Rickettsia akari (Rickettsialpox)

Authors: Didier Raoult, M.D., Ph.D., Max Maurin, M.D., Ph.D.


Rickettsia species are gram negative, strictly intracellular bacilli that multiply within the cytosol of endothelial cells. Rickettsia akari is the etiological agent of rickettsialpox. This species was classified in the spotted fever group rickettsiae because it cross reacts with other species of this group, and because it is found both in the cytoplasm and the nucleus of infected eukaryotic cells as for other spotted fever group rickettsiae.


The house mouse (Mus musculus) and its associated mite (Liponyssoides sanguineus formerly Allodermanyssus sanguineus) are involved in the maintenance and transmission of R. akari. Rickettsialpox was first recognized in eastern United States, especially in New York City in the 40's, and later in the former USSR. A high seroprevalence (~16%) of anti-R. akari antibodies was reported in intravenous drug users in 1999 in inner-city Baltimore, Maryland, U.S.A. (4). Rickettsialpox is still endemic in New York City (11, 17). The geographic spread of the disease is probably under-evaluated, as evidenced by recent reports of human infections in Northern Europe (Netherlands) (20) and Latin America (Mexico) (31).

Clinical Manifestations

Rickettsialpox is characterized by an incubation period of 7 to 10 days, and an acute onset, typically with fever, chills, headache, myalgia and photophobia. The mite bite is painless, and usually unnoticed by the patient. A red papule evolving into a vesicle with regional lymphadenopathy often develops at the site of the mite bite. A papulo-vesicular cutaneous rash typically supervenes 2 to 3 days after onset and becomes generalized. Vesicles may then dry out to be replaced by a crust which usually does not produce a scar. The formation of vesicles differentiates rickettsialpox from other spotted fever group rickettsiosis. In contrast the cutaneous lesions of rickettsialpox may suggest more severe diseases such as anthrax and chickenpox. Rickettsialpox is considered a benign disease with spontaneous resolution in 2 to 3 weeks. Complications and death are very rare.

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Laboratory Diagnosis

Laboratory diagnosis of rickettsial diseases still relies upon serological tests (3, 12, 18). Specific antibodies are usually detected only after 10 days from the onset of systemic symptoms, and antibody titers reach a peak after 3-4 weeks of evolution of disease, and even later if an antibiotic therapy has been administered. However, delay in antibiotic therapy is the main factor for poor prognosis in patients with rickettsial diseases. Thus appropriate antibiotic therapy should be administered upon clinical suspicion of Rickettsia sp. infection, without waiting for serological confirmation of diagnosis. Before rickettsial antigens were available for diagnosis, the Weil-Felix test was based on the observation that sera from patients recovering from most rickettsial infections reacted with antigens from different Proteus vulgarisstrains (OX-K, OX-2, OX-19). However, the Weil Felix test was negative in patients with rickettsialpox. Complement fixation (CF) test or indirect fluorescent antibody (IFA) test, using R. akari antigen, are the most frequently used tests nowadays. A single IgG titer of > 1:64 with the CF test or > 128 with the IFA tests are considered diagnostic of rickettsialpox, as well as fourfold or greater increase in titer between acute-phase and convalescent-phase sera. Culture of Rickettsia sp. in cell systems from blood or eschar biopsies is only available in reference laboratories and remains relatively insensitive. The amplification of R. akari DNA using PCR from cutaneous eschar biopsies in patients with rickettsialpox has been described (17). Real-time PCR assays are now more widely used for diagnosis of rickettsial diseases (5, 19). Skin eschar biopsies are the most useful diagnostic samples. PCR-based techniques allow both early diagnosis of a rickettsial diseases and accurate determination of the involved Rickettsia species.


R. akari is inoculated to humans through the skin via the bite of the mouse mite. 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.

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Because of their obligate intracellular life-style, susceptibility of rickettsiae to antibiotics cannot be assessed in conventional microbiological tests. Three types of 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.

Animal Models

Mice and guinea pigs have been most often used as animal models for rickettsial infections. However, the clinical manifestations in these infected animals do not correlate with those of human disease, and may vary with the animal species as well as with the rickettsial strain investigated. The possibility of extrapolation of results obtained in animal models to the clinical situation remains to be established. As for rickettsialpox, the activity chlortetracycline (Aureomycin) has been evaluated in mice infected intraperitoneally or intranasally with R. akari, and treated subcutaneously with this antibiotic, starting 24h following infection for a period of 12 days (30). Chlortetracycline (1mg daily) led to the survival of all infected animals whereas death occurred in 2/3 of untreated controls, whether infected by the intraperitoneal or the intranasal route (30).

Embryonated Egg Model

In the embryonated egg model, rickettsiae were injected into the yolk sac of the eggs. Death of the embryo usually occurred within the first week 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 untreated infected controls (Table 1). A rickettsiostatic effect of antibiotics allowed the embryos to survive up to the last day of experiments, usually 14 days. The rickettsiacidal activity of antibiotics was assessed from 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 were also informative regarding the action of antibiotics. Such a model, however, did not allow direct evaluation of the growth rate of rickettsiae. R. akari MK strain has been used in most of antibiotic susceptibility experiments. In early experiments, streptomycin was shown to display only a moderate activity at high concentrations (10,000 to 20,000 µg/egg) (23). The activity of gentamicin was more recently evaluated against R. akari Hartford strain (27). Embryo death was delayed by 48h at a concentration of 500 µg/egg (27), which confirmed the poor in vitro rickettsiostatic activity of aminoglycosides. PABA (para-aminobenzoic acid) was not effective at a concentration of 1000 µg/egg (23). A DMST of 2.3 days was obtained with 125 µg/egg of chloromycetin (22). Oxytetracycline (Terramycin) was more effective with a DMST of 2.3 days at only 10 µg/egg (25). Chlortetracycline allowed embryo death delay > 2.5 days at concentrations > 125 µg/egg (10, 16). In the same study chloramphenicol induced a DMST of 2 days at 125µg/egg, and 4.9 days at 250 µg per egg, showing a moderate rickettsiostatic activity (10). Ormsbee et al (16) tested the activity of chlortetracycline, oxytetracycline, erythromycin, chloramphenicol and thiomycetin against R. akari Davis # 7 strain. A DMST > 2.5 days was obtained with 130 µg/egg of chlortetracycline, 180 µg/egg for erythromycin, 162 µg/egg for chloramphenicol, and only 14 µg/egg with thiomycetin, and 15 µg/egg with oxytetracycline which confirmed the high activity of tetracycline molecules.

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 enumeration of viable rickettsiae (14, 15, 26, 28), and then adapted to determine in vitro antibiotic susceptibility (13, 15, 29). The plaque assay system is currently the recommended technique allowing evaluation of both the bacteriostatic and the bactericidal activity of antibiotics. Cells monolayers (usually Vero cells) are grown in tissue culture Petri dishes are acutely infected by rocking incubation with a rickettsial inoculum. Infected cells are then overlaid with Eagle MEM 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 7 to 10 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 control. A new cell culture system was described by Ives et al. (8, 9). 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 fluorescent antibody (IFA) test.

Early reports, using the plaque assay system, have demonstrated that beta-lactams and aminoglycosides are poorly effective against rickettsiae, including R. akari (13) (Table 1). Tetracyclines are the most effective antibiotic compounds, with MICs to doxycycline of 0.06 µg/ml. Chloramphenicol and thiamphenicol display in vitro rickettsiostatic activity (13, 21). Erythromycin was shown to be poorly effective (8, 13, 21), whereas josamycin, clarithromycin and azithromycin (an azalide) displayed lower MICs (8, 21). Nalidixic acid is poorly effective against R. akari (13). A more recent investigation indicates that R. akari is susceptible to the newer fluoroquinolones compounds, pefloxacin, ofloxacin, and ciprofloxacin (21). Less favorable MICs have been recently reported by Ives et al. (9) with their IFA test.

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Drug of Choice

The conventional antibiotic regimen for spotted fever group rickettsiosis is a 7 to 14 days oral course of doxycycline 200 mg daily (Table 2). Classically, the administration of a tetracycline should be avoided in children less than 8 years old because of the possibility of tooth discoloration (24). They are also contraindicated during pregnancy because of potential toxicity to the fetus (bone toxicity and discoloration of deciduous teeth when given after week 16 of gestation) (24). Tetracyclines have also been associated with serious hepatotoxicity, often with pancreatitis, in pregnant women (6). These antibiotics may also induce gastric intolerance and photosensitization as general side effects (24). However, a short course of doxycycline (100mg twice daily for 1 to 2 days) has been reported to be effective in patients involved with Rocky Mountain spotted fever (7) or Mediterranean spotted fever (1, 2), diseases that are usually more severe than rickettsialpox. The short course doxycycline treatment is also more effective than chloramphenicol therapy in children with Rocky Mountain spotted fever (7). Thus, short course administration of doxycycline may be considered the current most effective and safe alternative in children of less than 8 years old.

Monotherapy or Combination Therapy

Combination therapy is not indicated in common clinical presentations of rickettsialpox, which is primarily a disease with favorable spontaneous prognosis.

Alternative Therapy

Chloramphenicol for at least one week has long been considered a classical alternative to tetracyclines for treatment of rickettsial diseases (Table 2). However it is less effective than tetracyclines in vitro against Rickettsia spp., and it carries the potential risk of aplastic anemia. It is also contraindicated in the pregnant woman. Although the in vitro activity of fluoroquinolones, josamycin, and the newer macrolides (azithromycin, clarithromycin) and ketolides (telithromycin) seems promising, but no clinical data are available for rickettsialpox.


Successful therapy is associated with rapid defervescence usually 3 to 5 days following initiation of treatment. Antibiotic treatment should be continued at least 48 hours following apyrexia. Delay in apyrexia may be observed in patients with severe disease, especially those with multi-organ involvement. Failure to respond promptly to the antibiotic therapy has not been associated with antibiotic resistance to date. It should raise the suspicion of an alternate diagnosis, especially in patients with an atypical clinical presentation. There are no useful laboratory parameters for monitoring treatment.


There are no vaccines available for the Rickettsia akari.

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1. Bella-Cueto F, Font-Creus B, Segura-Porta F, Espejo-Arenas E, Lopez-Parez P, Munoz-Espin T. Comparative, randomized trial of one-day doxycycline versus 10- day tetracycline therapy for Mediterranean spotted fever. J Infect Dis 1987;155:1056-1058. [PubMed]

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Table 1. In Vitro Antibiotic Susceptibility of R. Akari MK Strain (ATCC VR-612) and Davis # 7 Strain. The Minimum Antibiotic Doses Or MAD (mg/egg) Allowing A DMST > 2.5 days In The Embryonated Egg Model, and MICs (mg/L) Obtained in Cell Culture Models Are Presented.

Antibiotics Embryonated eggs MAD
Cell Cultures MICs
Strain References
MK (21)
MK (23)
MK (23)
MK MK (27)(21)
250 162
30 1
MK Davis #7 MK MK (10)(16)(13)(21)
125 130
MK Davis #7 (10)(16)
15 30
Davis #7 MK (25)(16)
MK (13)
MK (21)
MK (21)
MK (21)
15 8 16 16
Davis #7 MK MK MK MK (16)(13)(8)(21)
MK (8)
MK (8)
2 2
MK MK (8)(21)
MK (21)
MK (21)
MK (21)
0.5 28.8
MK MK (21)
0.5 6.4
MK MK (21)
MK (9)
MK (9)

Table 2. Recommendations for Antibiotic Treatment of Rickettsialpox

Condition Antibiotic Dose Duration References
rickettsialpox in adult and
in child > 8 years old
1. doxycycline 100 mg b.i.d. p.o. (i.v. in case of severe disease) 7-14 days (3)
2. doxycycline 100-200 mg single dose authors' recommendation
3. chloramphenicol 500mg every 6 hours 7-14 days (3)
child of less than 8 years old 1. doxycycline 100-200 mg single dose authors' recommendation
2. chloramphenicol 50mg/Kg/day in divided doses every 6 hours 7-14 days

Rickettsialpox is still endemin in New York City (11, 17) but the geographic spread of the disease is probably wider than previously reported, with recent reports of human infections in Northern Europe (Netherlands) (20) and Latin America (Mexico) (31). Treatment is still based primarily on doxycycline administration, even in young children.



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