies, derived from P. papatasi collected in Sinai, was found infected. The sequence of the PCR product for this colony was identical to that previously reported for the Wolbachia in P. papatasi from Israel. The induction with tetracycline of cytoplasmic incompatibility (CI) in flies from the P. papatasi (Sinai) colony was then investigated, through reciprocal crosses between treated and untreated P. papatasi siblings. Partial CI expression was attained in the crosses involving antibiotic-treated (i.e. uninfected) females, whether the males used were infected with Wolbachia or had also been cleared of Wolbachia by antibiotic treatment. Most (75%) of the eggs oviposited by uninfected females that had been crossed with infected males, and most (58%) of those laid by uninfected females that had been crossed with uninfected males, failed to hatch. These results provide the first published evidence showing that Wolbachia infection in sandflies is advantageous to the insects. The failure to detect Wolbachia in one of the colonies derived from Egyptian P. papatasi or in the colonies derived from Egyptian P. bergeroti and P. langeroni may indicate that the inter- and intra-specific spread of Wolbachia is discontinuous, even within one country.

Emerging rickettsioses of the Thai-Myanmar border.

To investigate the presence of rickettsioses in rural residents of the central Thai-Myanmar border, we tested the blood of 46 patients with fever. Four patients had murine typhus, three patients had scrub typhus, and eight patients had spotted fever group rickettsioses, including the first case of Rickettsia felis infection reported in Asia.

Antibiotic therapy in murine filariasis (Litomosoides sigmodontis): comparative effects of doxycycline and rifampicin on Wolbachia and filarial viability.

The symbiosis of filarial nematodes and rickettsial Wolbachia endobacteria has been exploited as a target for antibiotic therapy of filariasis. Depletion of Wolbachia after tetracycline treatment results in filarial sterility because of interruption of embryogenesis and inhibits larval development and adult worm viability. The aim of this study was to investigate if antibiotic intervention of BALB/c mice infected with the rodent filaria Litomosoides sigmodontis with rifampicin or the combination of rifampicin and doxycycline can be used to shorten the treatment period. Both regimens, when given over a period of 14 days initiated with infection, were sufficient to deplete Wolbachia as evidenced by immunohistology and semiquantitative PCR. Worm development and filarial load were significantly reduced in experiments followed up until 63 days p.i. The therapy inhibited embryogenesis and led to filarial sterility. In contrast, treatment with doxycycline alone for 21 days led only to a modest reduction of Wolbachia, filarial growth retardation, worm viability and fertility. In conclusion, the combination of antirickettsial drugs could be used as a suitable tool to explore the minimum duration of therapy required for the depletion of Wolbachia in parasitized hosts subsequent to the onset of patency in human and animal filariasis and the prevention of adverse reactions in human infections.