Rickettsia rickettsii

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Rickettsia rickettsii
Rickettsia rickettsii.jpg
R. rickettsii in tick hemolymph cells visualized with Gimenez stain
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Bacteria
Kingdom: Pseudomonadati
Phylum: Pseudomonadota
Class: Alphaproteobacteria
Order: Rickettsiales
Family: Rickettsiaceae
Genus: Rickettsia
Species group: Spotted fever group
Species:
R. rickettsii
Binomial name
Rickettsia rickettsii
Brumpt, 1922

Rickettsia rickettsii is a Gram-negative, intracellular, cocco-bacillus bacterium that was first discovered in 1896. [1] Having a reduced genome, the bacterium harvests nutrients from its host cell to carry out respiration, making it an organo-heterotroph. Maintenance of its genome is carried out through vertical gene transfer where specialization of the bacterium allows it to shuttle host sugars directly into its tricarboxylic acid (TCA) cycle. [2]

Contents

These bacteria have membrane proteins that are useful in the identification of R. rickettsii strains and as a target for antibiotics. A capsule and slime layer encircling the bacterium allow for attachment to host cells and also acts as a defense mechanism for resisting phagocytosis. There are strains of R. rickettsii that have different genotypes and phenotypes, which alter the pathogenicity, virulence, and the appearance of the bacteria. [3] [4] [5]

R. rickettsii is the causative agent of Rocky Mountain spotted fever (RMSF) and is transferred to its host via a tick bite. It is one of the most pathogenic Rickettsia species [6] and affects a large majority of the Western Hemisphere, most commonly the Americas. [7] The pathogenic agent has been found on every continent, except Antarctica; however, Rocky Mountain spotted fever occurs mostly in North, Central, and South America. [7] This prevalence is due to the species's ability to thrive in warm, damp environments, [8] which provide sufficient conditions for the growth of the bacteria within a vertebrate host, such as a horse or dog. The disease is a zoonotic infection. [9]

Headache, high fever, and spotted rash are some effects of the disease with more severe cases resulting in organ damage and coma. [10] [11] [12] Antibiotics, such as doxycycline, target the ribosome of R. rickettsii and inhibit protein synthesis in the bacteria, providing a treatment for the disease. [13]

History

The first documented case of Rocky Mountain Spotted Fever (RMSF) was reported in Boise, Idaho in 1896 by a U.S. Army physician, Major Marshall H. Wood, who described cases of an unexplained illness. [1] At the time of discovery, not much information was known about the disease. It was originally called "Black Measles," due to dark appearance of the rash during the later stages of the disease. [14] The first clinical description of Rocky Mountain Spotted Fever was reported in Snake River Valley in 1899 by Edward E. Maxey. [15] It was theorized that the wood tick played a critical role as a vector of disease, based on apparent correlation between tick exposure and disease, as well as the geographic and seasonal presentation. [16]

Howard Ricketts (1871–1910), an associate professor of pathology at the University of Chicago 1902, was the first to identify and study R. rickettsii on a microbial level. [1] Beginning in 1906, his research consisted of interviewing victims of the disease, as well as collecting infected animals to study. He was also known to inject himself with pathogens to more accurately document their effects. Ricketts was the first to identify the pathogen responsible for RMSF as a gram negative bacillus, and confirm a route of transmission from infected ticks in a guinea pig model. [16] His research provided valuable information on the organism's vector and route of transmission. [1]

Simeon Burt Wolbach is credited for the first detailed, published description of the pathogenic agent that causes RMSF in 1916. [17] Wolbach described RMSF using the process of Giemsa staining, [1] and positively identified the bacterium as frequently residing within endothelial cells. [7] [16]

The once lethal infection, RMSF, has become treatable due to the modern availability of antibiotics. Broad spectrum antibiotics chloramphenicol and tetracycline-class drugs, like doxycycline, were first harnessed as treatment for RMSF in the late 1940s. [16] Before their discovery, 1 in 5 infected patients died. [18] Doxycycline was subsequently developed and became the preferred treatment for RMSF. Treatment recommendations changed in the 1990s to support primary therapeutic use of tetracycline-class drugs, and the current recommended treatment reflects this, as doxycycline is most commonly prescribed. [19] [20] This change in treatment recommendation coincided with a decrease in annual case-fatality rates (CFRs) from the 1980s on to the early 1990s. [21] Since then, the fatality rate has dropped to between 5 and 10%. [21]

Physiology

Metabolic pathways

R. rickettsii is an obligate intracellular bacteria, meaning they need a host cell to replicate and survive. R. rickettsii lacks a complete glycolytic-gluconeogenic pathway as well as a pentose phosphate pathway, hallmark pathways of central carbon metabolism. [22] [23] It is possible that R. rickettsii once possessed complete, complex metabolic pathways that allowed it to survive outside a host, evolutionary pressures associated to adaptation to an intracellular niche have led to progressive genomic reduction. [24] While metabolic pathways are limited, there are still many established pathways for carbohydrate and energy metabolism including the tricarboxylic acid cycle (TCA) as well as diversions to produce acetyl-CoA from pyruvate oxidation, and 2-oxoglutarate / oxaloacetate from the citrate cycle. [25] [23] R. rickettsii primarily obtains energy through a combination of oxidative phosphorylation of imported host-derived carbon sources and adenine nucleotide exchange of ATP via the ATP/ADP translocase Tlc1. [26] [22] Remnants of these lost metabolic pathways can be seen in analysis of R. rickettsii's genome, which contain some identified remnant enzymes of pathways that, to current study, appear to remain unfunctional in vivo, however, six biosynthesis pathways contain missing enzymes that suggest further study into these remnant pathways may lead to new discoveries. [2] [24] This decrease in available metabolic pathways has left R. rickettsii largely dependent on a range of transport systems to harvest essential amino acids, nucleic acids, and other metabolites from its host. This pilfering of host metabolites is characteristic of obligate intracellular bacteria, but, in the case of R. rickettsii, the extent of this process is unknown. [2] Pyruvate can serve a carbon source for R. rickettsii, though many other amino acids and TCA cycle intermediates such as glutamine, glutamate, serine, glycine, α-ketoglutarate, and malate can be used. [2] [22] For lipid metabolism, a comprehensive map of fatty acid synthesis enzymes has been identified, although these pathways depend on host-derived precursors. Its outer cell membrane also contains lipopolysaccharides (LPS), including lipid A, derived from these pathways. [27] Regarding synthesis of a peptidoglycan layer, although it is confirmed that R. rickettsii has a canonical peptidoglycan sacculus, there is speculation as to whether key components are synthesized internally or imported and modified for use. [28] [23] Pathways for producing critical small molecules such as riboflavin (B2), nicotinamide (B3), pantothenate (B5), pyridoxine (B6), thiamine (B1), and biotin (B7) are all missing key enzymes, forcing R. rickettsii to rely solely on transmembrane transport proteins. [23] [22]

Overall, R. rickettsii has a genome that does not encode many of the enzymes and proteins that are required for several metabolic pathways. These bacteria import many of the metabolic intermediates, cofactors, and byproducts from the host cells' metabolic pathways to use for their own synthesis of necessary structures and energy for survival. [2]

Morphology

Rickettsia rickettsii is a small, pleomorphic, Gram-negative coccobacillus. While published size estimates vary, common descriptions place it at less than 1 μm in width and approximately 0.5–2 μm in length. Because of its small size, most common staining methods are often ineffective for viewing requiring specialized staining methods like Gimenez stains. [29]

R. rickettsii has an inner membrane, a peptidoglycan-containing cell wall, and an outer membrane containing lipopolysaccharide (LPS) and membrane-associated proteins, hallmarks of Gram-negative bacteria. Electron-microscopy studies have also shown two external layers: a microcapsular layer and a more external slime layer. The appearance of these external layers varies with the physiological conditions experienced by the bacterium in its tick vector. In the bacteria from infected Dermacentor andersoni ticks, both layers were distinguishable in engorged ticks but lost their discrete appearance following starvation. Feeding the ticks or incubating them at 37 °C restored these layers structure, and were associated with reactivation of virulence. [30]

Staining studies has shown the slime layer to be largely polysaccharide in nature. Proposed functions include antigen display, phagocytosis inhibition, and host cell attachment, although these functions have not been conclusively established. [31] Surface-associated proteins, including YbgF and TolC, have also been studied as key immunogenic targets of the bacterium.

R. rickettsii has many vital proteins within its cellular membranes. Surface associated proteins such as YbgF and TolC have been investigated as potential protective antigens of R. Rickettsii. One of these proteins is YbgF, which maintains the structure of the cellular membrane. YbgF is found within both the inner and outer membranes along with another protein called TolC. TolC is a transport protein that connects to other transport proteins within the periplasmic space and inner membrane and has been shown to work as an efflux pump that likely aids in antibiotic resistance. These two proteins are believed to be associated with pathogenicity of this microbe and serve as specific points that antibodies can bind to in order to prevent the bacteria from interacting with host cells. [3]

Pathophysiology

Rickettsia rickettsii (red) infecting vascular endothelial cells (Immunohistochemical stain) Immunohistochemical Stain of Rickettsia rickettsii.png
Rickettsia rickettsii (red) infecting vascular endothelial cells (Immunohistochemical stain)

While humans are hosts for R. rickettsii, they do not contribute to rickettsial transmission. Rather, the pathogen is maintained through its vector: ticks. R. rickettsii invades vascular endothelial cells that line both small- and medium-sized blood vessels in the host's body. [32] There is an extensive immune response to this pathogen that triggers different pathways in the macrovascular and microvascular systems. [32] As the cells are damaged there is an increased permeability of the vessels (extravasation), microvascular hemorrhages, and necrosis. Additionally, there is evidence that suggests that R. rickettsii possesses the ability to cross the blood-brain barrier into the host's central nervous system, allowing the pathogen to target the brain's vasculature. [32] The pathogen causes changes in the host cell's cytoskeleton that induce phagocytosis.[ citation needed ] Consequently, R. rickettsii replicates further and infects other cells in the host's body. R. rickettsii's survival in the immune system cells increases the pathogen's virulence in mammalian hosts.[ citation needed ]

Nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS) as part of the innate immune system can inhibit R. rickettsii by disrupting energy metabolism, and has the ability to inhibit the pathogen by negatively affecting attachment, intracellular growth, and subversion of the host cell. [33] It does so by depleting R. rickettsii of ATP as nitric oxide targets cytochrome bo oxidase and cytochrome bd oxidase, components of the electron transport chain that are vital for ATP-synthase. The impact of nitric oxide on the metabolism however is significant enough to limit the pathogens ability to attach to host cells. As translation is also majorly ATP-dependent, the introduction of nitric oxide can greatly reduce the process of translation and therefore protein synthesis, making R.  rickettsii incapable of subverting the host cell. [33]

Actin-based motility (ABM) is a virulence factor that allows for the pathogen to evade the host's immune cells and spread to neighboring cells. The surface transporter protein Sca2 is vital this process as it promotes actin polymerization. In fact, recent studies in guinea pigs shows that disruptions in the Sca2 transsponson showed disruptions in the actin-based mobility of the microbe, reduced cell-to-cell spread, and lowered virulence which suggests Sca2 is an important virulence factor. [34]

Highly virulent strains of R. rickettsii are also able to suppress immune responses while dwelling in infected cells by creating inhibitory bacterial effector proteins such as Rickettsial ankyrin repeat protein 2 (RARP2) through a type IV secretion system. RARP2 mediates the fragmentation of TGN, or the trans-Golgi network, causing attenuation of vesicular transport and glycosylation defects in infected host cells. There are two important proteins within the host cell that are affected by these glycosylation defects: TGN46 and major histocompatibility complex class 1 (MHC-I). [35] MHC-I is an important protein for defending against pathogens as it functions as an antigen presenting complex signaling its infection status to lymphocytes. However, since RARP2 causes attenuation of vesicular transport, MHC-I is unable to be transported to the plasma membrane and the infected cell will not be able to alert host immune cells. Thus, the bacterial cells are able to avoid certain immune responses and allow for proliferation within a host cell. [36] [35]

A common host defense mechanism against obligate intracellular bacteria is the induction of apoptosis, or programed cell death, which kills the host cells and the resident bacteria, to stop the spread of the bacterium in the host. [37] R. rickettsii has been shown to avoid this immune response by inhibiting apoptosis in both mammalian and tick-derived cells. Firstly, in human endothelial cells, the microbe has been shown to inhibit the infection-induced activation of NF-κB which can prevent cell death via apoptosis. [38] Separately, as seen in studies on ticks, this microbe has also demonstrated apoptosis inhibition activity. It does so by affecting apoptosis regulators such as caspases, Bcl-2 proteins, or possibly the p53 tumor suppressor pathway. [39] This provides an advantage, allowing R. rickettsii to proliferate further due to prolonged survival and increased time for replication. By doing so, R. rickettsii also increases its transmission abilities. Without this process in place, the pathogen may not survive long enough in the vector to properly replicate and infect other hosts. [39] [38]

Genome and phenotypes

R. rickettsii is an obligate intracellular alpha proteobacterium that belongs to the Rickettsiaceae family. [6] Within the Rickettsia species, these bacteria are divided into four clades. The clades include the ancestral group, spotted fever group (SFG), typhus group, and transitional group. Factors for classifying each group may include phenotypic characteristics, phylogenetic organization, or the type of vector host it inhabits. R. rickettsii falls into the largest group of them all, the SFG group. [40] It has a genome that consists of about 1.27 Mbp with ~1,350 predicting coding sequences, [4] which is smaller in comparison to most other bacteria due to gene decay. Smaller genome sizes from genomic reduction in obligate intracellular bacteria allows for an intracellular lifestyle to proceed while maintaining increased pathogenicity. [41] It is maintained in its tick host by transovarial transmission. [6] The multiplication of R. rickettsii is by binary fission inside the cytosol. [1]

Genomic comparison of strains

R. rickettsii has a relatively small genome; however, variances in gene expression between different strains can lead to various functions of the bacteria. For instance, there are two major strains of R. rickettsii called the Iowa and the Sheila Smith strains. The Sheila Smith strain is a virulent strain, while the Iowa strain is an avirulent strain. Microarrays revealed that there were only four distinct differences in the gene expression of R. rickettsi; however, these four changes lead to complete differences in virulence, and thus the niche of the bacteria. [42] A key feature allowing for differentiation is the rickettsial outer membrane protein, rOmpB [4] which contributes to the identification of R. rickettsii strains as virulent. The Iowa (avirulent) strain reportedly contains a 660 bp deletion of a nucleotide poststart of ompA; a major surface antigen, rOmp B was noted as defective, mutations were noted in ankyrine repeat-containing proteins, and surface cell antigens Sca1 and Sca2 contained deletions that caused surface protein variation. [4] The detection of single nucleotide polymorphisms (SNPs) are used to differentiate these strains. [4]

In response to the Iowa strain’s 660 bp deletion poststart of ompA, protein truncation transpires. Truncation occurs when something creates an early stop codon during translation, causing interruption in genetic instruction; resulting in a shorter protein. [4] Noticeable truncation effects relate to decreased virulence. rOmp B, a major surface antigen, was noted as present, yet showed defects in proteolytic processing. [43] However, at this time is not ensured to be responsible for defective processing and is likely responsible for surface protein assembly and host cell interactions. [4] Mutations were also noted in ankyrine repeat-containing proteins. The Iowa strain contains a premature termination codon at amino acid position 68 in the ankyrin repeat protein RrIowa_0290 due to a nucleotide difference. Additionally, RrIowa_1113 contains a 558-bp deletion in both the avirulent Iowa and attenuated R strain compared to the Sheila Smith and Morgan strains. The final notable difference pertains to Sca1 and Sca 2 - two surface cell antigens. Sca1 and Sca2 contained deletions that caused surface protein variation. [4] To illustrate, Sca2 impacts the host cell’s infection dynamics via actin tail formation and intracellular motility. These deletions cause issues within virulence and motility.

Transmission cycle

Ecology

Ticks carrying R. rickettsii are found to be in the Ixodidae family. These are known as "hard body ticks" and are approximately 3 mm in length. They have tear-shaped bodies with brownish coloration. Ixodus ricinus 5x.jpg
Ticks carrying R. rickettsii are found to be in the Ixodidae family. These are known as "hard body ticks" and are approximately 3 mm in length. They have tear-shaped bodies with brownish coloration.

The most common hosts for R. rickettsii are ticks. [8] Ticks that carry R. rickettsii fall into the family of Ixodidae ticks, also known as "hard-bodied" ticks. [45] Ticks are vectors, reservoirs, and amplifiers of these bacteria. [8]

There are currently three known tick species that commonly carry R. rickettsii. The American dog tick (Dermacentor variabilis), mainly found in eastern, central, and Pacific coast United States, is the most common vector for R. rickettsii. The Rocky Mountain wood tick (Dermacentor andersoni), found in the Rocky Mountain States, and the brown dog tick ( Rhipicephalus sanguineus), found in select areas of the US-Mexico border and southern United States, are also known vectors of the pathogen. [45] [46] Other tick vectors include the Amblyomma genus commonly found in South America. Amblyomma cajennense, the cayenne tick, is the most comon vector in those areas, especially in Brazil, with Amblyomma aureolatum as a close second. A. cajennense often infects horses and capybaras in southeastern Brazil, serving as amplifier hosts for the bacteria. [47] Other small rodent species serve as amplifier hosts in the United States and South America. [9]

Transmission in ticks

Ticks usually acquire R. rickettsii by taking a blood meal during the larval or nymph stages from an infected vertebrate host. This mode of transmission from one stage of life to the rest of the tick's life is called transstadial transmission . [48] R. rickettsii is highly lethal to its Dermacentor andersoni and Dermacentor variabilis hosts. Infection during the nymph stage significantly decreases survival and decreases reproduction rates in females that do survive. [49] Both the American Dog Tick and the Rocky Mountain Wood Tick serve as long-term reservoirs for Rickettsia rickettsii, infecting the posterior diverticula of the midgut, the salivary glands, and the ovaries of the tick. [48] In addition, an infected male tick can transmit the organism to an uninfected female during mating, [50] and infected female ticks can transmit the infection to their offspring in a process known as transovarian passage . [51] There is evidence that this process is efficient in transmitting the bacteria to a new generation, but it is unlikely to play a major role in the maintenance of R. rickettsii within a population. [52] [53] Notably, R. rickettsii is inefficient at infecting the ovaries of adult female ticks, resulting in a lowered rate of vertical transmission, but still causing a lowered reproduction rate in the infected female ticks. [54] Rickettsial colonization of the ovaries has a higher success when ticks, especially in Rhipicephalus sanguineus, obtain the pathogen as a larva or nymph. [55] Reduced fecundity is also observed in ticks infected with R. rickettsii. [50] As a result of these limitations, long-term maintenance of R. rickettsii in populations of ticks relies mainly on horizontal transmission through the exchange of bacteria during feedings of infected hosts. [50] [56]

The duration of tick attachment, bacterial loads in tick saliva, and the transmission efficiency of R. rickettsii are important factors underlying transmission from ticks to humans. [57]

Transmission in mammals

Rickettsia rickettsii disseminates within its tick host to the salivary glands where it can be transmitted to mammals, including humans, during feeding. [48]

While transmission can occur in multiple ways the most common route of infection is via the bite of an infected tick. [58] During a feeding, the tick will inject its infected saliva into the host, allowing R. rickettsii access to the bloodstream. [57] Tick saliva contains immunomodulatory agents which affect immune defenses and hemostasis in the host, causing lowered host resistance to the bacteria. [57] Another way to contract the infection is through contact with exposed internal tick organs and fluids. [59]

Clinical manifestations

The U.S. Centers for Disease Control and Prevention states that the diagnosis of Rocky Mountain spotted fever (RMSF) must be made based on the clinical signs and symptoms of the patient and then later be confirmed using specialized laboratory tests. However, the diagnosis of Rocky Mountain spotted fever is often misdiagnosed due to its non-specific onset. [60] R. rickettsii infections in the continental United States are more likely to occur during the warmer months between April and September due to its most common method of transmission being via tick bite. [11] [61] Symptoms can take one or two days to up to two weeks to present themselves within the host. [10] The diagnosis of RMSF is easier when there is a known history of a tick bite or if the rash is already apparent in the affected individual. [62] If not treated properly, the illness may become serious, leading to hospitalization and possible fatality. [63]

Diagnostic tests

The specialized laboratory tests confirmed by the Center for Disease and Control for detection of RMSF antibodies are serology (IFA), polymerase chain reaction (PCR), and immunohistochemistry (IHC) and culture tests. [64] A clinician will decide which test to use based on the timing of symptom onset and specimens used for testing. [64]

Serological testing for Rickettsia rickettsii commonly uses indirect fluorescent antibody (IFA) test for immunoglobulin G (IgG) using R. rickettsii antigen. Serum samples should be collected two to ten weeks apart and paired to show changes in antibody levels. [64] A single early sample cannot detect early infection since antibody levels may still be negative during the first week. One limitation with serologic testing is that it cannot identify which spotted fever group species caused the infection because the species have similar antigens. [64]

Polymerase Chain Reaction testing, or more commonly PCR testing, detects R. rickettsii by expressing explicit regions of its DNA. PCR tests target genes such as ompA, ompB, gltA, and the 12-kDA protein-encoding gene. [65] One of the greatest gene targets, ompA, is found on the outer membrane of the cell, meaning that it contributes to serologic differences with its exposure to the host's immune system. [66] The gene, ompA, is such a target for PCR because it possesses distinguishable characteristics between species. [66] In clinical settings, PCR amplification is ran using DNA from whole blood serum or plasma. [64] This test is not always the first option for a provider to run since a negative results will not rule out the diagnosis. [64]

Immunohistochemistry and culture are laboratory techniques that can be used to detect R. rickettsii in clinical specimens. These diagnostic tests are performed on skin biopsies for people presenting with a rash. [64] IHC tests use specific antibodies to visualize R. rickettsii within infected tissue. Culture tests isolate the bacterium by growing it inside host cells. [64] Culture tests require specialized laboratories because R. rickettsii is an obligate intracellular pathogen that poses risk of laboratory acquired infection through aerosols. The culture test is rarely selected as the method of diagnosis because it requires specialized laboratories and techniques that are not widely available. [64]

Signs and symptoms

During the initial stages of the disease, individuals with RMSF may experience headaches, muscle aches, chills, and high fever. Other early symptoms may include nausea, vomiting, decreased appetite, and conjunctival injection (red eyes). A non-itchy rash may develop approximately 2-5 days after the onset of fever, although it may be absent during the early stages of infection or may never develop. [11]

The rashes are red, flat, and the non-itchy rash is present over the forearm and palm of the infected individual. Rocky mountain spotted fever.jpg
The rashes are red, flat, and the non-itchy rash is present over the forearm and palm of the infected individual.

The classic Rocky Mountain spotted fever rash occurs in about 90% of patients and develops typically 2-5 days after the onset of fever. The rash can differ greatly in appearance as the infection progresses. [11] It is typically not itchy and starts out as flat pink macules that usually appear on the wrists and ankles before spreading to other areas of the body. [62] During the course of the disease, the rash may form petechiae, which are small, reddish-purple spots caused by bleeding beneath the skin. The progression of petechiae indicates severe disease, although not all patients may get to this point. [67]

In rare cases, patients may present with chest pain due to myocarditis, which can cause chest pain. Additionally some survivors of severe RMSF experience sequelae that may last anywhere from 10 days to 4 years, symptoms include vision impairment, arthritis, or neurological challenges, such as impaired speech, dysphagia, ataxia, memory loss, cortical blindness, and decreased attention span. Necrosis of skin is another rare case of sequelae. [46] [68]

Severe infections

Patients with severe infections may require hospitalization. Severe symptoms occur later in response to vascular endothelial injury which can lead to thrombosis (blood clotting) caused by the R. rickettsii targeting vascular tissue. [10] [69]

One manifestation of this tissue damage is the development of a petechial rash. Petechial rashes are indicative of more severe disease progression. [70] Patients may become hyponatremic, develop elevated liver enzymes, and experience other more pronounced symptoms. Severe RMSF may involve complications with the respiratory, central nervous, gastrointestinal, or renal systems. In the case of meningoencephalitis, R. rickettsii causes cellular damage to brain tissue, resulting in inflammation. Additionally, acute respiratory distress syndrome and coagulopathy occur in cases that advance to severe stages of RMSF. [12]

Treatment

RMSF symptoms can vary from moderate to severe cases, and a delay in treatment is often associated with a higher case-fatality rate. [71] The annual mortality rate for RMSF is about 3.3%. [72] Deaths are usually caused by heart and kidney failure. [51] The most common and effective treatment for Rocky mountain spotted fever is the anti-microbial agent doxycycline. [20] Doxycycline is a tetracycline-class antibiotic which acts as a bacteriostatic drug by inhibiting protein synthesis via blockage of the 30S ribosomal subunit, interfering with the binding of aminoacyl-tRNA during translation. [13] [73] Treatment with doxycycline should begin when RMSF is suspected, without waiting for laboratory confirmation, to decrease risk of fatal outcomes.

Chloramphenicol has been used an alternative treatment for RMSF however, is less effective than doxycycline and has been associated with a case-fatality rate three times higher. [71] Chloramphenicol, like doxycycline, also functions as a bacteriostatic drug, but it binds to the 50S ribosomal subunit in order to prevent protein synthesis. [74] Macrolides target the 50S subunit as well; however, they block the exit site for peptides, while chloramphenicol blocks the aminoacyl-tRNA attachment site for transfer RNA. [75]

Prevention

"This photograph depicts, Field EIS officer, Heather Walker, DVM, MPH (EISO Class of '23), as she was placing a flea and tick collar on a community owned dog, for a Rocky Mountain Spotted Fever campaign in Arizona."-CDC Rocky Mountain Spotted Fever campaign in Arizona.jpg
"This photograph depicts, Field EIS officer, Heather Walker, DVM, MPH (EISO Class of '23), as she was placing a flea and tick collar on a community owned dog, for a Rocky Mountain Spotted Fever campaign in Arizona."-CDC

Prevention of Rocky Mountain Spotted Fever primarily involves avoiding bites from infected ticks. [11] Knowledge of where endemic areas are and taking precautions when inhabiting or traveling to those areas may also decrease the likelihood of contracting the disease. Those endemic areas include the eastern United States, where the American Dog Tick is an important vector of RMSF, and the north-western United States, where the Rocky Mountain Wood Tick is a vector. [11] There are no vaccines to prevent RMSF and preemptive antibiotic prophylaxis is strongly discouraged in the United States. [76]

Additional preventative measures may be taken especially when in areas with dense bush, grass, and wooded areas where ticks may be found. [77] Ticks also can travel on animals, so caution should be taken with pets. Before heading outside, the CDC recommends clothing treated with 0.5% permthrin. [77] On your way back indoors, the CDC recommends checking areas of the skin such as under the arms, within and around the ears, inside the belly button, back of the knees, within and around the hair, in between the legs, and around the waist when you have been in areas prone to ticks. [77] Clothing should also be placed in the dryer on high for at least 10 minutes or washed before drying with hot water when coming back inside from the outdoors. [77] Showering within two hours after leaving the outside environment also lowers the risk of obtaining tick associated diseases such as RMSF. [77]

An alternative measure is the use of Environmental Protection Agency (EPA)-registered insect repellents while in areas prone to ticks. These repellents should contain at least one of the following active ingredients; picaridin, IR3535, DEET, oil of lemon eucalyptus (OLE), para-menthane-doil (PMD), or 2-undecanone. Use of repellent that contains OLE or PMD are not safe for infants and toddlers, and should not be used until they reach 3 years of age. [77]

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