Treatment of Rocky Mountain spotted fever

INTRODUCTION — Rocky Mountain spotted fever (RMSF) is a potentially lethal, but usually curable, tick-borne disease. RMSF occurs throughout the United States, Canada, Mexico, Central America, and in parts of South America. The etiologic agent, Rickettsia rickettsii, is a gram-negative, obligate intracellular bacterium that causes a wide spectrum of clinical disease ranging from mild to fulminant infection. Mortality from RMSF has declined markedly, from 2.2 percent in 2000 to 0.3 percent in 2007 and has been essentially unchanged since that time [1,2].

The treatment of RMSF will be reviewed here. The basic biology of R. rickettsii, and the epidemiology, clinical manifestations, and diagnosis of RMSF are discussed separately. (See "Biology of Rickettsia rickettsii infection" and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)

APPROACH — We recommend empiric therapy with doxycycline for patients with suspected RMSF, even if the symptoms are mild. Early therapy for RMSF is critical since a delay in treatment has been associated with an increased risk of mortality.

When to suspect RMSF — A diagnosis of RMSF should be suspected in patients who are from an endemic area (or have visited one within the past 14 days) if they:

●Present in the spring and summer months with fever and at least one of the following: headache, rash, constitutional symptoms, RMSF-associated laboratory abnormalities (thrombocytopenia, elevated liver functions tests [LFTs], etc). (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Clinical manifestations' and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Laboratory findings'.)

and

●Have a known tick bite or an exposure to outdoor areas where ticks are common. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Epidemiology' and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Vectors'.)

Patients suspected to have RMSF — Antimicrobial therapy should be initiated as soon as possible in all patients who are suspected to have RMSF. (See 'When to suspect RMSF' above.)

It is particularly important that empiric therapy not be delayed if RMSF is suspected in patients who are severely ill (eg, severe headache or abdominal pain) and/or those who present with possible complications associated with RMSF (eg, seizures, hypotension, noncardiogenic pulmonary edema, jaundice). (See 'Importance of early therapy' below and 'Choice of antibiotic' below.)

Most patients will require empiric therapy for RMSF based upon clinical judgment and the epidemiologic setting since RMSF can rarely be confirmed or disproved in its early phase. Clinicians should not wait for the skin rash to develop before initiating treatment. (See 'Importance of early therapy' below.)

Patients with mild disease can generally be treated safely as an outpatient. By contrast, patients with severe symptoms should be hospitalized. Additional management considerations for patients with severe disease include:

●Empiric treatment for alternative diagnoses – Patients with RMSF may require empiric treatment for an alternative diagnosis while awaiting results from the initial diagnostic evaluation (see "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Differential diagnosis'). As an example, the early signs and symptoms of invasive meningococcal infection and RMSF are often difficult to distinguish. Thus, patients should receive empiric antibiotic therapy for both conditions if their symptoms are consistent with invasive meningococcal disease and RMSF. (See "Initial therapy and prognosis of community-acquired bacterial meningitis in adults" and "Bacterial meningitis in children older than one month: Treatment and prognosis".)

●Supportive care – Severely ill patients with RMSF should undergo hemodynamic monitoring since both hypovolemia and hypervolemia can occur. The tendency to hypervolemia in this setting is related to both the frequent presence of heart failure due to myocarditis and an increase in systemic vascular permeability [3,4]. Mechanical ventilation, dialysis, transfusions, and medications to control seizures also may be needed.

Importance of early therapy — Treatment should be initiated within five days of symptom onset. Early therapy for RMSF is important since a delay in treatment has been associated with an increased risk of mortality [5-8]. The importance of early therapy is illustrated in the following studies:

●In a retrospective study of 94 patients with RMSF, those who were treated within five days of symptom onset were significantly less likely to die than those who were treated after the fifth day (6.5 versus 22.9 percent) [5]. In this study, 90 percent of patients saw a clinician during the first five days of illness; however, over half did not receive antirickettsial therapy at that time. Failure to initiate antirickettsial therapy was associated with absence of a skin rash, presentation within the first three days of illness, and presentation from August through April.

●In a different study, 205 cases of confirmed or probable RMSF were retrospectively reviewed [8]. Among the patients who died, doxycycline was initiated ≥6 days after symptom onset (median seven days compared with three days in those who did not die). Late initiation of antimicrobial therapy may have been due, in part, to a delay in including RMSF in the differential diagnosis.

For some patients, a delay in therapy may result from providers being unaware of the importance of early treatment. As an example, in a study of 84 providers, 23 percent incorrectly stated that it was appropriate to wait for the development of a skin rash before initiating therapy for RMSF [9].

CHOICE OF ANTIBIOTIC

Doxycycline as preferred agent — We recommend orally or intravenously administered doxycycline for the treatment of RMSF in adults and children [10,11]. For patients who experience common side effects to doxycycline (eg, nausea, diarrhea), we administer supportive treatment, such as antiemetics and antimotility agents, to help them complete the course of treatment. (See 'Drug toxicity' below and 'Duration of treatment' below.)

The use of doxycycline as the preferred agent is based upon in vitro data, animal studies, and over 50 years of clinical experience [11]. In addition, studies have reported a higher incidence of death with chloramphenicol (the only alternative agent) compared with tetracyclines [7,12]. In one retrospective study that evaluated 6388 patients with RMSF from 1981 to 1998, there were 213 deaths; the case fatality rate for patients treated only with chloramphenicol was significantly greater than that for patients treated only with tetracyclines (7.7 versus 1.6; odds ratio 5.5; 95% CI, 3.9-7.7 [7]).

Nonpregnant adults — Doxycycline is given as 100 mg twice daily (orally or intravenously). For critically ill patients, we administer a single loading dose of 200 mg. Some providers give a loading regimen of doxycycline 200 mg intravenously every 12 hours for 72 hours since steady state serum concentrations of doxycycline are not achieved for up to 72 hours [13]. However, this theory has never been tested in vitro or in vivo.

Pregnant women — We prefer doxycycline for the treatment of pregnant women with RMSF rather than chloramphenicol. It should be administered as 100 mg twice daily (orally or intravenously). This approach is consistent with recommendations by the United States Centers for Disease Control and Prevention (CDC), which reflect the opinion of experts in the field [14].

Chloramphenicol had traditionally been the preferred treatment for most pregnant women with RMSF. Tetracyclines were generally contraindicated in pregnancy because of the risk of hepatotoxicity in the mother [11] and adverse effects on fetal bone and teeth (eg, permanent discoloration of deciduous teeth from in utero exposure in the second and third trimesters [15], incorporation into fetal long tubular bones with transient inhibition of growth [16]). However, these events are extremely rare with doxycycline, and subsequent evidence has supported the relative safety of doxycycline compared with older tetracyclines in both pregnancy and in children [17,18]. As an example, in a systematic review, there was no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children [17]. Thus, given the efficacy of doxycycline and the lack of other good alternatives, the benefits generally outweigh the risks.

Children — The dose of doxycycline for children who weigh ≤45 kg is 2.2 mg/kg/dose twice per day (maximum daily dose 200 mg) [11,19]. Children who weigh >45 kg should receive the adult dose. 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 [20], and in an observational study of 53 children who received approximately two courses of doxycycline for RMSF before they were eight years old, none developed dental staining in their permanent teeth [21]. The use of short courses of doxycycline in children of all ages is supported by the American Academy of Pediatrics [22].

Alternative agent — Chloramphenicol is the only known alternative agent for the treatment of RMSF. To our knowledge, no other alternative agents have been tested in humans. Although chloramphenicol has been found to have activity against RMSF in both animal and human studies [23-25], it appears to be less effective than doxycycline [7,19]. (See 'Doxycycline as preferred agent' above.)

Chloramphenicol is typically used in the rare setting when an individual has a history of a severe adverse reaction to doxycycline (eg, toxic epidermal necrolysis, severe hepatoxicity). The dose of chloramphenicol is 50 mg/kg per day in four divided doses (maximum 4 grams per day); dose reductions are required if used to treat neonates [26].

However, chloramphenicol may be difficult to rapidly obtain, and therefore, may not be a feasible option given the need to initiate therapy early in the course of disease. There is 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. If chloramphenicol cannot be obtained, doxycycline is the only studied treatment option. Novel tetracycline-like derivatives such as tigecycline, eravacycline, and omadacycline show promising in vitro activity against rickettsial species but have not yet been studied in human infection [27,28]. For individuals with a history of an adverse reaction to doxycycline, consultation with an allergist should be obtained, if possible, to help minimize the risk of an adverse event.

In the rare case in which there is a history of IgE-mediated allergy to doxycycline and chloramphenicol is unavailable or contraindicated, rapid desensitization to doxycycline has been successfully reported [29,30].

Drug toxicity

Doxycycline — Doxycycline is generally well tolerated except for mild nausea and vomiting. In addition, patients should be informed about photosensitivity associated with the use of doxycycline and counseled to take appropriate protective measures (eg, hat, long-sleeved shirts, sunscreen). Given the short duration of treatment, routine laboratory monitoring is not needed. Concerns related to the use of doxycycline in pregnancy are discussed above. (See 'Pregnant women' above.)

Chloramphenicol — Systemic chloramphenicol should be administered in an inpatient setting where close monitoring is available. A complete blood count should be obtained at baseline and repeated every two days. The drug should be discontinued if hematologic abnormalities are observed (eg, reticulocytopenia, leukopenia, thrombocytopenia, or anemia). However, irreversible bone marrow suppression may occur weeks or months after therapy has been discontinued.

If chloramphenicol is administered during the third trimester of pregnancy, it can be associated with "Gray baby syndrome" in premature infants and newborns [31]. "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 [32].

Although serum drug levels of chloramphenicol are typically measured in adults and children with hepatic or renal impairment, monitoring these levels is not practical in patients with RMSF, since the duration of therapy is short and most commercial labs do not perform this type of testing.

RESPONSE TO THERAPY — Most patients respond quickly to therapy with rapid improvement in their clinical signs and symptoms. In general, mortality associated with RMSF is uncommon if treatment is started within five days of the onset of symptoms. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Mortality'.)

Patients with mild illness will typically defervesce within 48 to 72 hours. However, patients with severe illness may remain critically ill and febrile for up to five days after institution of therapy. Clinical relapse has not been described in patients appropriately treated with either doxycycline or chloramphenicol.

Patients who survive the initial episode generally undergo complete recovery and cure of the rickettsial infection [33]. However, a small percentage of patients with severe RMSF develop long-term sequelae, such as peripheral neuropathy, hemiparesis, or deafness [34]. In addition, patients with severe neurological involvement after delayed treatment can rarely have persistent and even worsening evidence of neurological damage, as detected by magnetic resonance imaging, despite the use of appropriate antimicrobial therapy [35].

DURATION OF TREATMENT — Treatment should be continued for at least three days after the patient has become afebrile; most experts recommend a minimum of five to seven days of therapy. This recommendation is based upon clinical experience, as there are no controlled trials to suggest an alternative approach.

PREVENTION — There is no effective commercially available vaccine to prevent RMSF. Thus, early detection and removal of attached ticks is the best way to prevent disease transmission. Several hours of feeding are required for an infected tick to transmit R. rickettsii [36]. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Transmission'.)

Patients who report tick bites should be advised to inform their clinicians if any symptoms (eg, fever and headache) develop in the following 14 days. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Clinical manifestations'.)

Education about measures to prevent tick bites and reduce tick infestations are also important, as was illustrated in a community-based prevention program that was implemented in areas of hyperendemicity of RMSF in Mexico [37]. A more detailed discussion of how to prevent tick bites is found elsewhere. (See "Prevention of Lyme disease", section on 'Personal protection'.)

Prophylactic therapy with doxycycline or another tetracycline is not recommended following tick exposure [10,38]. Only a very small percentage of ticks (less than 2 percent) in endemic areas are infected with R. rickettsii [39-41], and animal data do not support the use of preventive antibiotics after a tick bite [42].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tick-borne infections (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Rocky Mountain spotted fever (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Rocky Mountain spotted fever (RMSF) occurs throughout the United States, Canada, Mexico, Central America, and in parts of South America. The etiologic agent, Rickettsia rickettsii, causes a wide spectrum of clinical disease ranging from mild to fulminant infection. (See 'Introduction' above.)

●If the diagnosis of RMSF is suspected, antimicrobial therapy should be initiated as soon as possible; delays in treatment of more than five days have been associated with an increased risk of mortality. Most patients will require empiric therapy based upon clinical judgment and the epidemiologic setting since RMSF can rarely be confirmed or disproved in its early phase. (See 'When to suspect RMSF' above and 'Importance of early therapy' above.)

•For adults and children, we recommend doxycycline (Grade 1B). We prefer doxycycline even for pregnant women, since there is increasing evidence of the relative safety of doxycycline in pregnancy compared with older tetracyclines. (See 'Approach' above and 'Choice of antibiotic' above.)

•Most patients respond quickly to therapy with a rapid improvement in their clinical signs and symptoms. Treatment should be continued for at least three days after the patient has become afebrile; most experts recommend a minimum of five to seven days of therapy. (See 'Response to therapy' above and 'Duration of treatment' above.)

●There is no commercially available vaccine to prevent RMSF. However, early detection and removal of attached ticks may prevent disease transmission. (See 'Prevention' above.)