Treatments and Disease Management

Due to the fact that there are many unknowns in the mechanisms of rickettsia infection, Rocky Mountain spotted fever can be difficult to treat, especially if not diagnosed for a long period of time after infection. The main drug that is used to treat Rocky Mountain spotted fever is the tetracycline antibiotic, Doxycycline (CDC). This drug is commonly known as one of the major antibiotics for treatment of malaria and various gram-negative bacterial infections. Another drug that has been used in the past to treat infection is chloramphenicol, but is not recommended due to the fact that it increases risk of fatal outcomes (CDC). The mechanism that doxycycline uses to treat Rocky Mountain spotted fever pertains to the fact that it is able to bind directly to bacteria. To treat rickettsia infections, Doxycycline binds to the 30S ribosomal subunit of the bacteria to inhibit its protein synthesis (Doxycycline). In R. rickettsii, the inhibition of protein synthesis causes for the bacteria to be unable to replicate and enter various endothelial cells. Treatment with this antibiotic should be continued until at least three days after the reduction of fever in patients, and on average total treatment ranges from approximately one to two weeks (CDC). In the past, studies have been done to see the effects of doxycycline as a treatment for rickettsia disease, but the desired results of were never quite obtained due the difficulty of dosage and side effects of the drug (Purvis and Edwards 2000). This study also alluded to that fact that one of the major side effects of the antibiotic is that it could potentially cause permanent staining of the teeth at higher doses.

Figure 1: Chemical structure of antibiotic Doxycycline. http://1.bp.blogspot.com/_gGsPNYFbzDc/TDbDPC5cPYI/AAAAAAAACDw/HqSnql_egyo/s1600/Doxycycline_Structural_Formulae.png
Figure 1: Chemical structure of antibiotic Doxycycline. http://1.bp.blogspot.com/_gGsPNYFbzDc/TDbDPC5cPYI/AAAAAAAACDw/HqSnql_egyo/s1600/Doxycycline_Structural_Formulae.png
Figure 2: Table describing antibiotic dosage and circumstances for use to treat Rocky Mountain spotted fever https://www.ebmedicine.net/topics.php?paction=showTopicSeg&topic_id=16&seg_id=166
Figure 2: Table describing antibiotic dosage and circumstances for use to treat Rocky Mountain spotted fever. https://www.ebmedicine.net/topics.php?paction=showTopicSeg&topic_id=16&seg_id=166

While there is no current vaccine for the disease, a study done in the past year shows an attempt to create immunity using recombinant forms of OmpB (Riley et al 2015). Similar attempts at enhancing protection from infection with R. rickettsii using recombinant forms of OmpB with adhesion 2 have shown some success in a series of studies conducted on infected mice (Gong et al. 2015). While this route is very similar to the study done by Riley et al., the results of Gong et al. showed some success due to the fact that the scientists focused heavily on protective antigens already present in the host. Even though these studies produced slightly enhanced protection from the disease, the research here falls short of finding a very viable way to increase immunoprotection of the disease (Gong et al. 2015). This is due to the fact that antibody response to R. rickettsii is already present in hosts not treated with additional OmpB and the enhancement of antibody response is not enough to cause immunity.

6 Replies to “Treatments and Disease Management”

  1. I very much enjoyed reading your page! Your scientific language is clear and concise – well done. I have a few questions – 1) Have there been studies performed specifically for Rocky Mountain Spotted Fever regarding the effects of using anti-inflammatories (ie. COX-1 or COX-2 inhibitors) to reduce the symptoms of the disease? If so, what have they shown? 2) Clinically, Rocky Mountain Spotted Fever typically presents with rashes starting at the extremities and progressing toward the trunk with time. Can this be explained by the infection’s mechanism of action, or do you think that this could be attributed to the nature of the inflammatory response? Also, it would be helpful to have links to your other pages on each specific page. Great work. – Zachary Shuler, Rutgers Robert Wood Johnson Medical School

    1. Hey Zach thank you for the compliments and great questions! For your first question about anti-inflammatories, I have not specifically come across treatment with just inhibitors of cyclooxygenase because of how other treatments are needed to prevent fatal outcomes. However, I find it interesting that you asked about COX-1 and COX-2 because of the study done by Rydkina et all 2009 showing that the bacteria regulates COX-2 expression. Additionally, in terms of the spread of the rash, I would have to assume that the mechanism does not explain why they move from the extremities to the trunk of the body and that inflammatory response is the likely reason. Yet, I also believe that the fact that ticks generally attach themselves to uncovered extremities rather than the the trunk of the body could explain why the rash starts there (at the entry into the host) and progresses inward. I think this question is also very difficult to answer due to the variety of ways that the rash can typically spread on an infected person dependent on the specific case.

  2. Hi there!
    I thought you did a great job pulling the whole picture of the disease together. I have a few questions.
    In medical school, we were taught that one of Doxycycline’s major adverse effects was the permanent staining of teeth. When you mentioned that Rocky Mountain Spotted Fever could cause the permanent teeth staining, did you find that the authors thought the disease could potentiate that side effect of Doxycycline? I found this interesting article that indicates that the staining effect of Doxycycline was not found in pediatric populations being treated for suspected Rocky Mountain Spotted Fever. (http://www.jpeds.com/article/S0022-3476(15)00135-3/pdf). Did you find anything in your research to that showed a different disease progression in children versus adults?

    Lastly, I am curious about what is known about how Rickettsia moves to an adjacent endothelial cell once it has infected the first cell. You talked about the bacteria being able to use actin to push through the filapodia of the infected cell. Do you know if the bacteria can push the filapodia directly through the adjacent cell, or does the bacteria still need to enter the adjacent cell through OmpB/Ku70? Or is there another mechanism of spreading? Nice work again!

    • Alec Vlahos
    1. Hey Alec thank you for the great questions! In terms of progression of the disease, I did not find any studies showing different progressions in children versus adults. The study you linked is very interesting and am surprised to see that no staining was observed after treatment with the antibiotic based on the study I provided by Purvis and Edwards in 2000. This contradiction between the two studies shows how much can actually change in the scientific research over 15 years. Now with regards to the mechanism of spreading for the bacteria, it is necessary for R. rickettsii to form a complex with the actin filaments to be able to push through the filapodia. Following this event, the bacteria are able to push directly through and into an adjacent endothelial cell without binding through the OmpB-Ku70 complex again. Thank you for pressing me on my clarification and I will be sure to add more information to the page to clear up how the bacteria is able to spread from one cell to another!

  3. Great project, you communicated a lot of information about the disease very clearly. I’m wondering how prevalent is doxycyclin resistance in Rickettsia, and if so do we know the molecular bases of the resistance? Is there a mechanism or structure of doxycyclin bound to the 30s ribosomal unit?

    1. Hey Elliot great questions! Your question about doxycycline resistance was very interesting because it caused me to find for some studies about this that I had not seen before. While it was difficult to find any specific studies on exactly how prevalent the resistance is, the literature seems to reflect that developing resistance is actually quite frequent. While there are multiple mechanisms of tetracycline antibiotic resistance, the one that seems the most prevalent at the molecular level relates to the efflux of doxycycline out of the bacteria by one of its intracellular proteins. Additionally, the mechanism of doxycyclin binding to the 30s ribosomal subunit involves the inhibition of the binding of the amino-acyl-tRNA to the mRNA-ribosome complex. This causes for protein synthesis to stop as a result of the amino acids no longer being able to be added to the growing peptide chain. Here is a general link for tetracycline mechanisms resistance that could provide some further clarifcation if my response is not sufficient! http://www.pharmacorama.com/en/Sections/Proteins-biosynthesis-2-2.php

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