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Other spotted fever group rickettsial infections

Other spotted fever group rickettsial infections
Literature review current through: Jan 2024.
This topic last updated: Jan 31, 2024.

INTRODUCTION — Rickettsia of the spotted fever group (SFG) cause human disease on six continents (table 1). Although the antimicrobial treatment of all SFG infections is similar, important differences exist in the epidemiology and clinical features of the individual diseases caused by these different SFG rickettsiae (table 2).

The overall incidence of these diseases remains unclear, as accurate surveillance of SFG rickettsial infections is problematic. Clinically mild illnesses due to SFG rickettsia are commonly mistaken for an undifferentiated viral illness, and confirmation of suspected SFG infections is often not obtained because of lack of access to or use of diagnostic testing modalities [1]. However, recent epidemiologic data suggests that the overall incidence of SFG rickettsioses is increasing over time [2].

Since millions of people now travel annually between continents and countries, physicians who practice in areas far removed from the site of primary infection may face returning travelers with unusual or unfamiliar clinical illnesses that are due to SFG rickettsiae [3]. This topic will review the epidemiology, clinical features, diagnostic methods, and treatment of infections due to select, clinically relevant SFG organisms other than Rickettsia rickettsii. Infection caused by R. rickettsii (Rocky Mountain spotted fever) and typhus group rickettsia are discussed separately. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Murine typhus" and "Epidemic typhus" and "Scrub typhus".)

TAXONOMY — Several human spotted fever group (SFG) rickettsiae have been identified in the past 20 years:

Rickettsia aeschlimannii

Rickettsia africae

Rickettsia amblyommii

Rickettsia felis

Rickettsia heilongjiangensis

Rickettsia honei

Rickettsia japonica

Rickettsia massiliae

Rickettsia monacensis

Rickettsia (sibirica) mongolotimonae

Rickettsia parkeri

Rickettsia philipii ('Rickettsia 364D')

Rickettsia slovaca

Only about half of the known species of SFG rickettsiae cause human disease, while the remaining organisms are likely nonpathogenic parasites of arthropods. However, it is likely that some "nonpathogenic" SFG rickettsiae will eventually be found to cause disease in humans. As an example, R. montanensis, which has long been considered a nonpathogenic SFG rickettsiae, was subsequently implicated as the cause of mild illness in humans [4].

Discovery and sequencing of new species results in periodic calls to modernize the taxonomic schema [5]. The discussion of SFG rickettsiae that follows is based upon consensus taxonomic schema [6], but it is likely that the present nomenclature will change as advances in molecular biology occur, new organisms are discovered, and new isolates of known SFG rickettsiae are made from humans and arthropods.

PATHOGENESIS — The literature on SFG rickettsiae is often confusing because clinical manifestations of illness due to one species may vary from region to region and host to host [7]. Thus, one patient with Mediterranean spotted fever (MSF) may have a mild disease while another may have severe, or even fatal, illness.

The determinants of these variations in virulence remain poorly understood [8]. Animal models suggest that dendritic cells may play an important role in augmentation of an adaptive Th1 cellular immune response against rickettsial infection [9]. Dendritic cells secrete pro-inflammatory cytokines that lead to natural killer (NK) cell activation and proliferation; expansion of this cellular compartment correlated with protection from lethal rickettsial challenge in a murine model.

The basic biology and pathogenesis of R. rickettsii, which share many elements with other rickettsiae, are discussed in detail elsewhere. (See "Biology of Rickettsia rickettsii infection".)

SPECIFIC INFECTIONS — The SFG rickettsial diseases are transmitted by ticks with two major exceptions: rickettsialpox is transmitted by mites, and R. felis is transmitted by cat fleas and occasionally by mosquitos [10].

Clinically, there are enough similarities among the diseases caused by SFG rickettsiae that certain clinical and epidemiologic features should suggest their presence. These include:

All SFG rickettsial infections can cause fever, headache, and intense myalgias.

All SFG rickettsial infections are arthropod-borne; known or potential exposure to ticks, fleas, or mites is an important clue to their early diagnosis. Humans and domestic animals are accidental hosts, as most SFG circulate in nature in wild vertebrates such as rodents.

Rash and/or a localized eschar (tache noire) occur in most, but not every, patient infected with SFG rickettsiae.

This section will provide a detailed discussion of specific infections caused by SFG rickettsia (listed alphabetically by organism).

R. africae (African tick bite fever) — Although recognized as a distinct clinical illness in the 1930s and shown to be caused by a unique SFG rickettsiae [11], African tick bite fever (ATBF) was later erroneously attributed to R. conorii infection [7]. Almost 60 years later, an isolate of a SFG rickettsiae was made from Amblyomma hebraeum ticks in Zimbabwe [12]. This isolate was shown to be genotypically distinct from R. conorii and was named R. africae. Subsequently, identical isolations have been made from humans. This organism is now assumed to be the same organism isolated decades earlier.

R. africae is the cause of ATBF, a distinct illness with these characteristics:

Mild clinical illness with headache, fever, and myalgias.

Solitary or multiple eschars associated with regional lymphadenopathy, which are common (picture 1).

A scant generalized rash that may be vesicular or maculopapular. In some cases, a skin rash may often be overlooked or completely absent.

Rarely, patients may develop a subacute neuropathy and myocarditis [13,14].

Rural Africans in endemic areas are commonly infected with R. africae. An outbreak in 13 French participants in an adventure race in South Africa illustrated that travelers to endemic regions can easily acquire infection [15]. This infection may be fairly common in returning travelers from Africa [16]. As an example, in another series of 120 travelers with tick bite-related disease, 117 of whom had traveled to Africa, all but one of the patients had R. africae infection [17]. ATBF is also endemic to the eastern Caribbean [18].

R. akari (Rickettsialpox) — Rickettsialpox was first described in New York City, but cases have also been reported from the Ukraine, Korea, and Slovenia [7]. Rickettsialpox is caused by Rickettsia akari and is transmitted by the bite of the house mouse mite (Liponyssoides sanguineous). Humans are typically bitten by mouse mites after mouse extermination programs result in starving mites that seek alternative sources for a blood meal. The principal reservoir of R. akari is the house mouse, but transovarial infection by R. akari occurs in infected mites; thus, mites may be considered both the vector and a reservoir of rickettsialpox.

Seven to 10 days after a mite bite, a painless red papule typically appears at the site of the inoculation. Fever characteristically begins 24 hours or less before the development of rash. This pattern was observed in 100 percent of 13 patients in one small series [19]. The inoculation papule typically becomes vesicular over the next several days and eventually crusts, producing an eschar. Eschars may be small and overlooked unless the skin is examined with care [20]. Regional lymphadenopathy often accompanies the inoculation lesion.

Patients typically develop fever, chills, myalgia, and headache at the same time as an inoculation papule or early eschar appears. A generalized rash can occur simultaneously with the primary inoculation lesion or follow its appearance by several days. This rash is typically maculopapular, but individual lesions frequently become vesicular. In cases in which a vesicular rash is prominent, a misdiagnosis of varicella may be made. Vesicular lesions normally develop crusts as they heal, but these lesions, unlike chickenpox, do not produce scars. Rickettsialpox is usually a mild self-limiting illness even without treatment, but symptoms may last three weeks if treatment is not administered early in the course of illness.

R. amblyommii infection — There are preliminary and still inconclusive data that suggest R. amblyommii may produce a mild infection in humans [21]. This organism is commonly found in Ambylomma americanum ticks in the Piedmont area of the southeastern United States [22,23].

R. australis (Queensland tick typhus) — Queensland tick typhus (QTT) is caused by Rickettsia australis and occurs along the entire east coast of Australia [24]. QTT is typically a mild disease, although fatal cases have been reported, and a small percentage of patients may require care in intensive care units and have severe long-term complications [25,26]. QTT is primarily transmitted by the scrub tick (lxodes holocyclus) and the organism circulates in nature between ticks, rodents, and small marsupials. As in other SFG rickettsial infections, man is only incidentally infected.

An eschar occurs in one-half to two-thirds of infected patients at the site of the tick bite. Regional lymphadenopathy often occurs in adjacent nodal regions. The skin rash in patients with QTT may be maculopapular, petechial, or vesicular. When a vesicular rash is present, the illness may be confused with chickenpox, which, as noted above, can also occur with rickettsialpox or MSF.

R. conorii (Mediterranean spotted fever) — Mediterranean spotted fever (MSF), also known as boutonneuse fever, is caused by R. conorii. R. conorii infection occurs in countries and regions adjacent to the Mediterranean Sea as well as in sub-Saharan Africa, Greece, India, and in areas around the Black Sea, such as Turkey, Bulgaria, and Ukraine. Sporadic cases have been described in non-endemic regions either in travelers or in patients who had contact with dogs infected from endemic areas.

Similar to Rocky Mountain Spotted Fever (RMSF), the onset of MSF is typically abrupt. Almost all patients have fever, headache, and a rash. In two large series of MSF from Southern Europe, rash was present in 97 and 99 percent of patients, respectively [19,27]. However, the rash is often absent during the first few days of illness as in other rickettsial diseases. The rash is most often maculopapular but is petechial in approximately 10 percent of cases [27].

Unlike RMSF, many patients with MSF have an eschar or black necrotic scabbed lesion (tache noire) at the site of the inoculating tick bite; in two large series, a tache noire was present in approximately 70 percent of patients [19,27]. Rarely, multiple eschars are present [28]. A papulovesicular or vesicular rash is uncommon in patients with MSF, but when vesicles occur, the illness may be mistaken for varicella.

MSF may follow a less severe clinical course than RMSF. In a review of 199 documented cases, for example, there were only three deaths [27]. However, the number of admissions for MSF tripled from 1994 to 2004 in Portugal. In a prospective study of risk factors associated with mortality among 140 hospitalized Portuguese patients with documented MSF, death occurred in 21 percent of patients. Patients who were infected with the Israel spotted fever strain (also known as R. conorii israelensis) had significantly higher case fatality ratios than patients infected with the Malish strain (ie, 29 versus 9 percent, respectively) [29]. Patients with severe infections may have neurologic, cardiac, ocular, or renal complications. The hemophagocytic syndrome has also been described in patients infected with R. conorii [13,30,31].

R. felis infection (flea rickettsiosis) — Cases of human infection with R. felis have been documented in patients on every continent except Antarctica, with most reports coming from Mexico, South America, the Caribbean Islands, and Africa [32-34]. In some tropical regions of Africa and Asia, the infection may be more common than previously thought, and there is increasing evidence of widespread presence of this pathogen in arthropod and animal species throughout the globe [34].

R. felis was first isolated from cat fleas in 1992, and bites from cat fleas may lead to human infection [35]. Data also suggest that book lice (commonly found in household dust) may be a major source of human acquisition [34]. Mosquito-based transmission has been documented as well [34,36].

The first human patient recognized with R. felis infection had a clinical illness nearly identical to that typically seen with murine typhus due to Rickettsia typhi [37]. As a result, when R. felis was first isolated, it was placed in the murine typhus group; however, this organism has subsequently been categorized in the spotted fever group even though it is a flea-borne pathogen.

The difficulty in distinguishing this species from R. typhi is complicated, since R. felis antibodies cannot be distinguished from R. typhi antibodies using standard immunofluorescent antibody (IFA) tests. In cases in which R. felis infection is suspected (eg, individuals with suspected or known contact with fleas from opossums or cats), it is possible to distinguish between the two pathogens using the polymerase chain reaction (PCR) that is available in a few research centers. (See 'Diagnosis' below.)

Humans infected with R. felis typically have fever, headache, myalgias, and a macular rash. However, the small number of cases reported thus far limits our understanding of the clinical spectrum of illness.

R. honei (Flinders Island spotted fever) — Flinders Island spotted fever was first recognized by an Australian general practitioner in the 1980s in patients living on a remote island in the Bass Straits between Tasmania and the Australian mainland [38]. The causative agent, R. honei, is genotypically distinct from the agent of QTT (R. australis), although the clinical manifestations of the diseases produced by the two organisms are almost indistinguishable [39]. Some cases of Flinders Island spotted fever have been caused by a strain that is genetically related to R. honei and has been designated the marmionii strain of R. honei [40].

R. honei has also been identified in other parts of the world. As examples, R. honei detected in a clinical specimen from a patient in Thailand may be responsible for a spotted fever group rickettsiosis formerly known as Thai tick typhus [41,42], and a case of severe illness due to R. honei was described in a patient in Nepal [43].

Flinders Island spotted fever is usually a mild disease. Approximately one-fourth of patients have a necrotic inoculation lesion, one-half have localized lymphadenopathy, and virtually all patients have fever, headache, and myalgias. Skin rash is usually maculopapular but rarely may be petechial.

R. japonica (Japanese spotted fever) — First described in 1984, Japanese spotted fever (JSF) has been confined mainly to southwest Japan and Korea [44], with one reported case in Thailand [45,46]. Several species of Dermacentor, Haemaphysalis, and lxodes ticks have been shown to transmit R. japonica [6].

JSF is caused by R. japonica and produces an illness very similar to Mediterranean spotted fever (MSF). In a review of 31 cases diagnosed at one hospital during a 12-year period, the following clinical features were noted [47]:

The onset was abrupt in 25 patients (80 percent).

Twenty-eight patients (90 percent) had tick bite eschars.

All of the patients had a skin rash. In most cases, it began as a macular erythematous eruption with lesions "the size of a grain of rice." The rash usually became petechial after three to four days.

Unlike scrub typhus, which occurs in the same geographic area, regional lymphadenopathy was absent. (See "Scrub typhus", section on 'Clinical manifestations'.)

Typical of other rickettsial diseases, thrombocytopenia occurred in most cases, and less than one-half of patients recalled having had a recent tick bite.

Recent reports describing fatal infection due to R. japonica have appeared [48].

R. parkeri infection — R. parkeri was first isolated from Gulf Coast ticks (Amblyomma maculatum) in the southern United States in 1937. In 2004, the first human infection was confirmed, followed by scattered case reports from Virginia, Brazil, and Uruguay [49-52]. A. maculatum ticks are also common in Central America, and human infections have been reported in Mexico and in a traveler returning from Honduras [53-55].

The largest case series to date examined clinical specimens from patients in the United States who had a history of an eschar or vesicular rash and resided within the range of A. maculatum (ie, Georgia, Kansas, Kentucky, North Carolina, Oklahoma, South Carolina, Tennessee, and Virginia) [56]. Laboratory diagnostic methods included at least one or more of the following: indirect immunofluorescence assays, histology, immunohistochemistry, cell culture (ie, Vero cells), and/or polymerase chain reaction (PCR). Six confirmed and six probable cases of R. parkeri rickettsiosis were identified from patients with possible rickettsial illness who were reported to the Centers for Disease Control and Prevention from 1998 to 2007. The majority of the patients became ill between late July and early September. Seven of 12 reported a history of a tick bite with resultant eschar formation.

Another five cases were subsequently identified at a single site in Georgia from 2012 to 2014, four of which were PCR-positive for R. parkeri in eschar biopsy samples using polymerase chain reaction testing [57]. There are also emerging data of infection well outside the traditional range of A. maculatum, as evidenced by a description of R. parkeri cases in southern Arizona in 2016 [58].

Eschars were described as crusted, nonpruritic, nontender or mildly tender, 0.5 to 2 cm in diameter, and surrounded by an indurated erythematous halo and occasional scattered petechiae. Two patients had multiple eschars. A maculopapular or vesiculopapular exanthem, involving primarily the trunk and extremities, was identified in 10 patients within 0.5 to 4 days after the onset of fever (picture 2) [56].

Low to moderate fever, myalgias, arthralgias, and headache were also common. Laboratory abnormalities included mild elevations of aminotransferases and mild thrombocytopenia and leukopenia.

Although documented infection is rare, it is possible that cases are misdiagnosed because of the lack of use of stringent identification techniques [59]. Antibodies generated to antigens of R. parkeri can react with R. rickettsii, R. akari, and other SFGR infections. Not only does this lead to diagnostic uncertainty, but epidemiologic trends of Rocky Mountain Spotted Fever (RMSF) may be clouded by a blending of other less severe rickettsial diseases.

R. parkeri rickettsiosis tends to be a milder illness than RMSF, which can lead to hospitalization, coma, and death if untreated. Helpful clinical features that distinguish R. parkeri rickettsiosis from RMSF include the presence of an eschar or a vesicular or pustular rash. The relative absence of gastrointestinal systems would also suggest R. parkeri rickettsiosis since nausea, vomiting, and diarrhea are commonly seen in RMSF.

R. philipii ('Rickettsia 364D') — Confirmed cases of human illness caused by the rickettsial species R. philipii (sometimes called "Pacific Coast Tick Fever"), have been reported in California [60-62]. This species had been described previously, but was not known to cause human illness. The organism is thought to be transmitted by Dermacentor occidentalis ticks. Most cases have been reported in children or the elderly, and have presented as a mild illness characterized by eschar formation, mild headache, malaise, lymphadenopathy, and low-grade fevers. This milder disease, along with the prevalence of R. philipii in D. occidentalis ticks in California (reported as high as 7 percent), suggest this illness may be more common than is recognized.

R. sibirica infection

Siberian tick typhus — Siberian tick typhus, caused by R. sibirica, was first recognized in Siberia during the 1930s. R. sibirica infection is now known to occur throughout much of northern and central Asia from Pakistan to northern China. Acute infection was reported in 4 of 13 paleontologists during an expedition to Mongolia; only two of the four recognized that they had been bitten by a tick [63].

Similar to R. rickettsii infection, patients with Siberian tick typhus typically develop rash, fever, and headache four to seven days after a tick bite. R. sibirica infection commonly causes an eschar at the inoculation site of the infecting tick bite and is rarely associated with serious complications or death, even if untreated. These characteristics are similar to R. conorii infection, but not RMSF. Patients frequently have regional lymphadenopathy near the site of their ulcerated or necrotic inoculation lesion. Skin rash, which may be maculopapular, petechial, or purpuric, typically appears two to four days after the onset of fever and other systemic symptoms.

Rickettsia heilongjangensis infection — Far-Eastern spotted fever (FESF) caused by R. heilongjangensis produces an illness similar to Siberian tick typhus in the Russian Far East and China. Illness due to this pathogen was distinguished from illness due to R. siberica using molecular methods, and is most common in endemic regions during the late summer [13].

R. sibirica subspecies mongolotimonae — R. sibirica subspecies mongolotimonae was first isolated from a tick in Inner Mongolia in 1991 [64]. Most of the recognized cases of infection with R. sibirica subspecies mongolitimonae have occurred in patients from southern France. However, cases have also been reported from Greece, Portugal, and South Africa [65-67]. Illness due to this pathogen has been called "lymphangitis-associated rickettsiosis" because it frequently presents with enlarged regional lymph nodes or lymphangitis. In addition to lymphadenopathy and/or lymphangitis, clinical manifestations often include fever, maculopapular rash, and one or more inoculation eschars [68]. Some patients may develop severe illness with complications such as acute renal failure, retinal vasculitis, and mental status changes. However, no fatalities have been reported.

R. slovaca infection — Infection with R. slovaca results in a syndrome that was initially called Tick-borne lymphadenopathy (TIBOLA) or Dermacentor-borne necrosis-eschar-lymphadenopathy (DEBONEL). Subsequently, the acronym SENLAT (scalp eschars and neck lymphadenopathy) has been proposed [13]. Infection with R. slovaca is common in the early spring and fall in a number of European countries, including France, Slovakia, Italy, Germany, Hungary, Spain, and Poland [13]. As an example, one report described 17 cases of R. slovaca infection from Hungary and France [69]. All patients had crusted scalp lesions at the site of a tick bite that were associated with occipital and/or cervical lymphadenopathy. Lymphadenopathy was painful in the majority of cases. Several patients also developed alopecia at the site of the tick bite after the local crusted lesion resolved. Fever and generalized skin rash were rare. For some, alopecia and/or asthenia persisted even after treatment. The propensity of skin lesions and tick bites to occur on the scalp has been reported by other investigators as well [70].

DIAGNOSIS — As with patients with Rocky Mountain Spotted Fever (RMSF), the diagnosis of other SFG rickettsial infections is usually based upon clinical features and epidemiologic clues (table 2). The presence of a characteristic rash in a febrile patient is usually the first tip-off to a diagnosis of SFG rickettsial disease. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and 'Specific infections' above.)

Confirmation of a clinical diagnosis can be achieved in four basic ways, as described below:

Serology (see 'Serology' below)

Immunologic detection of rickettsiae in tissue (see 'Immunologic detection of rickettsia in tissue' below)

Polymerase chain reaction (PCR) amplification of rickettsial DNA (see 'PCR-based detection of rickettsia' below)

Isolation of rickettsiae (see 'Isolation of rickettsiae' below)

The combined use of real-time quantitative PCR testing (qPCR) and serology may be the best diagnostic approach as the former modality is able to detect early infections before antibodies appear, whereas the serology is better able to confirm infection two weeks or more after onset of illness [71].

Serology — Serologic detection of convalescent antibodies is the mainstay of diagnosis of SFG rickettsial infection. The following serologic tests can be used:

Indirect immunofluorescence (IFA)

Microimmunofluorescent (MIF) antibody test

Enzyme-linked immunosorbent assay (ELISA)

Western blot immunoassay

Results from single-time point acute serologic samples drawn within the first week of illness should not be considered definitive evidence of the presence or absence of active disease. MIF antibody test, ELISA, IFA, and Western blot immunoassay methods do not detect convalescent IgM and IgG antibodies until 10 to 14 days after the onset of illness, and once they develop, low-moderate IgG antibody titers can persist for many years. This is similar to serologic assays used for the diagnosis of RMSF, ehrlichiosis, and anaplasmosis. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Human ehrlichiosis and anaplasmosis".)

Serologic cross-reactions commonly occur among SFG species, and none of the methods listed above can reliably distinguish between species of SFG rickettsiae. A modification of the ELISA test, utilizing epitope saturation by specific monoclonal antibodies, has been developed to serologically confirm the specific species of infective rickettsiae [72]; however, this test is not typically available.

Immunologic detection of rickettsia in tissue — Biopsies of skin rash, an eschar, or other tissues can be useful in the diagnosis of all SFG rickettsiae. However, such biopsies are rarely performed because specialized laboratory facilities needed to stain and process such tissues are not commonly available in areas where these diseases are endemic. Samples of tissue can be examined fresh (by frozen section) or after fixation in paraffin embedding. The tache noire lesion present in many SFG infections often contains large numbers of rickettsiae. Tissues can be stained with fluorescent-tagged conjugates or by immunoperoxidase staining.

PCR-based detection of rickettsia — Polymerase chain reaction (PCR) amplification from blood, skin biopsy samples, and other tissues can be performed for detection of rickettsial DNA. Due to the pathophysiology of rickettsial infections, PCR of tissue samples typically offers much higher sensitivity than PCR of whole blood. Detection of rickettsial DNA is commonly based upon recognition of sequences within the genes encoding 16S rRNA, a 17 kDa protein, citrate synthase (gltA), or ompA/B [73]. PCR testing is less useful after the onset of antimicrobial therapy and in late stages of illness.

One technique called "suicide PCR" uses primers from rickettsial genes in the genomes of R. conorii and Rickettsia prowazekii and is able to detect rickettsiae in skin biopsy specimens from patients with a variety of spotted fever group rickettsioses. In one report, this technique was able to detect rickettsial DNA in skin biopsy specimens from patients with R. conorii, R. africae, and R. sibirica infections [74]. Using a large cohort of patients with infection and corresponding controls, the estimated sensitivity and specificity were 68 and 100 percent, respectively. Suicide PCR was estimated to be 2.2 times more sensitive than culture and 1.5 times more sensitive than regular PCR techniques.

At present, quantitative real-time PCR methods are rarely used outside of research centers. However, PCR and culture (usually of eschars or crusts overlying eschars) are typically the most accurate way to make species-specific diagnoses [13,75].

Isolation of rickettsiae — Individual species of SFG rickettsiae can be isolated following inoculation into animals, such as guinea pigs, rats, or moles, or into embryonated eggs. Cell culture methods, including shell vial assay with early antigen detection by immunofluorescence, can also identify rickettsiae within 48 to 72 hours [7,76]. All isolation methods require specialized laboratory facilities with appropriate safety systems designed to prevent laboratory acquisition of human infection. Such facilities and specialized reagents are available in only a few research centers; thus, isolation of rickettsiae is rare in clinical practice.

TREATMENT

Overview — We treat symptomatic patients with spotted fever group (SFG) rickettsial infections to reduce the duration of symptoms and prevent complications. Antimicrobial therapy should not be delayed while awaiting diagnostic testing in a patient with appropriate epidemiology and a compatible syndrome [77].

Doxycycline is the preferred agent for the treatment of adults (both pregnant and nonpregnant) and children. The use of doxycycline for SFGR infections is supported by extensive clinical experience, and small clinical trials that have reported more rapid resolution of symptoms in those who received doxycycline compared with other agents [77-80].

Most patients can be treated with oral therapy as an outpatient, especially if the illness is detected and treated within five days of symptom onset. Antibiotics should generally be administered for five to seven days, although precise guidelines on the duration of treatment are not available. Support of cardiac, renal, and pulmonary systems may be necessary for those with severe disease.

Doxycycline as preferred agent

Adults — The dose of doxycycline for the treatment of SFG rickettsial infections is 100 mg twice daily administered orally or intravenously. Doxycycline should be used for both pregnant and nonpregnant patients. A more detailed discussion of the treatment of pregnant women is found below. (See 'Pregnant women' below.)

Children — The dose of doxycycline for children who weigh ≤45 kg is 2.2 mg/kg twice per day (maximum daily dose 200 mg) [77]. Children who weigh >45 kg should receive 100 mg twice daily. Tetracyclines can cause dental staining when administered to children younger than eight years. However, the risk of dental staining with doxycycline is minimal if a short course is administered [81,82].

Alternative regimens — Alternative agents to doxycycline for those with a history of hypersensitivity or hepatotoxicity depend upon the severity of disease (eg, mild versus severe). Special considerations in pregnant women are described below. (See 'Pregnant women' below.)

Mild disease — Azithromycin can be used as an alternative agent for individuals with mild disease (eg, mild headache, fever, myalgias), which is not due to R. rickettsii. The treatment of Rocky Mountain Spotted Fever is discussed separately. (See "Treatment of Rocky Mountain spotted fever".)

For adults, the dose is 500 mg daily; for children, the dose of azithromycin is 10 mg/kg orally once daily (maximum dose 500 mg daily) [83]. Although macrolides are not typically used for the treatment of rickettsial infections, they have shown efficacy in the treatment of children with Mediterranean spotted fever [84].

Severe disease — Chloramphenicol is reserved as an alternative inpatient treatment for severe rickettsial infections (eg, severe headache, hypotension, shortness of breath, neurologic manifestations). Chloramphenicol is dosed as 50 mg/kg per day intravenously in four divided doses (maximum dose 4 grams per day); dose reductions are required if used to treat neonates [83].

However, chloramphenicol can be difficult to rapidly obtain, and therefore, may not be a feasible option. There is also a low risk (1 in 25,000 to 40,000) of fatal aplastic anemia with chloramphenicol, and as a result, systemic use is restricted in many countries. A more detailed discussion of chloramphenicol is found elsewhere. (See "Treatment of Rocky Mountain spotted fever", section on 'Choice of antibiotic' and "Treatment of Rocky Mountain spotted fever", section on 'Drug toxicity'.)

Pregnant women — Doxycycline (100 mg twice daily) is the preferred treatment for pregnant women. Previously, chloramphenicol had been recommended for pregnant women with SFG rickettsial infections since tetracyclines have been generally contraindicated in pregnancy because of the risk of fetal bone and teeth malformations and hepatotoxicity in the mother [77,85]. However, there are increasing published data on the relative safety of doxycycline compared with older tetracyclines in both pregnancy and in children [86,87]. More detailed discussions of the use of doxycycline in pregnancy are found elsewhere. (See "Treatment of Rocky Mountain spotted fever", section on 'Pregnant women' and "Tetracyclines", section on 'Special populations'.)

For pregnant women who cannot take doxycycline, chloramphenicol should be used as an alternative agent. Chloramphenicol is dosed as 50 mg/kg per day intravenously in four divided doses (maximum dose 4 grams per day). If chloramphenicol is administered during the third trimester of pregnancy, it can be associated with "Gray baby syndrome" in premature infants and newborns [88]. "Gray baby syndrome" is characterized by cyanosis, abdominal distention, vasomotor collapse (often with irregular respiration), and death. The reaction appears to be associated with serum levels ≥50 mcg/mL [89]. Additional information on chloramphenicol is found elsewhere. (See "Treatment of Rocky Mountain spotted fever", section on 'Choice of antibiotic' and "Treatment of Rocky Mountain spotted fever", section on 'Drug toxicity'.)

We use azithromycin (500 mg daily for five to seven days) to treat pregnant women who are unable to take doxycycline or chloramphenicol; however, its efficacy in pregnant women has not been established. Although azithromycin has shown efficacy in children with Mediterranean spotted fever, there are no studies that have specifically evaluated azithromycin to treat SFG rickettsia in pregnancy. In addition, a review of approximately 100 pregnancies complicated by murine and scrub typhus found that azithromycin did not improve fetal/neonatal outcomes (eg, stillbirths, preterm births, low birth weight) [90]. (See "Murine typhus", section on 'Diagnosis' and "Scrub typhus".)

Agents with poor or uncertain efficacy — Fluoroquinolones are typically not recommended for the treatment of SFG rickettsial diseases. Although these agents had been considered a possible alternative to tetracyclines, fluoroquinolones were less effective than standard agents in patients with Mediterranean spotted fever [78]. They were also associated with deleterious outcomes in patients infected with R. conorii in a cell culture model [13]. In addition, certain rickettsiae (eg, Orientia tsutsugamushi) contain genes that encode known quinolone resistance factors [91].

Rifampin has also been suggested as an alternative agent for treatment for Mediterranean spotted fever (MSF) and African tick bite fever (ATBF; either alone or in combination with azithromycin) in isolated case reports [92]. In addition, R. conorii and R. sibirica subsp mongolotimonae have been shown to be susceptible to rifampin in vitro [13]. However, there are insufficient data to recommend the routine use of rifampin for treatment of SFG rickettsial infections.

Novel tetracycline-like derivatives such as tigecycline, eravacycline, and omadacycline show promising in vitro activity against rickettsial species but have not been studied for the treatment of human infection [29,30,93,94]. Until there are direct clinical data to support their use, we prefer doxycycline.

SUMMARY AND RECOMMENDATIONS

EpidemiologyRickettsia of the Spotted Fever Group (SFG), a class of arthropod-transmitted diseases, cause human disease on six continents. (See 'Introduction' above.)

Taxonomy – Approximately half of the known species of SFG rickettsiae cause human disease while the remaining organisms are likely non-pathogenic parasites of arthropods. (See 'Taxonomy' above.)

Pathogenesis – The various clinical illnesses that are seen in association with the individual Rickettsia vary significantly in severity. The determinants of virulence remain poorly understood. (See 'Pathogenesis' above.)

Vectors – The SFG rickettsial diseases are transmitted by ticks with two notable exceptions: Rickettsialpox is transmitted by mites, and Rickettsia felis is transmitted by cat fleas and mosquitos. (See 'Specific infections' above.)

Clinical manifestations – Regardless of species, infection with one of these Rickettsia leads to fever, headache, and intense myalgias, often in association with a rash or localized eschar. The presence of a characteristic rash in a febrile patient is usually the first clue to a diagnosis of SFG rickettsial disease (table 2).

Diagnosis – Similar to Rocky Mountain spotted fever, confirmation of a clinical diagnosis can be achieved in four basic ways: serology, polymerase chain reaction detection of DNA in blood or tissue samples, immunologic detection in tissue samples, and isolation of the organism. (See 'Diagnosis' above.)

Treatment - For most patients, the preferred treatment of all SFG rickettsial infections is doxycycline. The route of administration will depend upon the severity of disease, but most patients can be treated as outpatients with oral therapy. (See 'Treatment' above.)

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Topic 7908 Version 25.0

References

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