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Rickettsia species: (R. africae,R. australis, R. conorii, R. felis, R. honei, R. japonica, R. sibirica mongolotimonae, R. heilongjanhensis, R. slovaca, R. sibirica) R. raoultii, R. parkerii, R. aeschlimannii Updated October, 2008
GENERAL DESCRIPTION Microbiology Guided Medline Search Rickettsia species are gram negative, strictly intracellular bacilli, that multiply within the cytosol of endothelial cells. Spotted fever group rickettsiosis now includes 17 recognized human pathogens (Table 1) (37, 49). Rickettsia helvetica has been first isolated from Ixodes ricinus ticks in Europe, but recent investigations indicate that this species is a probable human pathogen including seroconversion against R. helvetica antigen in a 37-year-old man with prolonged fever in Alsace (France) (12, 35).The remaining rickettsiae have only been isolated from arthropods, but these species should be considered opportunistic pathogens (Table 4). Perez-Osorio CE, et al. Rickettsia felis as emergent global threat for humans. Emerg Infect Dis 2008;14:1019-1023. Epidemiology Guided Medline Search Ticks are both the vector and the main reservoir of spotted fever group rickettsiosis, except R. akari and R. felis. Humans are usually infected via the tick-bite or less frequently via the tick hemolymph after crushing the tick. Usual vectors and geographic distributions of spotted fever group rickettsiosis (other than Rocky Mountain spotted fever and Rickettsialpox) are summarized in Table 1. Clinical Manifestations Guided Medline Search Spotted fever group rickettsiosis are clinically characterized by the combination of fever, headache, myalgia, and a cutaneous maculopapular rash involving the entire body including palms and soles. An eschar may develop at the site of the tick bite, but remains most often unnoticed, with local lymphadenopathy. In one disease a rope-like bipolar lymphangitis has been described. Incubation period is usually 4 to 7 days. Truncated clinical presentations are frequent, and a delayed seroconversion in infected patients may lead to delayed diagnosis and antibiotic therapy, and thus more profound illness. Mediterranean Spotted Fever was first considered a generally benign disease, but severe forms are reported in 6% of patients and mortality may be as high as 2.5 %. Malignant forms may present with petechial rash and may lead to neurological, renal, or cardiac complications. In patients involved with either Israeli spotted fever or Astrakhan fever, a characteristic cutaneous eschar at the site of the tick bite is usually absent. Severe, and even fatal cases have been reported only for Israeli spotted fever. The Siberian Tick Typhus is characterized by a frequent central nervous system involvement. In patients involved with Japanese or Oriental spotted fever an eschar is often present at the site of the vector bite which is, in contrast to other spotted fever group rickettsiosis, often noticeable (27, 61). In Australia, both the Queensland Tick Typhus and the Flinders Island spotted fever are usually mild diseases. An eschar is rarely observed in patients involved with Flinders Island spotted fever, whereas regional lymph node enlargement is common (2, 60). The first documented human infection with R. africae was reported in Zimbabwe in 1992 (24), but the diseases is prevalent in all sub-Saharan Africa (13, 42) and in Guadeloupe in the Caribbean islands (36). African tick bite fever is usually a mild disease, characterized by headache, fever, eschar at the tick-bite site, regional lymphadenopathy, but a cutaneous rash is lacking or very transient in most cases. When present, it’s usually maculo-vesicular. Because several Amblyomma ticks may attack a human simultaneously, the presence of multiple eschars in an infected patient has been reported, and is characteristic of African tick bite fever. The first case of flea borne spotted fever caused by R. felis (previously named as the ELB agent), was described in 1994 in Texas (US) (56). Raoult et al. (45) demonstrated the presence of high anti-R. felis antibody titers in sera from two French patients and two Brazilian patients with clinical rickettsial diseases. Recent investigations indicate that this species is probably widespread (1). The first human case of Rickettsia sibirica mongolotimonae infection was documented in Marseille (France), in March 1996, a time of year when Mediterranean Spotted Fever is unlikely (41, 67). This patient presented with a mild disease, with only a few spots on the body and with an inoculation eschar. A second case has been diagnosed in Marseille in 1998 (15), in a patient with fever, cutaneous eschar, and a bipolar rope-like lymphangitis between the cutaneous eschar and a loco-regional lymph node, and thus the disease was named as lymphangitis associated rickettsiosis (LAR) (11). The first documented case of human infection with R. slovaca was reported in 1997 (39). Infected patients typically have a tick-bite on their hair, and present with fever, fatigue, headache, an eschar at the site of the tick-bite, an enlarged cervical lymph node, but no rash. he disease has been named as either Tibola (for tick borne lymphadenitis) or Debonel (for Dermacentor-borne necrosis erythema lymphadenopathy). It can be caused also by R. raoultii (14, 37, 44). Laboratory Diagnosis Guided Medline Search
Diagnosis of rickettsial diseases remains based upon serology (8,
26). An
antibody response is usually detected only after 10 days from the onset of
systemic symptoms, and antibody titers reach a peak after 3 to 4 weeks or later
if an antibiotic therapy has been administered. Thus an appropriate antibiotic
therapy should be administered upon suspicion of a rickettsial infection,
without awaiting for diagnostic confirmation using specific serological tests.
Delay in appropriate antibiotic therapy is the main factor for poor prognosis in
patients infected with the more severe spotted fever group rickettsial diseases,
such as Rocky Mountain spotted fever or Mediterranean spotted fever. Before
rickettsial antigens were available for diagnosis, the Weil-Felix test was based
on the observation that antibodies from patients recovering from rickettsial
infections were able to agglutinate antigens from different Proteus vulgaris
strains (OX-K, OX-2, OX-19). Sera from patients involved with spotted fever
group rickettsiosis (except rickettsialpox and Rocky Mountain spotted fever)
displayed cross reacting antibodies against Proteus vulgaris OX-2. More
recent serological tests use the different Rickettsia species grown in
cell cultures as antigen (26). Techniques which have been used include
complement fixation tests, microagglutination assays, indirect hemagglutination
tests, indirect fluorescent antibody (IFA) tests, and ELISA. IFA remains the
current reference, allowing determination of IgG and IgM. Using the IFA test, a
single IgG antibody titer of > 128, an IgM titer of > 32, or fourfold increase
in antibody titers between acute phase and convalescent phase sera are
considered diagnostic. However, serology most often does not allow accurate
determination of the Rickettsia species involved. Adsorption assays and
western blot may help in such a differentiation. Culture of Rickettsia
spp. from clinical samples (mainly blood or a cutaneous eschar biopsy) requires
cell culture systems and a level-3 equipped laboratory, and thus is only
available in reference laboratories. Sensitivity is low, especially when an
appropriate antibiotic therapy has been administered before collecting clinical
samples. Direct amplification of rickettsial DNA using PCR may be obtained from
blood (buffy coat), an eschar biopsy, or rarely from other clinical samples.
This technique may be especially useful early in the course of a rickettsial
disease, before an antibody response is detected. Pathogenesis Guided Medline Search Spotted fever group rickettsiae are inoculated to humans through the skin via the bite of ticks (or fleas for R. felis). Endothelial cells are the primary target cells for rickettsiae, leading to a generalized vasculitis. The diversity of the rickettsial microvascular injuries in the infected patient explains the wide spectrum of clinical manifestations and life threatening complications that may be encountered.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Because of their obligate intracellular life-style, susceptibility of rickettsiae to antibiotics cannot be assessed in conventional microbiological tests. Three experimental models have been developed to test the antibiotic susceptibility of rickettsiae: animal models, the embryonated egg model, and cell culture models. Animal models and the embryonated egg model were the first described, however, antibiotic doses used in these models were much higher than those usually used in humans, and therefore it is difficult to extrapolate data to the clinical situation. In vitro infected cell models have been more recently elaborated. These allow more convenient investigation of the antibiotic susceptibility of rickettsiae, and extracellular antibiotic concentrations used in these models may be compared to antibiotic concentrations obtained in human sera. Single Drug Animal Models: Guinea pigs and mice were most commonly used as experimental models for spotted fever group rickettsiae to test in vivo antibiotic activity. Rickettsiae were most often injected by the intraperitoneal or intranasal routes, which do not correspond to the natural route of human infection. Antibiotics were administered either orally or subcutaneously. Infection in animals has been assessed by the presence of fever, specific serological response, and death ratio, as compared to untreated infected controls. However, clinical manifestations in infected animals do not reproduce those of human disease and the reliability of animal models for rickettsial infections remains to be established. R. rickettsii, the agent of Rocky Mountain Spotted Fever, was the only spotted fever group rickettsia for which antibiotic susceptibility was evaluated in an animal model, in experiments showing complete protection against fever in infected guinea pigs treated with chlortetracycline (Aureomycin) (66). Embryonated Egg Model: In the embryonated egg model, rickettsiae were injected into the yolk sac of the eggs. This resulted in death of the embryo usually within a few days following infection. Antibiotics were administered by the same route and usually within the first hour following rickettsial inoculation. Antibiotic activity was deduced from the difference in mean survival time (DMST) of infected embryos receiving antibiotics as compared to infected untreated controls. A rickettsiostatic effect of antibiotics allowed the embryos to survive up to the last day of experiments, usually day 14. The rickettsiacidal activity of antibiotics was assessed by subculture of yolk sacs from surviving eggs at 14 days post infection. Direct smear examination prepared from infected tissues and stained with the Gimenez technique has also been used to evaluated the action of antibiotics. Such a model did not however allow direct evaluation of the growth rate of rickettsiae. In an early report, Jackson (22) showed that R. conorii was susceptible to chlortetracycline (DMST of 2.6 days at 125 µg/egg), and to a lesser extent chloramphenicol (3.8 days DMST at 500 µg/egg). More recently, pefloxacin was reported to be rickettsiostatic against R. conorii, with a DMST of 2.5 days when using 50 µg/egg (48). Very few data on the antibiotic susceptibility of spotted fever group rickettsiae other than R. rickettsii and R. conorii are available. Streptomycin was not effective against R. orientalis at concentrations up to 20,000 µg/egg (58). Chlortetracycline and chloramphenicol were shown to display a bacteriostatic activity against the South African tick bite fever rickettsia and the North Queensland Tick Typhus rickettsia, with DMST > 2.5 days for both species, respectively at concentrations > 125 µg/egg for chlortetracycline and > 250 µg/egg for chloramphenicol (22). Cell Culture Models: The primary target cells for rickettsiae are endothelial cells. However a number of eukaryotic cell lines can be infected with rickettsiae in vitro, including fibroblasts, macrophages, primary chick embryo cells, and human endothelial cells. The plaque formation in infected cell cultures was first used for numeration of viable rickettsiae (30, 31, 63, 64), and then adapted to determine their in vitro antibiotic susceptibility (30, 32, 65). The plaque assay system is currently the recommended technique allowing evaluation of both the bacteriostatic and the bactericidal activity of antibiotics. Cell monolayers (usually Vero cells) grown in tissue culture Petri dishes are acutely infected by rocking incubation with a rickettsial inoculum. Infected cells are then overlaid with Eagle Minimal Essential Medium with 2% fetal calf serum and 0.5 % agar. Antibiotics are added at different concentrations at the same time, whereas no antibiotics are added in drug-free controls. Petri dishes are incubated 4 days at 37°C in a 5% CO2 atmosphere. Cell monolayers are then stained with neutral red dye, allowing visualization of the plaques. The MICs are defined as the lowest antibiotic concentration allowing complete inhibition of plaque formation, as compared to a drug-free growth control. A disk assay was proposed as a convenient modification of the plaque assay. In this model antibiotic disks are placed on the surface of the agar overlay. The diameter of the plaque formation inhibition zone around the antibiotic disk represents a measure of the anti-rickettsial activity of the antibiotic. More recently a microplaque colorimetric assay or dye uptake assay has been described as a more convenient technique allowing accurate and more rapid determination of MICs of several strains of spotted fever group rickettsiae (47). Vero cells cultured in 96-well microtiter plates are infected with 2000 PFU rickettsiae. Antibiotics are added at different concentrations in different rows. Drug-free rows infected with either 2000 PFU, 200 PFU, 20 PFU, or 0 PFU serve as controls. After 4 days incubation of the plates at 37°C in 5% CO2 atmosphere, cell monolayers are washed and neutral red dye is introduced in the wells. The optical density at 492 nm of each well is determined using a spectrophotometer. The MIC corresponds to the lowest antibiotic concentration for which the mean OD at 492 nm is lower than that of the 20 PFU controls. Comparisons between the dye uptake assay and the plaque assay for determination of MICs have given consistent results. A new cell culture system was recently described by Ives et al. (19). Authors determined the inhibition of Rickettsia proliferation, by comparison of rickettsial growth in infected Vero cell cultures incubated in the presence of an antibiotic to that in drug-free controls. Infected cells were revealed by an indirect immunofluorescent antibody method. A few strains of Rickettsia conorii have been used in in vitro antibiotic susceptibility studies, including Moroccan strain and strain 7 (Table 2). Tetracycline, doxycycline, chloramphenicol, and rifampin were all shown to have bacteriostatic activity (47). Erythromycin and spiramycin were poorly effective with MICs of 4 µg/ml and 16 to 32 µg/ml, respectively (46, 47). More recently clarithromycin was found to rickettsiostatic, with MICs of 2 and 4 µg/ml against R. conorii Moroccan strain (29) and R. conorii strain 7 (19), respectively. Azithromycin, roxithromycin, and dirithromycin were rather less effective with MICs of 16 µg/ml (19). Josamycin remains the most effective macrolide compound tested with a MIC of 1 µg/ml (46). The new ketolide compound, telithromycin, was highly effective in vitro with an MIC of 0.5µg/ml (51). The fluoroquinolone compounds pefloxacin, ofloxacin and ciprofloxacin were shown to be rickettsiacidal, both in the plaque assay and the dye uptake assay (21, 48, 50). Less favorable results have been recently reported by Ives et al. Using an IFA test (20) for ofloxacin and ciprofloxacin. Levofloxacin, the l-isomer of ofloxacin, was demonstrated to be more active than the racemic compound ofloxacin (20, 28). Sparfloxacin was also effective with MICs of 0.25 to 0.5 µg/ml (20, 40). Only a few studies on in vitro antibiotic susceptibilities of spotted fever group rickettsiae other than R. conorii, R. rickettsii, and R. akari are available (Tables 3 and 4). The more extensive study has been recently published (52) and include 9 species : R. sibirica, israelian spotted fever rickettsia, R. australis, R. japonica, R. honei, Astrakhan fever rickettsia, R. africae, Rickettsia mongolotimonae, and R. slovaca. Antibiotic susceptibilities were highly homogeneous among the rickettsial species and strains tested. Amoxicillin and gentamicin were poorly effective with MICs ranging from 128 to 256 µg/ml and 4 to 16 µg/ml, respectively. Cotrimoxazole was not effective with MICs > 8/1.6 µg/ml respectively for sulfamethoxazole and trimethoprim, for all the strains tested. Doxycycline was the most effective compound with MICs ranging from 0.06 to 0.125 µg/ml. MICs to thiamphenicol were 0.5 to 2 µg/ml. Erythromycin and pristinamycin were poorly effective with MICs of 2 to 8 µg/ml and 1 to 8 µg/.ml, respectively. MICs to josamycin and clarithromycin ranged from 0.5 to 1 µg/ml and 0.5 to 4 µg/ml, respectively. Fluoroquinolones compounds (pefloxacin, ofloxacin, and ciprofloxacin) were rickettsiostatic with MICs of 0.5 to 2 µg/ml. MICs to rifampin were 0.03 to 1 µg/ml. In the same study, antibiotic susceptibilities of rickettsial species isolated only from arthropods were also tested, including R. bellii, R. canada, R. helvetica, R. conorii M1 strain, R. parkeri, Thai tick typhus rickettsia, strain Bar 29, R. massiliae, R. aeschlimanii, R. montan using, and R. rhipicephali. Although these strains showed antibiotic susceptibility patterns comparable to the rickettsial species previously described, an heterogeneity of susceptibility to rifampin among the different species was shown. Strain Bar 29 (as previously reported (3)), R. massiliae, R. aeschlimanii, R. montanensis, and R. rhipicephali were more resistant to rifampin with MICs > 2 µg/ml. It is of interest to note that all five rickettsial strains belong to a same phylogenetic cluster. Such results led us to speculate that heterogeneity in rifampin susceptibility, among various rickettsial species and in different geographical areas, may explain clinical failures using this antibiotic to treat patients suffering from rickettsial diseases. The activity of the new ketolide compound, telithromycin, has been more recently evaluated against R. africae and for the Israelian tick typhus rickettsia, with an MIC of 0.5µg/ml for both species (51). Recently, R. felis was tested using a new technique including RT-PCR and was found to have a susceptibility comparable to that of other spotted fever (53), especially being erythromycin resistant. This is contradicting early studies (38) resulting from a cell contaminated by R. typhi.
ANTIMICROBIAL THERAPY Smart search Drug of Choice Guided Medline Search The conventional antibiotic regimen for spotted fever group rickettsiosis is a 7 to 14 day oral course of doxycycline 200 mg daily (Table 6). Tetracyclines are contraindicated in children less than 8 years old because of the possibility of tooth discoloration (59). They are also contraindicated during pregnancy. Tetracyclines may be toxic to the fetus, including bone toxicity and discoloration of deciduous teeth when given after the 16th week of gestation (59). Tetracyclines have also been reported to cause serious hepatotoxicity, often with pancreatitis, in pregnant women (17). These antibiotics may also induce gastric intolerance and photosensitization as general side effects (59). Short course therapy with doxycycline (100 mg twice daily for 1 to 2 days) has been reported to be effective for Rocky Mountain spotted fever (18) and Mediterranean Spotted Fever (4, 6). As compared to conventional antibiotic regimen, the short- course regimen presents the advantages of being well tolerated in almost all patients and cost effective. It may represent an effective and safe alternative in children less than 8 year sold, preventing the occurrence of tooth discoloration. The use of a tetracycline even for short duration remains more problematic in the pregnant woman and cannot be currently encouraged. Monotherapy or Combination Therapy Antibiotic combinations have not been tested against rickettsiae in vitro. To date, no antibiotic combination has been shown to be superior in vivo to doxycycline alone. Combination therapy is not indicated in common clinical presentations of spotted fever group rickettsiosis. In severely ill patients, early administration of doxycycline before definite diagnosis is made is critical. Special Situations In severely diseased patients, doxycycline should be administered first by the intravenous route at 200 mg daily, and a prolonged duration up to three days following apyrexia should be considered. There is no clinical indication that other drugs should be more effective than tetracycline, even in patients with neurological complications. Alternative Therapy Randomized clinical trials comparing various antibiotic regimens for Mediterranean spotted fever are summarized in Table 5. These alternative therapies are summarized in Table 6. Chloramphenicol (administered for at least 1 week) has long been considered the main alternative for rickettsial infections. However, chloramphenicol presents the potential risk of aplastic anemia, acute hemolytic anemia in patients with the Mediterranean form of glucose-6-phosphate dehydrogenase (G6PD) deficiency, and is contraindicated in the pregnant woman. Moreover, recent in vitro and in vivo data indicate that chloramphenicol is much less effective than tetracyclines. Prognosis in children involved with of Rocky Mountain spotted fever is significantly worse when chloramphenicol rather than a tetracycline has been administered (18). Relapse was reported in an Israeli patient suffering Mediterranean Spotted Fever who died despite completion of the chloramphenicol therapy (57). Fluoroquinolones, including pefloxacin, ofloxacin, and ciprofloxacin have been shown to be effective for the treatment of Mediterranean Spotted Fever (7, 23, 43, 50). A 10 to 15 day oral regimen of either 200 mg bid of ofloxacin, 400 mg bid pefloxacin, or 500 mg bid of ciprofloxacin has been recommended. Shorter duration of antibiotic therapy was used with ciprofloxacin (50). A 2 day regimen of 500 mg bid of ciprofloxacin was compared to a 2 day course of doxycycline 200mg daily. All patients treated with ciprofloxacin resolved. However, apyrexia was delayed in the short-term ciprofloxacin therapy group as compared to the doxycycline group. Fluoroquinolones administered for 7 to 10 days may be considered as a safe alternative to tetracyclines to treat spotted fevers. However, as for tetracyclines, fluoroquinolones are contraindicated in the child and the pregnant woman. Among the macrolides, erythromycin is not considered a safe alternative for Mediterranean Spotted Fever (34). Following in vitro studies, josamycin has been proposed as a possible alternative to tetracyclines. The usefulness of josamycin has been assessed in a randomized trial for antibiotic therapy of Mediterranean Spotted Fever, both in adults and children (6). Josamycin 1g tid orally (50 mg/kg of body weight bid in children) was as active as the single day therapy with doxycycline (200mg bid for adults, 5mg/ kg of body weight in children). The clinical efficacy of clarithromycin (15mg/kg/day orally for 7 days) as compared to chloramphenicol (50mg/kg/day orally for 7 days) was recently assessed in a randomized control trial in 51 children with Mediterranean spotted fever (10). Mean time to defervescence were respectively 36.7h with clarithromycin and 47.1h with chloramphenicol. Azithromycin (10mg/kg/day orally for 3days) has also been evaluated comparatively to doxycycline (5mg/kg/day orally for 5 days) in 30 children with Mediterranean spotted fever (33), and both regimens had equal efficacy. More recently, azithromycin and clarithromycin were comparatively evaluated in 97 children suffering from Mediterranean spotted fever (9), with comparable efficacy. The mean time (+/- SD) to defervescence was 46.2 +/- 36.4 h in the clarithromycin-treated group and 39.3 +/- 31.3 h in the azithromycin-treated group. Thus, josamycin (50mg/Kg/d in two divided doses, for 7 days) and the newer macrolide compounds azithromycin (10mg/Kg/d in 1 dose for 3-5 days) and clarithromycin (15mg/Kg/d in 2 divided doses for 7 days), which have superior in vitro activity against rickettsiae as compared to erythromycin, may represent a current safe alternative to tetracyclines in children less than 8 years old. Josamycin may also represent a safe alternative to tetracyclines in the pregnant woman, but clinical data are lacking. Recently, Cascio et al. (10) reported a successful outcome in a 20-year old woman with in the 13th week of gestation who was treated with the combination of erythromycin and rifampin for Mediterranean spotted fever. Cotrimoxazole is not useful to treat rickettsioses, and potentially may worsen the outcome of the disease (54). In vitro, isolation of spotted fever group rickettsiae from ticks was obtained in cell culture systems despite adding cotrimoxazole in the culture medium (25). A regimen of rifampin (10mg/kg bid for 5 days) was compared to the one day doxycycline therapy schedule, in the region of Catalonia, in Spain (5). Outcome was favorable in both groups. However, delayed apyrexia was noticed in patients receiving rifampin. Moreover 4 patients become apyretic only after 5 days therapy which is comparable to usual time of spontaneous fever resolution. In one patient rifampin therapy was considered a failure and was changed for doxycycline. Failures in patients with Mediterranean Spotted Fever in Catalonia (Spain) after treatment with rifampin has been tentatively correlated with recent isolation of rickettsial strains with natural resistance to this antibiotic (R. massiliae) from Rhipicephalus ticks in this region (3). This rickettsiae have been found recently to be human pathogens (62). It may be hypothesized that the existence of rifampin-resistant rickettsiae in some areas may explain therapy failures when using this antibiotic, as well as contradictory reports from different areas on the effectiveness of rifampin to treat rickettsial diseases. More isolates are needed to resolve this hypothesis. (Printable Version of Antimicrobial Therapy for Rickettsia species)
VACCINES Guided Medline Search There are no vaccines available for Rickettsia spotted fever.
TABLES Table 1: Spotted Fever Group Rickettsiosis other than Rocky Mountain Spotted Fever (due to R. rickettsii), and rickettsialpox (due to R. akari) which are presented in specific chapters. Table 2: In Vitro antibiotic susceptibility of R. conorii. MICs (mg/L) are presented for R. conorii Moroccan (ATCC VR-141) and Seven (ATCC VR-141) and Seven (ATCC VR-613) strains as determined by using the plaque assay and the dye uptake assay, and for R. conorii Seven as determined by using an indirect fluorescent antibody (IFA) test. Table 4: In Vitro antibiotic susceptibility of Rickettsiae isolated only from ticks. Minimum Inhibitory Concentrations (mg/L) as determined in the plaque assay are summarized (52).
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