12 One Pill Of Doxycycline Is Not Enough To Prevent Early Lyme Disease

This paper is being passed around the Lyme disease patient community that has everyone's attention. It's about the most effective timing and the use of one 200 mg capsule of doxycycline as prophylaxis to prevent Lyme disease after a tick bite.

The bottom line from the authors of the study: One 200 mg capsule of doxycycline is totally ineffective in preventing Lyme disease if it is administered 48 hours after a tick bite.

And even if administered in less than 48 hours, it is no guarantee of successfully preventing infection.

The following commentary comes from Dr. Elizabeth Maloney:

Since 2001 the IDSA has been recommending preventive treatment of a single dose of doxycyline for tickbites under certain narrow conditions.  Piesman et al. have just published a new article concluding that if the treatment is given as little as 24 hours after the bite, only 47% of the mice were cured. Piesman also concludes that "Prophylactic treatment was totally ineffective when delivered ≥2days (48hrs) after tick removal." The IDSA recommends treating if:

• Tick is estimated to have been attached for ≥36 hours (based upon how engorged the tick appears or the amount of time since outdoor exposure)

• Antibiotic treatment can begin within 72 hours of tick removal 

"If the person meets ALL of the above criteria, the recommended dose of doxycycline is a single dose of 200 mg for adults and 4 mg/kg, up to a maximum dose of 200 mg, in children ≥ 8 years"

In 2004 Zeidner et al. noted that the "sustained release" doxy was curative, but regular doxy only 43% effective. [ Antimicrob Agents Chemother. 2004 Jul;48(7):2697-9. Sustained-release formulation of doxycycline hyclate for prophylaxis of tick bite infection in a murine model of Lyme borreliosis.]

In 2008 Dolan et al. reported on the success of 14 days of exposure to antibiotic bait formulations..

Am J Trop Med Hyg. 2008 May; 78(5):803-5.
A doxycycline hyclate rodent bait formulation for prophylaxis and treatment of tick-transmitted Borrelia burgdorferi.Dolan MC, Zeidner NS, Gabitzsch E, Dietrich G, Borchert JN, Poché RM, Piesman J.

Abstract

The prophylactic and curative potential of doxycycline hyclate formulated in a rodent bait at concentrations of 250 and 500 mg/Kg was evaluated in a murine model of Lyme borreliosis. 

Both bait formulations prevented tick-transmitted Borrelia burgdorferi infection in 100% of C3H/HeJ mice (N = 16), as well as cured acute, established infection in mice (N = 8) exposed to bait for 14 days. 

Spirochete infection was cleared in 88.9% to 100% of infected nymphs feeding on mice fed 250 and 500 mg/Kg antibiotic bait formulations, respectively. These data provide evidence for exploring alternative techniques to prevent transmission of Lyme disease spirochetes.

In 2011 Wisconsin Journal of Medicine published a review detailing the failure of one-dose doxycycline prophylaxis and proposing an alternative, more effective treatment option. (Maloney, B. The management of Ixodes scapularis bites in the upper Midwest. WMJ. 2011 Apr;110(2):78-81; quiz 85.) 

The full text article is available at: http://www.wisconsinmedicalsociety.org/_WMS/publications/wmj/pdf/110/2/78.pdf

This month Peisman and Hoigaard note that "prophylactic treatment was totally ineffective when delivered ≥2days after tick removal." [2 days = 48 hrs]

Ticks Tick Borne Dis. 2012 Mar 13. [Epub ahead of print] Protective value of prophylactic antibiotic treatment of tick bite for Lyme disease prevention: An animal model. Piesman J, Hojgaard A.

Abstract

Clinical studies have demonstrated that prophylactic antibiotic treatment of tick bites by Ixodes scapularis in Lyme disease hyperendemic regions in the northeastern United States can be effective in preventing infection with Borrelia burgdorferi sensu stricto, the Lyme disease spirochete. 

A large clinical trial in Westchester County, NY (USA), demonstrated that treatment of tick bite with 200mg of oral doxycycline was 87% effective in preventing Lyme disease in tick-bite victims (Nadelman, R.B., Nowakowski, J., Fish, D., Falco, R.C., Freeman, K., McKenna, D., Welch, P., Marcus, R., Agúero-Rosenfeld, M.E., Dennis, D.T., Wormser, G.P., 2001. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N. Engl. J. Med. 345, 79-84.). 

Although this excellent clinical trial provided much needed information, the authors enrolled subjects if the tick bite occurred within 3days of their clinical visit, but did not analyze the data based on the exact time between tick removal and delivery of prophylaxis. An animal model allows for controlled experiments designed to determine the point in time after tick bite when delivery of oral antibiotics would be too late to prevent infection with B. burgdorferi. 

Accordingly, we developed a tick-bite prophylaxis model in mice that gave a level of prophylactic protection similar to what had been observed in clinical trials and then varied the time post tick bite of antibiotic delivery. We found that two treatments of doxycycline delivered by oral gavage to mice on the day of removal of a single potentially infectious nymphal I. scapularis protected 74% of test mice compared to controls. When treatment was delayed until 24h after tick removal, only 47% of mice were protected; prophylactic treatment was totally ineffective when delivered ≥2days after tick removal. 

Although the dynamics of antibiotic treatment in mice may differ from humans, and translation of animal studies to patient management must be approached with caution, we believe our results emphasize the point that antibiotic prophylactic treatment of tick bite to prevent Lyme disease is more likely to be efficacious if delivered promptly after potentially infectious ticks are removed from patients.

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There is only a very narrow window for prophylactic treatment to be effective post tick removal.

In my opinion, a study like this one should have been done long ago. How many studies were used to make the original determination that one 200 mg capsule of doxycycline would be an appropriate method of prophylaxis against Lyme disease? 

 And the obnoxious thing is, I was given this treatment! I had a tick bite, I had an EM rash, I was concerned about Lyme disease - and the first doctor I saw said there was no Lyme disease in the area in which I had been bitten, but I was given the one pill of doxycycline as some sort of consolation prize... The implication from the doctor being that the bite was most likely nothing to worry about and the pill being given to me to placate me.

Well, this prophylaxis apparently was not very prophylactic, now, was it?

I am pretty sure I saw the doctor 3-4 days after the tick bite, when I was given the prescription paper to fill it for one capsule of doxycycline.

This prophylactic approach never made sense to me from the day I first learned about the one pill preventative.

Since my failed experience of preventing Lyme disease, I've learned that different strains/subspecies of Borrelia burgdorferi disseminate at different rates, with different bacterial loads from different bites. If infection is present - one pill is hardly going to stop it. And if a coinfection is present, it may have an impact on the immune system which is hard to predict and may alter how effective an antibiotic is on the big picture.

One of the things I've learned in the past couple of weeks of doing research on Russian web sites about how patients are affected by Lyme disease and what treatments are given to patients there is that there is more of a sense of urgency of treating Lyme disease early and also aggressively. This is not to say that the Russian approach of managing Lyme disease is the best overall - they too have a problem with chronic Lyme disease - and so far as I can see, have not found the perfect treatment for it.

But if what I read so far is to be taken into account, then their approach has been to treat Lyme disease as early as possible and have doctors remove ticks as soon as one has a tick bite because research has shown the earlier a tick is removed properly, the greater the risk is reduced in transmitting infection.

In addition to encouraging immediate professional tick removal and early treatment during the acute stage, a number of medical clinics and web sites recommend a few days of prophylactic doxycycline - rather than one pill.

I am still looking for Russian research papers which support this approach - so perhaps take this information with some caution. But here are two sites which mention this approach which would appear to be legitimate resources:

First site, the equivalent of city council pages for  Lipetsk:

From an order marked:

ORDER KM Lipetsk region from 09.09.2004 N 523, SEC in the Lipetsk region dated 04.08.2004 N 78-ns, "ESTABLISHMENT OF Surveillance of Ixodes tick-borne borreliosis in the region" (with "GUIDELINES", "PLAN OF SCIENTIFIC AND PRACTICAL WORK on the prevalence of Ixodes tick-borne borreliosis in Lipetsk region for 2004 - 2005 HS. ")

Administration of Lipetsk Region

DEPARTMENT OF HEALTH
on September 9, 2004 N 523

SEC in the Lipetsk Region
on August 4, 2004 N 78-ns

ORDER ON Surveillance FOR Ixodes tick-borne borreliosis -- Excerpt:

"Carry an emergency antibiotic prophylaxis should be based only on display in the pathogen attached ticks. In the case of the pathogen in the vector and not later than 3 days. of tick suction in patients prescribed a course of doxycycline at 0.1 x 1 time per day for 5 days (children under 8 years of this antibiotic is not indicated).

Later on the third day from the time course of doxycycline tick suction extended to 10 days. Other antibiotics, which can be used for preventive treatment, drugs are prolonged penicillin: bicillin 3 or retapen (ekstentsillin) at a dose of 2.4 million units. intramuscularly once after a skin test on the individual tolerance of antibiotic.

Has a high efficiency combination drug amoxicillin with clavulanic acid (amoxiclav) to 0.375 g, 3 times a day, 5 days.

When carrying out emergency prophylaxis following should be considered (Appendix 9):
- Epidemiological history - a fact suction to the skin of ticks;
- Results of microbiological studies, parazitologo - detection of Borrelia in the attached ticks by dark-field microscopy or PCR;
- Start of antibiotic timing - as soon as possible after the suction (after the 5th day of tick suction inappropriate use of approved schemes), early prevention of borreliosis - a day after the suction of an infected tick Borrelia - can be recommended only when a negative result of the study attached ticks in the ELISA CEA antigen;
- A good individual tolerability of recommended antibiotics;
- Carrying antibiotics under medical supervision;
- Follow-up visit within 1 - 3 months after the course of antibiotic prophylaxis in SDS"

In Russian:

ПРИКАЗ УЗ Липецкой области от 09.09.2004 N 523, ЦГСЭН В Липецкой области от 04.08.2004 N 78-пв "ОБ ОРГАНИЗАЦИИ ЭПИДЕМИОЛОГИЧЕСКОГО НАДЗОРА ЗА ИКСОДОВЫМ КЛЕЩЕВЫМ БОРРЕЛИОЗОМ В ОБЛАСТИ" (вместе с "МЕТОДИЧЕСКИМИ РЕКОМЕНДАЦИЯМИ", "ПЛАНОМ ПРОВЕДЕНИЯ НАУЧНО-ПРАКТИЧЕСКОЙ РАБОТЫ ПО ИЗУЧЕНИЮ РАСПРОСТРАНЕНИЯ ИКСОДОВОГО КЛЕЩЕВОГО БОРРЕЛИОЗА НА ТЕРРИТОРИИ ЛИПЕЦКОЙ ОБЛАСТИ НА 2004 - 2005 ГГ.")

2.8. Экстренная антибиотикопрофилактика ИКБ

Проводить экстренную антибиотикопрофилактику следует только на основании индикации возбудителя в присосавшемся клеще.

В случае обнаружения возбудителя в переносчике и не позднее 3 сут. после присасывания клеща пациентам назначают курс доксициклина по 0,1 х 1 раз в сутки в течение 5 дней (детям до 8 лет данный антибиотик не назначают).

Позже третьего дня от момента присасывания клеща курс доксициклина продлевается до 10 дней. Другими антибиотиками, которые могут быть использованы для превентивного лечения, являются препараты пролонгированного пенициллина: бициллин-3 или ретапен (экстенциллин) в дозе 2,4 млн. ед. внутримышечно однократно после проведения внутрикожной пробы на индивидуальную переносимость антибиотика.

Высокой эффективностью обладает комбинированный препарат амоксициллина с клавулановой кислотой (амоксиклав) по 0,375 г 3 раза в сутки 5 дней.

При проведении экстренной антибиотикопрофилактики необходимо учитывать следующее (приложение 9):
- данные эпидемиологического анамнеза - факт присасывания к кожным покровам иксодовых клещей;
- результаты паразитолого-микробиологических исследований - выявление боррелий в присосавшихся клещах методом темнопольной микроскопии или ПЦР;
- сроки начала антибиотикопрофилактики - как можно раньше после присасывания (позже 5-го дня после присасывания клеща использование рекомендованных схем нецелесообразно), ранняя профилактика боррелиоза - через сутки после присасывания зараженного боррелиями клеща - может быть рекомендована только при отрицательном результате исследования присосавшегося клеща в ИФА на антиген КЭ;
- хорошая индивидуальная переносимость рекомендуемых антибиотиков;
- проведение антибиотикопрофилактики под контролем врача;
- контрольное обследование через 1 - 3 месяца после проведенного курса антибиотикопрофилактики на ИКБ.

Source: Network of Lipetsk Region http://lipetsk.news-city.info/docs/sistemsv/dok_oegvgi/index.htm

And then here's another, for Nizhny Novgorod State Medical University, which has been around since 1920:

"At the present time in Nizhny Novgorod and the region is high infection of ticks with borreliae, there are also ticks infected with tick-borne encephalitis. You must know the pattern of action in the case of tick suction.

First, you must remove the tick, while maintaining its viability. You can do it yourself or by contacting the trauma center in your area.

Remote mite be sent to study in Nizhny Novgorod Research Institute of Epidemiology and Microbiology. Academician I. Blokhina (St. Georgia 44, 433-76-55, 434-17-71, www.micro.nnov.ru). Within a day you will get the result of the study.

If the tick was infected with Borrelia, to conduct preventive 10-day course of doxycycline (T. Doxiciclini 0,1 to 1 m, 2 times a day).

If the tick was infected with tick-borne encephalitis, showed immunoglobulin, but the free drug can qualify only if after the bite was not more than 4 days."

The above, in Russian:

"В настоящее время на территории Нижнего Новгорода и Нижегородской области высока инфицированность клещей боррелиями, встречаются также клещи, инфицированные вирусом клещевого энцефалита. Необходимо знать схему действий в случае присасывания клеща.

Во-первых, клеща необходимо удалить, сохранив его жизнеспособность. Сделать это можно самостоятельно либо обратившись в травмпункт Вашего района.

Удаленного клеща необходимо отправить на исследование в Нижегородский НИИ эпидемиологии и микробиологии им. академика И.Н. Блохиной (Ул. Грузинская 44, 433-76-55, 434-17-71, www.micro.nnov.ru). В течение 1 суток Вам предоставят результат исследования.

В случае, если клещ был инфицирован боррелиями, необходимо проведение профилактического 10-дневного курса доксициклина (T. Doxiciclini 0,1 по 1 т. 2 раза в день).

Если клещ был инфицирован вирусом клещевого энцефалита, показано введение иммуноглобулина, но на бесплатный препарат можно претендовать лишь в том случае, если с момента укуса прошло не более 4 дней."

Source: http://www.nizhgma.ru/studentu/kafedry/infekc/uchmat/klesh/


So far as I can see, the use of a longer period of prophylactic treatment is advised - but the public health department also makes an effort to test the tick you have had on you for the presence of bacteria and viruses. The turn around time is less than 24 hours for results.

The only problem with this approach is that if you get a tick bite which is not obvious and it is not found right away, the odds of getting Lyme disease and/or Tick-borne encephalitis (TBE) are greater. Treatment may come too late to help a patient - particularly in the case of  TBE, where immunoglobulin for TBE and antiviral medication will only help if administered in under 72-96 hours after the tick bite.

There are three reasons I suspect Russia is more aggressive in its approach:

1) While the odds of getting TBE are lower than the odds of getting Lyme Borreliosis, TBE has a much higher risk of leading to acute severe illness and death. The older one is when they are infected with TBE, the higher the odds are of serious complications and fatality.

2) The most common strain of Borrelia people are infected with in Tomsk - a highly endemic area of Russia - is B. garinii, and a specific type of B. garinii quickly disseminates to the CNS more quickly than other strains. To prevent neuroborreliosis and widespread dissemination to other organs, a longer prophylactic course is needed as soon as possible.

3) Polymicrobial or coinfection is not uncommon. It is possible to be infected with both Lyme Borrelia and TBE, or more than one strain of Borrelia burgdorferi, and perhaps throw in Anaplasmosis in there as well. One has to be very careful of how to treat such cases - if TBE is present, it must be treated first since it moves fast, is more dangerous, and early antibiotic use is contraindicated in its presence.

All this said, I do wonder how it was determined that prophylaxis should be 5-10 days, based on circumstances surrounding the bite. This is a much longer course than the IDSA has suggested.

And frankly, this sort of treatment is what I wish I had if it would have prevented the situation in which I now find myself.

If you found this post interesting and informative, you may want to read this one as well:
http://campother.blogspot.com/2010/12/dr-david-volkmans-letter-to-idsa-lyme.html

Addendum [April 29, 2012]: I wanted to add the following passage from a paper from The Canadian Entomologist:

"Studies of the transmission dynamics of B. burgdorferi in I. scapularis indicate that the risk of transmission of strain B31 by a single bite from an infected tick is about 2% and that the risk increases with the length of time that the tick is attached (Hojgaard et al. 2008). 

When a tick first attaches, spirochetes are still found in the midgut and are producing outer-surface protein A (OspA), which helps spirochetes adhere to a midgut protein, TROPSA. When feeding begins, the spirochetes are exposed to warm mammalian blood and lowered pH, and OspA is downregulated while OspC is upregulated. Spirochetes then migrate from the midgut to the salivary gland and transmission to the vertebrate host can be achieved (e.g., Hojgaard et al. 2008). This delay in transmission explains why transmission is reduced when ticks are removed within 24 h of attachment (Hojgaard et al. 2008). 

In Europe, transmission of B. burgdorferi s.s. and B. afzelii by I. ricinus occurs in less than 24 h, but the risk of transmission still increases over time (Kahl et al. 1998; Crippa et al. 2002). In a further complication of the host—tick—pathogen interaction, B. burgdorferi s.l. is able to increase expression of an Ixodes salivary protein, Salp 15, to protect against complement-mediated killing of Borrelia by the host's innate immune system (Ramamoorthi et al. 2005). This protective effect was greater when the vector was I. ricinus rather than I. scapularis (Schuijt et al. 2008). The early expression of ospC appears to be essential for B. burgdorferi to escape innate immunity and disseminate in the host (Gilbert et al. 2007), and yet persistent infection of the host is only possible when ospC is downregulated after infection because acquired antibodies to OspC allow the spirochetes to be cleared (Tilly et al. 2007). Current understanding of the interactions of tick saliva and B. burgdorferi is discussed in Anderson and Valenzuela (2007)."

Source: http://www.bioone.org/doi/full/10.4039/n08-CPA04

Janet L.H. Sperling, Felix A.H. Sperling. Lyme Borreliosis in Canada: Biological Diversity and Diagnostic Complexity from an Entomological Perspective. The Canadian Entomologist 141(6):521-549. 2009 doi: http://dx.doi.org/10.4039/n08-CPA04

The above passage is important to note because it outlines the fact that the rate of transmission of spirochetes from the tick to its host varies based on a number of factors including Borrelia strain, the type of tick involved, Salp15 production levels, expression of ospC, and length of time the tick has been attached.

Based on this research, it is clear additional research is needed to determine if strains of Borrelia burgdorferi other than B31 in Ixodes scapularis and Ixodes pacificus would have differing transmission times tested under the factors mentioned. The same sort of studies would be beneficial for Europeans on Ixodes ricinus and other European Ixodes ticks.

[Edited March 22, 2012 - First paragraph said "100 mg capsule of doxycycline", was changed to "200 mg capsule of doxycycline".]


Image credit: Doxycycline 100 mg capsules. By Shorelander, Wikimedia Commons.

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