Rickettsia rickettsii (Rocky Mountain Spotted Fever)

Authors: Lucas S. Blanton, M.D., David H. Walker, M.D.

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Microbiology

Rickettsia rickettsii is an obligately intracellular, small (0.3 by 1.0 μm), gram negative bacterium that resides free in the cytosol and occasionally the nucleus of endothelial and, less frequently,vascular smooth muscle cells and macrophages. Organisms of the genus Rickettsia have evolved through extraordinary genome reduction, and as a result, have taken advantage of the host cells' cytosolic environment to maintain the necessary biochemical processes of life. Remarkably, despite the shedding of unnecessary genetic elements,many of these agents have gained virulence (35). Rickettsia rickettsii has a genome of approximately 1.27 Mb, which encode about1,350 predicted genes. It is the most virulent of the rickettsiae.

The rickettsia has two major outer membrane proteins, rickettsial outer membrane protein (Omp) A and Omp B, both of which have the characteristics of β-autotransporters (8, 57, 68). Among the adhesins by which spotted fever group (SFG) rickettsiae attach to the host cell are OmpA (81), OmpB, Sca1, andSca2; Omp B is quantitatively the major surface-exposed rickettsial protein,apparently forming a geometrical array or S-layer. The outer rickettsial membrane also contains abundant lipopolysaccharide and a 17 kDaprotein with sequence similarity to lipoprotein (7). Conformational epitopes on Omp A and Omp B are the basis for antigenic differences between R. rickettsii and other spotted fever group rickettsiae (5). Although Omp A is relatively highly conserved among all spotted fever group rickettsiae, it is the protein with the greatest diversity identified thus far (33, 50, 56). A domain of tandem repeat units (with 13 of them in R. rickettsii)appears to be the source of the greatest diversity among spotted fever group rickettsiae. Typhus group as well as spotted fever group rickettsiae contain the relatively highly conserved Omp B (36).

Different isolates of R. rickettsii are so similar that only two strains can be designated: R strain and HLP strain (4, 5, 6). All human isolates from patients with Rocky Mountain spotted fever (RMSF)have been antigenically indistinguishable except for limited epitope differences between strains from the eastern and western United States (5). Genomic comparison of a virulent human isolate (Sheila Smith) and avirulent tick isolate (Iowa) revealed genetic defects resulting in the truncation of OmpA and in the processing of OmpB, which likely explain virulence differences in these two isolates. A 10-kb region found in R. rickettsii Iowa is absent in R. rickettsii Sheila Smith – a finding suggestive of ongoing genome reduction between isolates (43). Analysis of DNA sequences among human isolates of R. rickettsii have been unable to delineate the molecular basis for the apparent differences in virulence as observed in the guinea pig model (29).

More than 40 years ago, a series of spotted fever group isolates from ticks and humans were designated as R, S, T, or U type according to their virulence for guinea pigs (104). The primary basis for classifying rickettsial species isolated from ticks in the United States such as R. parkeri, R. rhipicephali, R. montanensis, R. bellii,and R. amblyommii has been the antigenic differences. These species also differ in virulence for guinea pigs. Such a system as proposed by Price would not be valid if current microbiological methods are utilized (20, 23, 24, 96, 100, 101). Indeed, studies that have compared human isolates from the eastern and western United States have revealed that R and S strains (as determined by the method of Price) are actually present in both areas. A widely accepted explanation for observation for the disproportionately high case fatality rates observed during the pre‑antibiotic era among patients in the Bitterroot Valley of western Montana as compared to much lower case fatality rates among patients from the eastern United States is the assumption that rickettsial strains from the two locations were of different virulence (63, 103, 141). However, it is quite possible that the high mortality rate in patients from Montana can be explained at least in part by the more frequent occurrence of infection in adult males (135). Furthermore, the erroneous belief that strains of R. rickettsii from the eastern United States are less pathogenic is strongly refuted by the frequent occurrence off at al cases in the East even among children and healthy young adults.

The HLP strain of R. rickettsii was originally isolated from the rabbit tick Haemaphysalis leporispalustris (97). Although it is less virulent for guinea pigs than R strain, from which it can be distinguished by monoclonal antibodies (4), there appears to be some difference in virulence between HLP isolates of different geographic locations (72). As yet, no DNA sequence differences have been reported between the HLP strain and other strains of R. rickettsii,and the observed antigenic differences do not explain the differences in virulence. The rabbit tick rarely bites humans, so exposure and subsequent disease by this strain may be much more limited than that of the R strain. Although the HLP strain has never been isolated from humans, molecular evidence from the tissues of a fatal case of Rocky Mountain spotted fever suggests the HLP strain has the potential to cause severe disease (94).Indeed, the low mortality (3%) of Rocky Mountain spotted fever in the original classical description of Rocky Mountain spotted fever in Idaho by Maxey in 1899 has never been explained (84). The ability to treat this infection by inhibiting the growth of the infectious agent did not occur until nearly a half century later in the1940's.

Epidemiology

Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever (RMSF), causes a life threatening disease that has been reported in 48 of the United States, Canada, Mexico,Costa Rica, Panama, Colombia, Argentina, and Brazil (25, 26, 28, 39, 51, 54, 65, 67, 99, 113, 120). Because of its transmission by tick bite, the disease is generally highly seasonal reflecting the feeding activity of the tick. The natural hosts and vectors of R. rickettsii are ticks: Dermacentor variabilis (the American dog tick) in the eastern two‑thirds and areas in the far west of the United States; Dermacentor andersoni (the Rocky Mountain wood tick) in most of the western third of the United States and Canada; Rhipicephalus sanguineus (the brown dog tick) in Arizona, Brazil, and northern Mexico; Amblyomma cajenennse (thecayenne cattle tick) in Argentina, Brazil, and Colombia; and Amblyomma aureolatum in Brazil (25, 26, 38, 39, 89, 91).

Rickettsia rickettsii has evolved for maintenance in the tick by transovarian transmission (21, 86). Apparent low-level pathogenicity for ticks is balanced by moderate horizontal transmission to rodents, some of which become rickettsemic at levels sufficient to infect feeding ticks (24). In a phenomenon termed interference, the transovarial transmission of R. rickettsii is blocked by the presence of another rickettsial agent. This has been described with R. peacockii, also known as the East Side Agent, which is abundant in D. andersoni ticks on the eastern side of the Bitterroot Valley of Montana, where Rocky Mountain spotted fever occurred less frequently than in the western side of the valley(22). Although R. peacockii is genetically similar to R. rickettsii Sheila Smith, gene deletions and genome shuffling havestifled its virulence (50). The microbial factors that enable the shift from relative avirulence in the tick at ambient temperature to virulence in the mammalian host at 34to 37°C are incompletely characterized, but it appears that blood feeding and temperature shift modulate the transcriptional profile of R. rickettsii within the tick (52). Rocky Mountain spotted fever is seasonal, reflecting the activity of questing ticks seeking a blood meal and the frequency of their contact with humans.

The disease occurs with the highest incidence in the southeastern United States, particularly in the belt extending from North Carolina to Oklahoma. Broad long cyclic fluctuations in the incidence of reported cases have generally ranged between 500 and 1000 cases annually. In a recent cyclical increase beginning in the early 2000s, the Centers for Disease Control and Prevention reported 2553 cases occurring in the U.S. in 2010, a remarkable number in comparison to peaks reported during previous decades. Several issues plague this appearance of a skyrocketing incidence of Rocky Mountain spotted fever. First, there are a low proportion of laboratory-confirmed cases (91). In endemic areas, many healthy persons have antibodies reactive with R. rickettsii, which may be related to exposure to other cross-reactive spotted fever group rickettsiae. The emergence of an eschar-related spotted fever caused by R. parkeri and the high infection rates of R. amblyommii within the prevalent and aggressive Amblyomma americanum tick likely play a role in explaining the high prevalence of anti-spotted fever group antibodies (91, 123). The case fatality rate of 3 to 5% reflects the benefit of doxycycline treatment.

Clinical Manifestations

Typically patients with Rocky Mountain spotted fever present with fever,severe headache, and myalgia (67). A maculopapular rash is the characteristic sign typically associated with Rocky Mountain spotted fever. It appears in 90% of patients, usually between days 3 and 5, but at times after 6 or more days of illness. Only 49% have the presence of rash in the first 3 days of illness, which may delay a clinical diagnosis when patients present to medical care early in their course of illness. The rash typically begins around the wrists and ankles and spreads proximally, but may be initially noted on the trunk. Involvement of the palms and soles is a late finding, occurring in 36– 82%. Skin necrosis and gangrene of the digits and extremities may develop in severe cases of Rocky Mountain spotted fever (78). Eschars at the tick bite site have been described, but this is an extremely rare finding (11, 137). Some, in association with glucose-6-phosphate dehydrogenase deficiency, have a fulminant course of 5 or fewer days with either no rash or a rash that rapidly coalesces into large ecchymoses (138).

Usually early in the course, gastrointestinal symptoms including nausea, vomiting, and anorexia are prominent and potentially confusing diagnostically (67, 87). Prominent gastrointestinal symptoms may even mimic a surgical abdomen.

Headache is often severe. Other neurologic manifestations such as transient deafness, photophobia, and meningismus suggest meningoencephalitis. Indeed, analysis of the cerebrospinal fluid (CSF) reveals pleocytosis(lymphocytic or polymorphonuclear) in one third of patients. An elevated CSF protein concentration is also found in one third, but hypoglycorrhachia is found in only 8% of patients (74). Neurologic sequelae may consist of encephalopathy, ataxia, blindness,and behavioral disturbances (18, 59). These complications occur more frequently in those who experience severely impaired states of consciousness. They are much less frequent in those receiving prompt antimicrobial therapy.

In one study, renal failure (defined as a serum creatinine of over 2 mg/dL) was found in almost20% of cases (32). Acute kidney injury, a result of hypovolemia and prerenal azotemia, is reversible with the administration of intravenous fluids, but may progress to acute tubular necrosis necessitating hemodialysis (16, 139). Multisystem involvement reflects the disseminated endothelial infection that is life threatening as non-cardiogenic pulmonary edema, adult respiratory distress syndrome, and encephalitis with seizures and coma in the most severe cases.

Laboratory Diagnosis

In most situations,empiric antirickettsial treatment is given based on the clinic epidemiologic diagnosis, and a definitive laboratory diagnosis is achieved later by demonstration of seroconversion. A diagnostic titer of antibodies is seldom detectable at the time of presentation. Isolation of R. rickettsii requires a BSL-3 laboratory, particular expertise, and even under ideal conditions at least a few days for detection of growth (80). Polymerase chain reaction amplification of DNA of R. rickettsii from blood has yielded disappointingly low diagnostic sensitivity, presumably owing to the presence of organisms mainly within endothelial cells rather than in the circulating blood (121, 130). Real time PCR assays offer increased sensitivity but are still not adequate enough to effectively rule out Rocky Mountain spotted fever in the setting of negative results (76). Immunohistochemical identification of spotted fever group rickettsiae in biopsies of cutaneous lesions offers a sensitivity of 70% and specificity of 100% in the hands of an experienced pathologist, but is offered in only a few laboratories (40, 105, 140).

Pathogenesis

Following inoculation of R. rickettsii into the skin in the infected saliva of a feeding tick, organisms spread throughout the body via the bloodstream. The organisms induce phagocytosis by their target cells, the vascular endothelium, through several surface proteins (OmpA, OmpB, Sca1, and Sca2)and grow principally free in the cytosol of endothelium throughout the body(27, 70, 81, 82, 131). Rickettsiae multiply within the cell by binary fission. They polymerize the host cells' actin filaments to propel themselves within the cytosol and break through to infect adjacent cells (66). There is substantial evidence for endothelial cell injury by its production of reactive oxygen species, and rickettsial phospholipase A2 and protease activities have also been suggested as potential pathogenic mechanisms (45, 46, 136).

Rickettsial growth is associated with increased vascular permeability, leakage of intravascular fluid into the extravascular space, hypovolemia, hypotension, pre-renal azotemia, and, in severe cases, shock (64). Vasodilation and increased vascular permeability are a result of endothelial cell induction of heme oxidase and cyclooxygenase, production of prostaglandins, and phosphorylation-induced destabilization of endothelialcadherin (58, 115, 116, 117). As a result of vascular leakage and hypovolemia, the secretion of antidiuretic hormone results in hyponatremia (75). Site-specific manifestations such as rash, interstitial pneumonia,myocarditis, and encephalitis correspond to local vascular injury and the lymphohistiocytic host response.

The local consumption of platelets at multiple foci of infection causes thrombocytopenia in up to 52%of patients, but frank hemorrhage is rarely clinically evident (67, 74). Endothelial injury also leads to a procoagulant state with: release of procoagulant components, activation of the coagulation cascade, generation of thrombin, increased antifibrinolytic factors,platelet activation, increased antifibrinolytic factors, activation of the kallikrein-kinin system, and consumption of natural anticoagulants (37, 55, 106, 133, 144). Despite these perturbations, disseminated intravascular coagulation occurs only very rarely (42).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drug

In vitro susceptibility testing for obligately intracellular organisms such as R. rickettsii has yet to be standardized and validated by studies in experimentally infected animals and in adequately controlled clinical studies. Cell cultures using fibroblasts and Vero cells, embryonated eggs and animal models have been used to test susceptibility of spotted fever group rickettsiae. However, all of these in vitro and in vivo methods have technical limitations. Furthermore, clinical trials of the efficacy of treatment of human rickettsial infection are arduous to undertake because of difficulties in case acquisition and recognition. Studies that have been undertaken have usually been limited because of difficulties in matching clinical cases in terms of prognostic factors such as age, length of illness prior to treatment and severity of disease before starting treatment.

Numerous antimicrobial agents such as erythromycin, nitrofurantoin, and penicillin have been shown to exhibit anti‑rickettsial activity in cell culture systems; yet these agents have been found to be clinically ineffective (48, 142). Rickettsia rickettsii is susceptible to fluoroquinolones in a cell culture system. For example,the minimal inhibitory concentration of levofloxacin and ciprofloxacin against R. rickettsii is 0.5 μg/ml and 1 μg/ml, respectively (73, 83). Although fluoroquinolones are effective against experimental Rocky Mountain spotted fever in dogs and against R. rickettsii in cell culture,fluoroquinolone treatment of humans with Rocky Mountain spotted fever has not been reported (17, 73).

Rifampin has been shown to have in vitro activity against R. rickettsii and R. conorii. It has also been shown to lengthen the life of embryonated eggs infected with R. rickettsii, but there is no clinical evidence to support its use in human infections (107).

Both tetracycline and chloramphenicol have been shown to be effective anti‑rickettsial agents in guinea pigs and embryonated chicken eggs as well as in cultured cells. Both of these antibiotics are rickettsiostatic. It is difficult to quantitate the relative activity of the two agents against R. rickettsii,but in the systems employed thus far, tetracycline appears to be slightly superior to chloramphenicol (85, 122, 124).

Prior to the development and introduction of tetracycline and chloramphenicol,penicillin had been proven to provide no beneficial effect in guinea pigs experimentally infected with R. rickettsii. Sulfonamide drugs are not only ineffective, but actually exacerbate experimental Rocky Mountain spotted fever (126, 128). However, an analogue of sulfonamide, para‑aminobenzoic acid (PABA), has rickettsiostatic activity (9, 61, 62). PABA has clear therapeutic benefit inexperimentally‑infected guinea pigs. In the 1940's prior to the availability of tetracycline and chloramphenicol, PABA was used successfully to treat Rocky Mountain spotted fever (108, 112, 125). Because PABA is absorbed and excreted very rapidly, doses of 1‑3 gm were administered every two hours day and night to maintain a blood concentration of 30 to 60 mg/dl. Bicarbonate was given in order to maintain a neutral or slightly alkaline urine pH to avoid the precipitation of PABA in the urinary system. PABA was discontinued 48 hours after defervescence or when the leukocyte count fell below 3,000/ml, when the neutrophil differential was less than 25%, or when PABA crystals appeared in the urine. Despite the fact that these observations were made over 50 years ago,neither the mechanism by which PABA inhibits rickettsial growth nor the mechanism of how sulfonamides exacerbate rickettsial disease has been elucidated.

Combination Drugs

Combination drug therapy offers no advantage for etiologically diagnosed Rocky Mountain spotted fever, and thus there are no relevant susceptibility data. However, combination therapy is useful when considering empiric coverage of several possible diagnoses (e.g.,rickettsioses, meningococcemia, typhoid fever). Patients whose differential diagnosis includes infection with Neisseria meningitidis may be treated with a combination of doxycycline and a third generation cephalosporin (i.e., ceftriaxone or cefotaxime) to provide therapeutic coverage for these organisms and R. rickettsii. Alternatively, chloramphenicol is an option when empirical therapy is begun in a patient with illness compatible with both Rocky Mountain spotted fever and meningococcemia. It is often difficult to distinguish between Rocky Mountain spotted fever and another important group of tick‑borne diseases: ehrlichiosis and anaplasmosis. In such cases, doxycycline provides therapeutic coverage for both diseases and is preferable to chloramphenicol, an agent whose anti‑ehrlichial activity is less certain (13, 47).

ANTIMICROBIAL THERAPY

Drugs of Choice

For most situations, doxycycline is the drug of choice for treatment of Rocky Mountain spotted fever. Chloramphenicol is the accepted alternative treatment in pregnancy, tetracycline hypersensitivity, or in rare situations where there is another contraindication to the use of tetracycline (53, 69). A retrospective epidemiologic and clinical analysis of 5,600 cases of Rocky Mountain spotted fever reported to the Centers for Disease Control and Prevention between 1981 and1998 included an evaluation of antimicrobial agents (71). Analysis of these cases addressed the relative efficiency of tetracyclines and chloramphenicol. The case fatality rate was significantly higher for patients treated with chloramphenicol (7.6%) than those treated with atetracycline (1.5%). That age was not a confounding factor was demonstrated by the higher case fatality rates for those treated with chloramphenicol than tetracyclines in patients both younger and older than10 years of age. Furthermore, duration of illness and delay in treatment were not an explanation as patients with beginning of therapy with chloramphenicol both less than or greater than five days after onset of illness had higher case fatality rates than those treated similarly with atetracycline. In a previous study outpatients treated with tetracycline were significantly less likely to be hospitalized subsequently(11%) than those treated with chloramphenicol (30%) (34).

For adult patients and infected children weighing more than 40 kg who are not vomiting or in a coma and are able to take oral medication, the preferred treatment for Rocky Mountain spotted fever is doxycycline given in two oral doses of 100 mg daily. For smaller children, doxycycline should be given in two equally divided doses totaling4.4 mg/kg body weight/day. An equivalent pediatric dose of tetracycline is 25 to 50 mg/kg body weight/day in four divided doses, but doxycycline is the preferred form of tetracycline therapy in children since doxycycline binds less strongly to calcium than tetracycline and thus is less likely to stain the permanent teeth (49). Long a controversial topic, staining of teeth is unlikely to occur after one or even as many as five therapeutic courses of tetracycline For this reason doxycycline is the treatment of choice for Rocky Mountain spotted fever in children (60, 102).

Although chloramphenicol could also be used to treat children with Rocky Mountain spotted fever, the routine use of chloramphenicol for the empiric treatment of Rocky Mountain spotted fever in children carries a small but measurable risk of fatal aplastic anemia, a complication that occurs in an estimated 1 in25,000‑40,000 courses of chloramphenicol treatment.

Although adults with Rocky Mountain spotted fever can also be treated with oral tetracycline (2 g/day in four divided doses),doxycycline is also the preferred agent against R. rickettsii infection in patients >15 years of age. Oral tetracycline must be taken in the absence of food. Patient compliance with oral tetracycline therapy, a regimen requiring 4 doses a day, is unlikely to be as good as with doxycycline which requires only two doses per day and can be taken with or without food. Photosensitization is an occasional problem when ambulatory patients are given oral doxycycline therapy. Patients should be informed of this potential side effect and advised to use sunscreen creams and to avoid prolonged skin exposure to sunlight when possible. Patients with Rocky Mountain spotted fever who are seriously ill and require hospitalization and patients who are unable to take oral medications because of vomiting or altered mental status should receive parenteral therapy, and the preferred agent is also doxycycline given intravenously at the same dose (100 mg every 12 hours) as is used for oral therapy.

Chloramphenicol (2 gm/day in four divided doses for adults) either orally or intravenously provides effective treatment when given early enough in the course of Rocky Mountain spotted fever (Table 1). Although available in much of the world, the oral formulation of chloramphenicol is no longer manufactured or available in the United States. Intramuscular administration of chloramphenicol has produced low serum levels in some but not all studies. In one study intramuscular administration of chloramphenicol resulted in peak serum levels to 2/3rds of the levels seen with intravenous administration of chloramphenicol (41).The pediatric dose of chloramphenicol is 50 to 75 mg/kg body weight/day in four divided doses.

Although there are few therapeutic situations in which tetracyclines or chloramphenicol could not be used, should such an unlikely event occur,oral ciprofloxacin (1.5 g/day in two divided doses) or oral ofloxacin (400 mg/day in two divided doses) might be tried in adult patients. These regimens have been used successfully to treat Mediterranean spotted fever (114),but more recent observations suggest that fluoroquinolone use may be associated with more severe illness in those infected with R. conorii (15). Therefore, use of these agents should be used with great caution if attempted in those with Rocky Mountain spotted fever. Except in unusual situations (e.g., cystic fibrosis), quinolones are contraindicated in children.

One study, treatment with rifampin resulted in a delayed response to treatment as well as therapeutic failures in 4 of 15 patients with Mediterranean spotted fever. Thus, it is likely that it would have equally disappointing activity when used in those with Rocky Mountain spotted fever, a more severe rickettsiosis (14).

Special Situations

Pregnancy: Maternal administration of tetracycline may result in tetracycline deposition in the human fetal skeleton as early as the eleventh week of gestation and result in temporary inhibition of bone growth (31). Tetracycline can also cause staining of the deciduous teeth of infants born to mothers who receive it after their 16th week of gestation (30). In addition, all drugs in the tetracycline class have been associated with severe hepatotoxicity and pancreatitis when given to pregnant women (69). (Table 1)

When chloramphenicol is given to neonates, they may develop gray baby syndrome consisting of abdominal distention, pallor,cyanosis, and vasomotor collapse. Although gray baby syndrome has not been reported in neonates after maternal administration of chloramphenicol,it is theoretically possible since fetal levels of chloramphenicol reach30‑80% of the maternal serum level (111). Because of the potential for gray baby syndrome, many authorities advise against using chloramphenicol in women at or near term. However, if pregnant women develop Rocky Mountain spotted fever, it is probably safer to treat with chloramphenicol than with doxycycline or a tetracycline (53).There is no proven teratogenicity for either chloramphenicol or tetracycline, although limb hypoplasia secondary to the use of tetracycline in the first trimester of pregnancy has been reported (31).

Monitoring of Chloramphenicol: Because of the uncertainty of serum chloramphenicol levels owing to individual differences in absorption and metabolism, serum chloramphenicol levels should be monitored in selected situations. Serum chloramphenicol levels can be monitored using a bioassay, radioenzymatic assay,competitive enzyme‑linked immunoassay, or high performance chromatography. Whatever assay is used, serum levels should be maintained between10‑30μg/ml. Toxic chloramphenicol levels may produce severe cardiac dysfunction (127). We do not advise monitoring serum levels in patients who receive chloramphenicol for 3‑5 days (as is often the case in treating mild cases of Rocky Mountain spotted fever or when empirical therapy is started before results of bacterial cultures and skin biopsy results return). However, monitoring of serum chloramphenicol levels is advisable when treating newborns and young children (<2 years old), in all patients with hepatic disease, and inpatients taking interacting drugs (which include agents such as phenytoin,coumadin, rifampin, and phenobarbital). The doses of chloramphenicol do not need to be modified in renal failure. Even though chloramphenicol metabolites actually accumulate in renal insufficiency, the active drug level is not dependent upon renal function. However, dosages of chloramphenicol should be adjusted in hepatic insufficiency (as evidenced by the presence of jaundice or ascites). In such cases the adult dose should not exceed 2 gm/day, and therapy should not exceed 10‑14 day duration. Chloramphenicol may produce a hemolytic anemia in patients with the Mediterranean form of glucose‑6‑phosphate dehydrogenase (G6PD) deficiency. However chloramphenicol‑induced hemolysis does not occur in type A G6PD deficiency (which commonly occurs in African-Americans).

Alternative Therapy

There is no alternative therapy. Every group of antimicrobial agent, including beta-lactams,aminoglycosides, and macrolides, has been given to patients with fatal RSMF during their course of illness. Sulfonamides appear to exacerbate Rocky Mountain spotted fever as well as other rickettsioses.

ADJUNCTIVE THERAPY

Patients who develop severe illness due to Rocky Mountain spotted fever often have multi-organ dysfunction. This dysfunction may manifest as renal failure, seizures,diffuse pulmonary infiltrates, or a variety of neurological problems ranging from altered mental status, to seizures to coma. Such patients often require hemodynamic monitoring and the careful administration of intravenous fluids and vasopressors. In addition some patients develop signs and symptoms of adult respiratory distress syndrome and ultimately require ventilatory support. Patients with hypoxia, hypotension, cardiac conduction abnormalities, renal failure and seizures usually require specialized and intensive care. Disorders of coagulation including thrombocytopenia and prolongation in the prothrombin and partial thromboplastin times may result in bleeding that requires transfusion. Rarely abdominal pain may be a prominent feature of Rocky Mountain spotted fever, and a small number of patients may develop signs and symptoms of peritonitis. Most of these patients can be managed medically with anti-rickettsial therapy and supportive care without abdominal surgical intervention. However,gangrenous digits and extremities are usually amputated after demarcation during the period of recovery.

ENDPOINTS FOR MONITORING THERAPY

Generally, patients with uncomplicated Rocky Mountain spotted fever and those who are treated with an anti‑rickettsial drug within 96 hours of onset of symptoms defervesce within 48 to 72 hours and rapidly exhibit evidence of clinical improvement. In general anti‑rickettsial therapy should be continued for at least 48 hours after defervescence has occurred and until there is unequivocal evidence of clinical improvement (such as a return of appetite and general sense of well being). Severely ill patients and especially patients with multi‑organ dysfunction typically require longer to defervesce; some patients with severe illness may remain in coma,ventilator‑dependent, or require amputations for gangrene even after rickettsiae have been cleared from the perfused parts of the body. Some patients with extensive tissue damage may die as a result of widespread tissue and organ injury even if rickettsial sterilization has occurred as a combined result of the antimicrobial therapy and the patient's immunedefenses. For these patients there is no clear end‑point for treatment. It is not possible to predict the extent of recovery after treatment of severe infection. In some cases neurological or organ damage may remain permanent; whereas in other cases even severe neurological and renal impairment may disappear with time and supportive care (10, 32).

VACCINES

There are no vaccines that are available to prevent Rocky Mountain spotted fever. Historic vaccines prepared from killed R. rickettsii propagated in ticks, embryonated chicken eggs, and cell culture failed to protect against the disease. It is very likely that they ameliorated the disease and reduced the case-fatality rate.

PREVENTIVE MEASURES

Avoidance of tick bite by wearing protective clothing and use of tick repellants is more feasible than eliminating exposure by not entering tick-containing environments. Studies have demonstrated the effectiveness of permethrin treated clothingin both controlled and field conditions (88, 132). Removal of ticks reduces the likelihood of inoculation of reactivated rickettsiae by the feeding tick. In an animal model, unfed ticks may take up to 10 hours to transmit R. rickettsii, but ticks that are partially fed may transmit the bacterium in as few as 10 minutes of attachment (118). Careful inspection of the body and prompt removal of attached ticks is paramount.

CONTROVERSIES AND COMMENTS

The controversy regarding the previous recommendations of the American Academy of Pediatrics and the Centers for Disease Control and Prevention that chloramphenicol should be used instead of tetracycline for the treatment of Rocky Mountain spotted fever in children less than 9years of age has been reconsidered (1). The 2012 edition of the Red Book of the American Academy of Pediatrics continues to endorse the use of doxycycline for the use in children of any age with suspected Rocky Mountain spotted fever (3).

Although it is generally thought that relapse does not occur in patients who have recovered from Rocky Mountain spotted fever, relapse of others potted fever group infections has been reported (10, 69) as have anecdotal reports of relapse in a few patients with Rocky Mountain spotted fever (44). In one instance a patient with severe Rocky Mountain spotted fever was found to have viable R. rickettsii in a lymph node one year after he had recovered from his rickettsial infection (98). Another controversy surrounds the practice of prescribing a prophylactic antirickettsial drug to healthy persons giving a history of tick bite. Such prophylaxis is not recommended because of the very low prevalence of R. rickettsii in ticks and experimental evidence that the rickettsiostatic drug merely prolongs the incubation period and does not prevent the disease in prophylactically treated guinea pigs (77).

A critically important problem in effectively treating Rocky Mountain spotted fever is determining which febrile patients are likely to have Rocky Mountain spotted fever. Unfortunately many patients with Rocky Mountain spotted fever are erroneously treated with penicillins, cephalosporins, aminoglycosides, erythromycin, or sulfonamides because the correct diagnosis is initially not suspected or because epidemiologic and clinical clues to the correct diagnosis were either not sought or not evident. In some cases patients who are initially treated with beta‑lactam antibiotics or sulfonamides are erroneously thought to have drug eruptions when they later manifest a skin rash. Thus such patients are not recognized as having a key clinical clue to diagnosis, skin rash due to rickettsia‑induced vasculitis. The diagnosis of Rocky Mountain spotted fever may be delayed in other patients because a skin rash is absent. A small percentage of patients with Rocky Mountain spotted fever have delayed onset of skin rash. Other patients with Rocky Mountain spotted fever may have atypical skin rashes that are either asymmetrical or localized to a small area of the body surface. Still other patients never manifest a skin rash. Such spotless or almost spotless cases often have severe illness; some spotless cases succumb to their infection before the correct diagnosis is appreciated and before appropriate treatment can be administered (119).

There are no published criteria for hospitalization in patients with known or suspected infection with R. rickettsii. Certainly not all patients with Rocky Mountain spotted fever require hospitalization. Many patients who are treated within 5 days of onset of illness can be safely managed as outpatients (79). However, careful clinical follow‑up is mandatory for all such patients, and hospitalization is warranted if nausea or vomiting develop or if a prompt clinical response is not observed. Patients with severe thrombocytopenia, renal insufficiency, increased levels ofbilirubin or aspartate aminotransferase, focal or severe neurological signs or symptoms, and those more than 40 years of age have been shown by univariate analysis to have a worse prognosis. Of these factors only the presence of neurological involvement and an elevated serum creatinine at admission were independently associated with increased mortality by multivariate analysis (32). Another study in children showed that acute kidney injury during the course of Rocky Mountain spotted fever was also associated with increased mortality (1.5). On the basis of these data, we advise hospitalization for all patients with suspected Rocky Mountain spotted fever who have renal insufficiency, or any of the laboratory or clinical findings mentioned above. In addition we advise hospitalization for patients with suspected Rocky Mountain spotted fever in whom oral therapy is not suitable because of concurrent gastrointestinal symptoms such as severe nausea or vomiting.

The role of corticosteroid therapy in the treatment of severe Rocky Mountain spotted fever is unresolved. Although early uncontrolled human studies suggested benefit when steroids were used along with chloramphenicol (143), convincing evidence demonstrating benefit of steroid therapy in Rocky Mountain spotted fever has never been published, and we do not advise the use of steroids even in severe cases of R. rickettsii infection.

REFERENCES

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Tables

Table 1. Antimicrobial Regimens for Patients with Rocky Mountain Spotted Fever

Patient Characteristics	Drug of Choice	Dose Regimen*
Non-pregnant adult	doxycycline	100 mg bid IV or orally
Pregnant	chloramphenicol	500 mg qid IV or orally maintaining monitored serum levels of 10-30 mg/ml
Child > 45 kg Child < 45 kg	doxycycline doxycycline	100 mg bid IV or orally 4.4 mg/kg/day IV or orally in 2 divided doses
Patient allergic to tetracyclines	chloramphenicol	500 mg qid IV or orally maintaining monitored serum levels at 10-30 mg/ml in newborns, children < 2 years old, and patients with hepatic disease and interacting drugs