One Dose Doxy
One Dose Of Doxy STILL- 2016
One dose of Doxycycline does NOT prevent or cure Lyme disease, but the IDSA is STILL promoting this treatment. To limit treatment options even further and increase the risks of contracting tick borne diseases the IDSA recommends one ineffective dose of doxycycline only IF all the conditions below on the blue slide are met.
TREAT THE BITE
The Right Way
For current recommendations
For treating a tick bite click here.
Shapiro (IDSA guideline author) stating parents of children referred to his clinic with Lyme disease symptoms don't have Lyme disease, they have- "health care seeking behaviors" and "patients are trying to get often get treated unnecessarily with antimicrobials." See 3 minute video by clicking here.
Original Flawed Study- Nadelman, et al.
(IDSA Supporters & Guideline Authors)
N Engl J Med. 2001 Jul 12;345(2):79-84.
Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite.
Nadelman RB1, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, Welch P, Marcus R, Agüero-Rosenfeld ME, Dennis DT, Wormser GP; Tick Bite Study Group.
Abstract
BACKGROUND:
It is unclear whether antimicrobial treatment after an Ixodes scapularis tick bite will prevent Lyme disease.
METHODS:
In an area of New York where Lyme disease is hyperendemic we conducted a randomized, double-blind, placebo-controlled trial of treatment with a single 200-mg dose of doxycycline in 482 subjects who had removed attached I. scapularis ticks from their bodies within the previous 72 hours. At base line, three weeks, and six weeks, subjects were interviewed and examined, and serum antibody tests were performed, along with blood cultures for Borrelia burgdorferi. Entomologists confirmed the species of the ticks and classified them according to sex, stage, and degree of engorgement.
RESULTS:
Erythema migrans developed at the site of the tick bite in a significantly smaller proportion of the subjects in the doxycycline group than of those in the placebo group (1 of 235 subjects [0.4 percent] vs. 8 of 247 subjects [3.2 percent], P<0.04). The efficacy of treatment was 87 percent (95 percent confidence interval, 25 to 98 percent).
Objective extracutaneous signs of Lyme disease did not develop in any subject, and there were no asymptomatic seroconversions.
Treatment with doxycycline was associated with more frequent adverse effects (in 30.1 percent of subjects, as compared with 11.1 percent of those assigned to placebo; P<0.001), primarily nausea (15.4 percent vs. 2.6 percent) and vomiting (5.8 percent vs. 1.3 percent).
Erythema migrans developed more frequently after untreated bites from nymphal ticks than after bites from adult female ticks (8 of 142 bites [5.6 percent] vs. 0 of 97 bites [0 percent], P=0.02) and particularly after bites from nymphal ticks that were at least partially engorged with blood (8 of 81 bites [9.9 percent], as compared with 0 of 59 bites from unfed, or flat, nymphal ticks [0 percent]; P=0.02).
CONCLUSIONS:
A single 200-mg dose of doxycycline given within 72 hours after an I. scapularis tick bite can prevent the development of Lyme disease.
RESPONSES TO THIS STUDY
Comment in
Single-dose doxycycline for the prevention of Lyme disease. [N Engl J Med. 2001]
Single-dose doxycycline prevented Lyme disease after an Ixodes scapularis tick bite. [ACP J Club. 2002]
Antibiotic prophylaxis for Lyme disease: how the way of reporting a clinical trial can alter the perception of effectiveness. [Arch Dermatol. 2003]
Single-dose doxycycline for the prevention of Lyme disease. [N Engl J Med. 2001]
Doxycycline for tick bites--not for everyone. [N Engl J Med. 2001]
Single-dose doxycycline for the prevention of Lyme disease. [N Engl J Med. 2001]
Single-dose doxycycline for the prevention of Lyme disease. [N Engl J Med. 2001]
Free full text
http://www.ncbi.nlm.nih.gov/pubmed/11450675
More Inaccurate Info
CDC
http://www.cdc.gov/ticks/tickbornediseases/tick-bites-prevention.html
New Hampshire Health Department
https://www.manchesternh.gov/portals/2/Departments/health/Prophylaxis%20following%20tick%20bites.pdf
Follow up report from IDSA- Quote... "In addition, even if antibiotic prophylaxis is given, it is important for persons to continue to inspect the site of the tick bite for erythema migrans, since prophylaxis is not 100% effective in preventing infection." More info- click here.
When Effective Really Means NOT Effective?
The word "effective" can be used in a conclusion if the data supports it. IDSA Lyme disease guideline author (Shapiro) and friends concluded the use of preventative clothing and tick repellents on skin "are effective in preventing LD" (Lyme disease), when 60% of the time protective clothing wasn't effective and 80% of the time the use of tick repellents was not effective.
Shapiro, et al Quote- "Use of protective clothing was 40% effective; routine use of tick repellents on skin or clothing was 20% effective.... We concluded that use of protective clothing and of tick repellents (on skin or clothing) are effective in preventing LD."
NOTE- Shapiro took it upon himself to undiagnose children with Lyme disease who were referred to his pediatric clinic. He renamed the children's chronic Lyme symptoms "medically unexplained symptoms" (MUS often presumed to be a psychiatric diagnosis). He admits over 50% of parents of children with Lyme were NOT happy with results of the consults at his clinic and went on to get additional treatment. It was "very common" he states for parents to seek additional providers.
Shapiro refers to the parent's as having problems, such as- "health care seeking behaviors where where patients are trying to get often get treated unnecessarily with antimicrobials." He continues- "so that's one of the interesting and most important aspects of what is going on with Lyme disease today." See 3 minute video by clicking here.
Shapiro's study...
Emerg Infect Dis. 2008 Feb;14(2):210-6. doi: 10.3201/eid1402.070725.
Effectiveness of personal protective measures to prevent Lyme disease.
Vázquez M1, Muehlenbein C, Cartter M, Hayes EB, Ertel S, Shapiro ED.
Abstract
After the manufacture of Lyme vaccine was discontinued in 2002, strategies to prevent Lyme disease (LD) have focused on personal protective measures. Effectiveness of these measures has not been conclusively demonstrated.
The aim of our case-control study was to assess the effectiveness of personal preventive measures in a highly disease-endemic area. Case-patients were persons with LD reported to Connecticut's Department of Public Health and classified as having definite, possible, or unlikely LD. Age-matched controls without LD were identified.
Study participants were interviewed to assess the practice of preventive measures and to obtain information on occupational and recreational risk factors. Use of protective clothing was 40% effective; routine use of tick repellents on skin or clothing was 20% effective.
Checking one's body for ticks and spraying property with acaricides were not effective.
We concluded that use of protective clothing and of tick repellents (on skin or clothing) are effective in preventing LD.
PMID:
PMCID:
DOI:
[PubMed - indexed for MEDLINE]
ONE DOSE OF DOXYCYCLINE
DOES NOT WORK!
For a one page handout with updated treatment recommendations that you can print and take to your doctor with you, please go to the Treat The Bite website. There are two ways to address a tick bite; the IDSA way, or the right way.
Ticks Tick Borne Dis. 2012 Jun;3(3):193-6. doi: 10.1016/j.ttbdis.2012.01.001. Epub 2012 Mar 13.
Protective value of prophylactic antibiotic treatment of tick bite for Lyme disease prevention: an animal model.
1Bacterial Diseases Branch, Division of Vector-Borne Diseases, The Centers for Disease Control and Prevention, 3150 Rampart Road, Fort Collins, CO 80521, USA.
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 3 days 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 24 h after tick removal, only 47% of mice were protected; prophylactic treatment was totally ineffective when delivered ≥2 days 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. There is only a very narrow window for prophylactic treatment to be effective post tick removal.
Published by Elsevier GmbH.
http://www.ncbi.nlm.nih.gov/pubmed/22421585
Protective value of prophylactic antibiotic treatment of tick bite for Lyme disease prevention:
An animal model ☆
http://www.sciencedirect.com/science/article/pii/S1877959X1200012X
Journal of Medical Microbiology (2008), 57, 463–468 DOI 10.1099/jmm.0.47535-0
Nordin S. Zeidner Naz2@cdc.gov
Received 25 July 2007 Accepted 21 December 2007
A sustained-release formulation of doxycycline hyclate (Atridox) prevents simultaneous infection of Anaplasma phagocytophilum and Borrelia burgdorferi transmitted by tick bite
Nordin S. Zeidner,1 Robert F. Massung,2 Marc C. Dolan,1 Eric Dadey,3 Elizabeth Gabitzsch,1 Gabrielle Dietrich1 and Michael L. Levin2
1Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, CO 80522, USA
2Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
3QLT Laboratories, Fort Collins, CO 80525, USA
Current prophylaxis for infected tick bites consists of personal protective measures directed towards ticks. This study compared the efficacy of a single oral dose of doxycycline with that of a single injection of sustained-release doxycycline in a model of Lyme borreliosis and Anaplasma phagocytophilum infection.
Dosages of doxycycline were equilibrated based on previously determined peak plasma levels in mice [oral, 2.4 mg (ml plasma)”1; sustained release, 1.9 mg (ml plasma)”1] determined 8 h after inoculation. In challenge experiments where five Borrelia burgdorferi-infected and five A. phagocytophilum-infected nymphs were used per mouse, only 20 and 30 % of mice were protected from B. burgdorferi and A. phagocytophilum infection, respectively, using oral doxycycline.
In contrast, 100 % of mice receiving sustained-release doxycycline were protected from A. phagocytophilum infection, as indicated by real-time PCR of blood samples, quantitative PCR and culture isolation of spleen samples, and protected against B. burgdorferi infection as demonstrated by culture of ear, heart and bladder. Although 15–40 copies of A. phagocytophilum could be amplified from the spleens of mice treated with sustained-release doxycycline, no viable A. phagocytophilum from these spleens could be cultured in HL-60 cells.
In contrast, 7/10 mice receiving oral doxycycline were PCR- and culture-positive for A. phagocytophilum, with copy numbers ranging from 800 to 10 000 within the spleen, as determined by quantitative PCR. Other correlates with A. phagocytophilum infection included a significant difference in spleen mass (mean of 110 mg for sustained-release treatment versus a mean of 230 mg for oral treatment) and the number of splenic lymphoid nodules (mean of 8 for sustained-release treatment versus mean of 12.5 for oral doxycycline) as determined by histopathology. These studies indicate that a single injection of a sustained-release formulation antibiotic may offer a viable prophylactic treatment option for multiple infectious agents in patients presenting with tick bites.
INTRODUCTION
Lyme borreliosis is the most common vector-borne disease reported in the USA (CDC, 2004). Human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis) is an emerging tick-borne disease first described in the midwestern USA, and now routinely found along the north-eastern seaboard and upper midwestern states (Bakken & Dumler, 2000; McQuiston et al., 1999). The aetiological agent of human granulocytic anaplasmosis is Anaplasma phagocytophilum and is transmitted in these parts of the USA by Ixodes scapularis, the same tick vector that transmits Lyme disease in these geographical regions (Massung et al., 2004; Pancholi et al., 1995).
Both of these zoonotic pathogens are maintained in cycles comprising I. scapularis ticks and Peromyscus leucopus reservoir mice (Stafford et al., 1999). Infection with one of these agents may accompany infection of the other, both in vector ticks and reservoir hosts (Adelson et al., 2004; Stafford et al., 1999). Moreover, within endemic areas, humans may acquire combined infections, leading to overlapping disease symp- tomatology (Aguero-Rosenfeld et al., 2002; Krause et al., 2002).
Clinical delineation of this becomes important, as acknowledging dual infection may affect the inclusion of appropriate and effective chemotherapy for A. phagocytophi- lum, which may be different from treatment for acute Lyme borreliosis (Maurin et al., 2003; Nadelman et al., 1997).
Doxycycline is the drug of choice for treating patients with acute A. phagocytophilum infection. Likewise, although amoxicillin is widely used to treat acute Lyme borreliosis, studies indicate that doxycycline may be as effective (Wormser et al., 2003).
Similarly, some success has been obtained using a single dose (200 mg) of doxycycline hyclate for prophylactic treatment of people exposed to an I. scapularis tick bite (Nadelman et al., 2001). Our laboratory has reported that delivery of a single dose of a sustained- release formulation of doxycycline hyclate is 100 % effective in preventing tick-transmitted Borrelia burgdorferi infection in a murine model of Lyme borreliosis (Zeidner et al., 2004a).
Moreover, similar results have been reported in a murine model of tick-transmitted A. phagocytophilum (Massung et al., 2005). Compared with the rapid clearance of orally delivered doxycycline, sustained-release doxycy- cline plasma levels in these studies were sustained over a 19 day period after delivery at a concentration below the MIC reported for B. burgdorferi (Johnson et al., 1990) and with no apparent toxicity.
In general, controlled-release delivery systems for antimicrobial agents have been shown to increase the bioavailability of short-lived antibiotics to mammalian tissues and to enhance treatment efficacy (Matschke et al., 2002).
In contrast to previous studies looking at treatment of a single infectious agent transmitted by ticks, the current studies were done to compare the effectiveness of a single oral administration of doxycycline hyclate with a single subcuta- neous administration of sustained-release doxycycline to prevent dual transmission of A. phagocytophilum and B. burgdorferi simultaneously delivered by I. scapularis ticks.
METHODS
Tick transmission of B. burgdorferi and A. phagocytophilum. Laboratory-reared, B. burgdorferi-infected I. scapularis nymphal ticks were raised as described by Piesman (1993) and have been shown previously to be free of A. phagocytophilum and Babesia microti(Zeidner et al., 2004a). These ticks were infected with low-passage- number B. burgdorferi strain B31. Likewise, laboratory-reared nymphal I. scapularis ticks that had previously fed as larvae on P. leucopus mice infected with a low-passage-number of A. phagocyto- philum Webster strain (Massung et al., 2004) were used for tick inoculation studies.
In dual-infection studies, a total of ten infected nymphs (five of each infected with B. burgdorferi or A. phagocyto- philum) were placed on the head and neck areas of specific-pathogen- free, 6-week-old female C3H/HeJ mice (n55 per group, mass equal to 20.1±0.2 g; Jackson Laboratory). In single infection control studies, only five infected nymphs harbouring either B. burgdorferi or A. phagocytophilum were placed on mice. These studies were then repeated with n55 mice per group. At 72 h after tick infestation, the partially engorged ticks were removed from all mice as described previously (Massung et al., 2005; Zeidner et al., 2004a). The mice were then randomly assigned to receive either 2 mg oral doxycycline
hyclate in water, 4.2 mg sustained-release doxycycline hyclate co- polymer formulation (Atridox) (QLT Laboratories), or water or DL- lactide in N-methyl-2-pyrrolidone co-polymer (QLT Laboratories) vehicle treatment controls. These dosages of doxycycline were previously shown to deliver equivalent peak levels of drug in mouse plasma measured 8 h after inoculation (Zeidner et al., 2004a). Oral doxycycline was delivered by gavage in 0.1 ml tissue-grade water.
The sustained-release doxycycline hyclate (Atridox) was mixed according to the manufacturer’s specifications and transferred to a 1 ml Luer Lock syringe (Becton Dickinson) fitted with a 25-gauge needle for subcutaneous injection. A total of 0.05 ml was then delivered to each mouse along the dorsal midline of the animal between the scapulae.
Determination of B. burgdorferi and A. phagocytophilum infection in mice. Mice were bled weekly for 3 weeks post-tick infestation to determine the A. phagocytophilum infection status in blood. These EDTA-treated blood samples were frozen at 280 uC until analysed. At 3 weeks post-treatment, all mice were euthanized and skin (ear biopsy), heart and bladder were cultured in Barbour–Stenner– Kelly medium (Schwartz et al., 1992) to determine the B. burgdorferi infection status (Sinsky & Piesman, 1989).
Samples were also placed in tissue fixative (Streck Laboratories) to determine histopathology. Likewise, spleen samples were taken to determine A. phagocytophiluminfection levels, both by PCR and by direct culture using HL-60 cells. All spleens were first weighed, and equal amounts of tissue were either frozen at 280 uC until analysed by PCR, or homogenized and co- cultured on human promyelocytic HL-60 cells. The remainder of the spleen was then placed into tissue fixative for histopathological evaluation. Growth of A. phagocytophilum in HL-60 cells was monitored by light microscopy after methanol fixation of cytocen- trifuge preparations and staining with the Diff-Quik diagnostic stain (Dade Behring).
DNA extraction and quantification of A. phagocytophilum copy number. A real-time PCR assay (Massung et al., 2004, 2005) was utilized to determine the presence of A. phagocytophilum in peripheral blood, and a quantitative PCR assay was used to determine A. phagocytophilum copy number in spleen samples. DNA was extracted from tissues as described previously (Massung et al., 2004, 2005) using a DNeasy tissue kit (Qiagen). In the case of blood, 200 ml whole blood per mouse was used, and copy numbers in spleen were determined [copy number (mg spleen tissue)21]. The real-time PCR assay utilized primers and probe to amplify the spacer region between the single-copy 23S and 5S rRNA genes as described previously (Massung et al., 2004). Real-time PCR assays were performed on each sample in triplicate and the mean was determined per sample. Both positive and negative controls were included in all PCR assays.
Determination of histopathology. Tissue sections were prepared as described previously (Zeidner et al., 2004b). Briefly, specimens placed in Streck’s tissue fixative were subjected to standard processing, embedded in paraffin and sectioned at 5 mm. Sections were then stained with haematoxylin and eosin for standard light microscopy evaluation. All tissue sections were read and analysed in a coded, blind fashion.
Statistical analysis. Fisher’s test was utilized to determine significant differences among treatment groups. Student’s t-test was used to determine significant differences in splenic copy numbers of A. phagocytophilum among treatment groups. In both cases, P,0.05 was considered a statistically significant difference between groups.
RESULTS
As shown in Table 1, sustained-release doxycycline hyclate completely protected mice (100 %) from both B. burgdorferi
Prophylaxis for A. phagocytophilum and B. burgdorferi Table 1. Treatment efficacy of sustained-release doxycycline hyclate against B. burgdorferi co-transmitted with A. phagocytophilum
Ap, A. phagocytophilum; Bb, B. burgdorferi; NA, not applicable.
*Culture results of skin biopsy analysed at 28 days, and heart and bladder at 56 days post-tick infestation. DResults of quantitative PCR analysis and culture (spleen) at 21 days post-tick infestation.
No. of mice infected with Protection No. of mice infected with Protection Bb/no. tested (%)* Ap/no. tested (%)D
Sustained-release doxycycline DL-Lactide co-polymer control
Oral doxycycline Water control
0/10 100 0/10 100 7/10 NA 7/10 NA
8/10 20 7/10 30 10/10 NA 8/10 NA
and A. phagocytophilum infection transmitted simulta- neously by infected ticks. In comparison, 70 and 80% of mice receiving a single dose of oral doxycycline became infected with either A. phagocytophilum or B. burgdorferi, respectively, which was not statistically different from either the co-polymer or water control mice (P50.2). In the case of B. burgdorferi, infection status was based on culture of skin (ear), heart and bladder. Where animals were infected with B. burgdorferi, all three tissues were consistently infected and demonstrated pathology of the heart, spleen and bladder (data not shown). In the case of A. phagocytophilum infection, A. phagocytophilum DNA could not be detected within the peripheral blood on days 7, 14 and 21 in mice receiving sustained-release doxycycline, and that were infected with A. phagocytophilum alone or simultaneously challenged with B. burgdorferi (Fig. 1a). In contrast, DNA could be amplified from the blood of 7/10 mice receiving oral doxycycline on days 7, 14 and 21 (Fig. 1a). As previous studies have indicated that the spleen is a site of A. phagocytophilum replication and accumulation, we analysed the spleen on day 21 by quantitative, real-time PCR and by direct isolation of A. phagocytophilum from cultured HL-60 cells. As shown in Fig. 1(b), mice challenged with A. phagocytophilum-infected ticks alone or simultaneously with B. burgdorferi-infected ticks, and treated with Atridox, demonstrated mean values of 21.6 and 15.3 copies (mg spleen)21, respectively, as measured by quantitative PCR. These copy numbers were significantly different from those in mice treated with oral doxycycline (dual infection, mean of 987 copies mg21, P,0.001; A. phagocytophilum infection alone, mean of 3892 copies mg21, P,0.001). Moreover, there was no statistically significant difference in A. phagocy- tophilum splenic copy number between mice treated with oral doxycycline and the co-polymer or water control (dual infection, mean of 987 versus 1181 copies mg21, P50.76; A. phagocytophilum infection alone, mean of 3892 versus 768 copies mg21, P50.24). Attempts to culture A. phagocyto- philum from spleen homogenates from mice treated with sustained-release doxycycline hyclate showed no growth, suggesting that the PCR-positive spleens from these mice did not contain viable organisms (data not shown).
Previous studies have indicated that replication and accumulation of A. phagocytophilum occurs within the
spleen (Massung et al., 2004, 2005). As shown in Fig. 2, a marked difference in the size of spleens was noted when comparing mice treated with oral doxycycline with those
(a) 30
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7 14 21 Time post-tick infestation (days)
Treatment group
Ap+Bb (oral doxycycline) Ap+Bb (co-polymer C) Ap (Atridox)
Ap (oral doxycycline)
Ap (water C)
Fig. 1. (a) PCR amplification of A. phagocytophilum from the blood of tick-infested mice. Blood samples were harvested on days 7, 14 and 21 post-tick infestation for quantitative real-time PCR analysis as described in Methods. Points represent the mean values per treatment group (n510) of mice. (b) Representative copy numbers of A. phagocytophilum PCR-amplified from the spleen of mice 21 days after tick infestation. Lines represent the mean copy number value per treatment group. Ap, A. phagocy- tophilum; Bb, B. burgdorferi.
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(a) (b)
Sustained-release doxycycline
Oral doxycycline
Fig. 2. Histopathology following dual B. burgdorferi and A. phagocytophilum challenge. (a) A representative spleen sample (magnification 3⁄45) of an animal treated with sustained-release doxycycline hyclate (Atridox). Arrows indicate discrete lymphoid follicles. (b) A representative tissue sample (magnification 3⁄45) of an animal treated with oral doxycycline, which was both PCR- and culture-positive for A. phagocytophilum, as well as culture-positive for B. burgdorferi.
treated with Atridox. Marked lymphoid hyperplasia and an increase in cellular infiltrate (monocytes, neutrophils and plasma cells) within the red pulp were noted for animals treated with oral doxycycline who were both PCR- and culture-positive for A. phagocytophilum (Fig. 2b). In contrast, those animals in which A. phagocytophilum and B. burgdorferi infection was prevented retained a normal splenic architecture with discrete lymphoid follicles and no extraneous cellular infiltrate within the red pulp (Fig. 2a).
Moreover, gross spleen mass was significantly different when comparing treatment groups (n510). Those animals in which infection was prevented by treatment with Atridox demonstrated spleen masses ranging from 98.6 (dual infection) to 121 mg (A. phagocytophilum infection alone) similar to normal (n510) C3H/HeJ spleens (mean of 107±0.2 mg, P50.28) (Fig. 3a). In contrast, animals treated with oral doxycycline had spleen masses ranging from 213 to 244 mg (Fig. 3a), which was statistically significant (P,0.0005). Moreover, there was no difference in spleen masses of animals treated with oral doxycycline compared with the water- or co-polymer-treated controls (P50.51).
We noted that the increase in spleen mass could be due to the marked lymphoid hyperplasia in PCR-positive spleens, as well as the number of lymphoid nodules enumerated (Fig. 3b). In Atridox-treated mice, which resisted infection, the mean number of lymphoid nodules was 7.6, equivalent to the number of nodules found in normal C3H/HeJ mice (mean of 7.0±0.3, P50.51) (Fig. 3b).
In contrast, in animals treated with oral doxycycline or vehicle treatment controls, which did not resist infection, the average number of lymphoid nodules ranged from 11.9 to 12.6 (P,0.001). As with spleen mass, there was no statistically significant difference between animals treated with oral doxycycline and those receiving vehicle controls (Fig. 3b), whether water or co-polymer (P50.13).
DISCUSSION
Previous studies in our laboratory have demonstrated that a single injection of a sustained-release form of doxycycline hyclate completely protects mice from tick-transmitted B. burgdorferi infection (Zeidner et al., 2004a). A second study in our laboratory indicated 100 % protection against tick-transmitted A. phagocytophilum infection in a similar
(a) 300
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Ap+Bb (Atridox)
Ap+Bb (co-polymer C) Ap+Bb (oral doxycycline) Ap (Atridox)
Ap (water C)
Ap (oral doxycycline)
** Control mice
Fig. 3. (a) Comparative spleen masses of mice following tick infestation. The bars represent the mean mass per treatment group±SD (n510). **, P,0.05 between the Atridox-treated group and the co-polymer- or water-treated vehicle control mice. (b) Quantitative histopathology of spleens 21 days after tick infesta- tion. The bars represent the mean number of lymphoid nodules per treatment group (n510). **, P,0.05 between the Atridox-treated groups and the co-polymer- or water-treated vehicle control mice. Ap, A. phagocytophilum; Bb, B. burgdorferi.
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Splenic nodules
Mass (mg)
Prophylaxis for A. phagocytophilum and B. burgdorferi
mouse model (Massung et al., 2005). Our previous studies indicated that oral delivery of 2 mg doxycycline hyclate to mice gave peak levels of 2.43 mg doxycycline (ml plasma)21 at 8 h after delivery, slightly higher than the peak levels in mice given 4.2 mg sustained-release doxycycline [1.89 mg doxycy- cline (ml plasma)21] (Zeidner et al., 2004a).
The present study was undertaken to determine whether a single injection of sustained-release doxycycline hyclate would be effective at preventing both B. burgdorferi and A. phagocytophilum delivered simultaneously by I. scapularis ticks. Although several in vitro studies have indicated that A. phagocytophilum is highly sensitive to doxycycline (Horowitz et al., 2001; Maurin et al., 2003), our study is the first to demonstrate that a sustained-release formulation of doxycycline is completely effective against simultaneous delivery of B. burgdorferi and A. phagocytophilum by questing ticks in vivo.
In these studies, a single dose of oral doxycycline prevented B. burgdorferi infection in only 20 % of the animals tested (Table 1), which was not significantly different from animals given a co- polymer or a water vehicle treatment control. These results are in contrast to the 43% protection achieved in earlier studies against B. burgdorferi (Zeidner et al., 2004a), possibly due to the increased number of ticks placed on each animal (n510) to achieve dual infection.
Although not analysed in this study, tick saliva has been shown previously to enhance both viral and bacterial transmission in vivo (Nuttall & Labuda, 2004; Zeidner et al., 2002), and this effect may be limiting the effectiveness of this dose of oral doxycycline.
Moreover, we do not know from these studies whether the simultaneous delivery of both B. burgdorferi and A. phagocytophilum had any effect on the subsequent metabol- ism of doxycycline hyclate administered orally.
Quantitative real-time PCR data (Fig. 1) indicated that, in productive A. phagocytophilum infection (both PCR- and culture-positive spleen), the copy number for A. phagocy- tophilum ranged from 800 to 10 000 copies within the spleen (Fig. 1b).
Moreover, these studies indicated that a threshold value of 100 copies of A. phagocytophilum in the spleen may be associated with productive infection in vivo. In animals that were below this threshold copy number (Fig. 1b), DNA could not be detected in the peripheral blood, and spleens were subsequently culture-negative when co-cultured on HL-60 cells.
Likewise, no splenomegaly, lymphoid hyper- plasia or splenitis (Fig. 2) was noted in those animals that were successfully treated and resisted tick-transmitted infection. In these studies, splenomegaly and lymphoid hyperplasia correlated with treatment failure (Fig. 3). The gross mass of the spleens of animals receiving either vehicle control or oral doxycycline were twice that of Atridox- treated mice (213–244 mg versus 99–121 mg), which had spleens similar to normal, uninfected C3H/HeJ mice. This change in size was due to marked and expansive lymphoid hyperplasia of the white pulp with an influx of inflammatory cells, correlating with our ability to culture A. phagocyto- philum on HL-60 cells.
It has been known for some time that the primary tick and vertebrate reservoirs for Lyme disease in the north-east and Midwest regions of the USA are I. scapularis ticks and the white-footed mouse, P. leucopus (Bakken & Dumler, 2000; McQuiston et al., 1999; Stafford et al., 1999).
Other pathogens, including Babesia microti and A. phagocytophi- lum, have been identified in these natural reservoirs, and co- transmission of these agents with B. burgdorferi has been well documented (Adelson et al., 2004; Stafford et al., 1999).
It has also been reported that the duration of symptoms reported by patients co-infected with these agents exceeds that for patients with B. burgdorferi infection alone, making early diagnosis and successful treatment of co-infections with appropriate antimicrobial therapy imperative (Duffy et al., 1997; Krause et al., 2002).
Our studies indicate that a sustained-release formulation of doxycycline can prophy- lactically block co-transmission of B. burgdorferi and A. phagocytophilum by I. scapularis ticks, as indicated by PCR, culture isolation and histopathology.
It remains to be tested whether similar treatment with a single injection of Atridox would be more efficacious in the elimination of an early, established co-infection than the current oral dosing schedule of doxycycline in humans. Moreover, preliminary work in mice suggests that a strategy could be devised to potentially eliminate co-infection of B. burgdorferi and A. phagocytophilum in rodent and tick reservoirs in nature with other novel formulations and delivery vehicles of doxycy- cline hyclate. Our laboratory is currently evaluating such strategies for use in field trials to prevent the enzootic transmission of these pathogens.
REFERENCES
Adelson, M. E., Rao, R.-V. S., Tilton, R. C., Cabets, K., Eskow, E., Fein, L., Occi, J. L. & Mordechai, E. (2004). Prevalence of Borrelia burgdorferi, Bartonella spp., Babesia microti, and Anaplasma phagocytophila in Ixodes scapularis ticks collected in northern New Jersey. J Clin Microbiol 42, 2799–2801.
Aguero-Rosenfeld, M. E., Donnarumma, L., Zentmaier, L., Jacob, J., Frey, M., Noto, R., Carbonaro, C. A. & Wormser, G. P. (2002). Seroprevalence of antibodies that react with Anaplasma phagocyto- phila, the agent of human granulocytic ehrlichiosis, in different populations in Westchester County, New York. J Clin Microbiol 40, 2612–2625.
Bakken, J. S. & Dumler, J. S. (2000). Human granulocytic ehrlichiosis. Clin Infect Dis 31, 554–560.
CDC (2004). Lyme Disease – United States, 2001–2002. MMWR Morb Mortal Wkly Rep 53, 365–369.
Duffy, J., Pittlekow, M. R., Kolbert, C. P., Rutledge, B. J. & Persing, D. H. (1997). Coinfection with Borrelia burgdorferi and the agent of human granulocytic ehrlichiosis. Lancet 349, 399.
Horowitz, H. W., Hsieh, T. C., Aguero-Rosenfeld, M. E., Kalantarpour, F., Chowdhury, I., Wormser, G. P. & Wu, J. M. (2001). Antimicrobial susceptibility of Ehrlichia phagocytophila. Antimicrob Agents Chemother 45, 786–788.
Johnson, R. C., Kodner, C. B., Jurkovich, P. J. & Collins, J. J. (1990).
Comparative in vitro and in vivo susceptibilities of the Lyme disease spirochete Borrelia burgdorferi to cefuroxime and other antimicrobial agents. Antimicrob Agents Chemother 34, 2133–2136.
Krause, P. J., McKay, K., Thompson, C. A., Sikand, V. K., Lentz, R., Lepore, T., Closter, L., Christianson, D., Telford, S. R. & other authors (2002). Disease-specific diagnosis of coinfecting tickborne zoonoses: babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 34, 1184–1191.
Massung, R. F., Priestley, R. A. & Levin, M. L. (2004). Transmission route efficacy and kinetics of Anaplasma phagocytophilum infection in the white-footed mouse, Peromyscus leucopus. Vector Borne Zoonotic Dis 4, 310–318.
Massung, R. F., Zeidner, N. S., Dolan, M. C., Roellig, D., Gatitzsch, E., Troughton, D. R. & Levin, M. L. (2005). Prophylactic use of sustained- release doxycycline blocks tick-transmitted infection by Anaplasma phagocytophilum in a murine model. Ann N Y Acad Sci 1063, 436–438.
Matschke, C., Isele, U., Hoogevet, P. V. & Fahr, A. (2002). Sustained- release injectables formed in situ and their potential use for veterinary products. J Control Release 85, 1–15.
Maurin, M., Bakken, J. S. & Dumler, J. S. (2003). Antibiotic susceptibilities of Anaplasma (Ehrlichia) phagocytophilum strains from various geographic areas in the United States. Antimicrob Agents Chemother 47, 413–415.
McQuiston, J. H., Paddock, C. D., Holman, R. C. & Childs, J. E. (1999).
The human ehrlichioses in the United States. Emerg Infect Dis 5, 635–642.
Nadelman, R. B., Horowitz, H. W., Hsieh, T. C., Wu, J. M., Aguero- Rosenfeld, M. E., Schwartz, I., Nowakowski, J., Varde, S. & Wormser, G. P. (1997). Simultaneous human granulocytic ehrlichiosis and Lyme borreliosis. N Engl J Med 337, 27–30.
Nadelman, R. B., Nowakowski, J., Fish, D., Falco, R. C., Freeman, K., McKenna, D., Welch, P., Marcus, R., Aguero-Rosenfeld, M. E. & other authors (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.
Nuttall, P. A. & Labuda, M. (2004). Tick–host interactions: saliva- activated transmission. Parasitology 129, S177–S189.
Pancholi, P., Kolbert, C. P., Mitchell, P. D., Reed, K. D., Dumler, J. S., Bakken, J. S., Telford, S. R., III & Persing, D. H. (1995). Ixodes
dammini as a potential vector of human granulocytic ehrlichiosis. J Infect Dis 172, 1007–1012.
Piesman, J. (1993). Standard system for infecting ticks (Acari: Ixodidae) with the Lyme disease spirochete Borrelia burgdorferi. J Med Entomol 30, 199–203.
Schwartz, I., Wormser, G. P., Schwartz, J. J., Cooper, D., Weissensee, P., Gazumyan, A., Zimmermann, E., Goldberg, N. S., Bittker, S. & other authors (1992). Diagnosis of early Lyme disease by polymerase chain reaction amplification and culture of skin biopsies from erythema migrans lesions. J Clin Microbiol 30, 3082–3088.
Sinsky, R. J. & Piesman, J. (1989). Ear punch biopsy method for detection and isolation of Borrelia burgdorferi from rodents. J Clin Microbiol 27, 1723–1727.
Stafford, K. C., Massung, R. F., Magnarelli, L. A., Ijdo, J. W. & Anderson, J. F. (1999). Infection with agents of human granulocytic ehrlichiosis, Lyme disease, and babesiosis in wild white-footed mice in Connecticut. J Clin Microbiol 37, 2887–2892.
Wormser, G. P., Ramanathan, R., Nowakowsk, J., McKenna, D., Holmgren, D., Visintainer, P., Dornbush, R., Singh, B. & Nadelman, R. B. (2003). Duration of antibiotic therapy for early Lyme disease. Ann Intern Med 138, 697–704.
Zeidner, N. S., Schneider, B. S., Nuncio, M. S., Gern, L. & Piesman, J. (2002). Coinoculation of Borrelia spp. with tick salivary gland lysate enhances spirochete load in mice and is tick species-specific. J Parasitol 88, 1276–1278.
Zeidner, N. S., Brandt, K. S., Dadey, E., Dolan, M. C., Happ, C. & Piesman, J. (2004a). Sustained-release formulation of doxycycline hyclate for prophylaxis of tick bite infection in a murine model of Lyme borreliosis. Antimicrob Agents Chemother 48, 2697–2699.
Zeidner, N. S., Carter, L. G., Monteneiri, J. A., Petersen, J. M., Schriefer, M., Gage, K. L., Hall, G. & Chu, M. C. (2004b). An outbreak of Francisella tularensis in captive prairie dogs: an immunohisto- chemical analysis. J Vet Diagn Invest 16, 150–152.
Journal of Medical Microbiology 57
Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease
Open access
DOI:
10.1586/14787210.2014.940900
Daniel J Cameron*a, Lorraine B Johnsonb & Elizabeth L Maloneyc
pages 1103-1135
Publishing models and article dates explained
Published online: 30 Jul 2014
EXCERPTS...
Q1. Does a single 200 mg dose of doxycycline following a tick bite provide effective prophylaxis for Lyme disease?
Organizational values
The panel placed a high value on preventing disease, thereby avoiding both the unnecessary progression from a potentially preventable infection to one that is chronic and associated with significant morbidity and costs. The panel placed a high value on not causing the abrogation of the immune response. The panel also placed a high value on the ability of the clinician to exercise clinical judgment. In the view of the panel, guidelines should not constrain the treating clinician from exercising clinical judgment in the absence of strong and compelling evidence to the contrary.
Recommendation 1a
Clinicians should not use a single 200 mg dose of doxycycline for Lyme disease prophylaxis
Recommendation 1b
Clinicians should promptly offer antibiotic prophylaxis for known Ixodes tick bites in which there is evidence of tick feeding, regardless of the degree of tick engorgement or the infection rate in the local tick population. The preferred regimen is 100–200 mg of doxycycline, twice daily for 20 days. Other treatment options may be appropriate on an individualized basis
Q2. Should the treatment of an EM rash be restricted to 20 or fewer days of oral azithromycin, cefuroxime, doxycycline and phenoxymethylpenicillin/amoxicillin?
Organizational values
The panel placed a high value on avoiding both the unnecessary progression from a potentially curable infection to one that is chronic and the morbidity and costs associated with chronic disease. The panel also placed a high value on the ability of the clinician to exercise clinical judgment. In the view of the panel, guidelines should not constrain the treating clinician from exercising clinical judgment in the absence of strong and compelling evidence to the contrary.
Recommendation 2a
Treatment regimens of 20 or fewer days of phenoxymethyl-penicillin, amoxicillin, cefuroxime or doxycycline and 10 or fewer days of azithromycin are not recommended for patients with EM rashes because failure rates in the clinical trials were unacceptably high. Failure to fully eradicate the infection may result in the development of a chronic form of Lyme disease, exposing patients to its attendant morbidity and costs, which can be quite significant.
Recommendation 2b
Clinicians should prescribe amoxicillin, cefuroxime or doxycycline as first-line agents for the treatment of EM. Azithromycin is also an acceptable agent, particularly in Europe, where trials demonstrated it either outperformed or was as effective as the other first-line agents [46–49].
Initial antibiotic therapy should employ 4–6 weeks of amoxicillin 1500–2000 mg daily in divided doses, cefuroxime 500 mg twice daily or doxycycline 100 mg twice daily or a minimum of 21 days of azithromycin 250–500 mg daily. Pediatric dosing for the individual agents is as follows: amoxicillin 50 mg/kg/day in three divided doses, with a maximal daily dose of 1500 mg; cefuroxime 20–30 mg/kg/day in two divided doses, with a maximal daily dose of 1000 mg and azithromycin 10 mg/kg on day 1 then 5–10 mg/kg daily, with a maximal daily dose of 500 mg. For children 8 years and older, doxycycline is an additional option. Doxycycline is dosed at 4 mg/kg/day in two divided doses, with a maximal daily dose of 200 mg. Higher daily doses of the individual agents may be appropriate in adolescents.
Selection of the antibiotic agent and dose for an individual patient should take several factors into account. In the absence of contraindications, doxycycline is preferred when concomitant Anaplasma or Ehrlichia infections are possibilities. Other considerations include the duration [27,32,50] and severity [50–53] of symptoms, medication tolerability, patient age, pregnancy status, co-morbidities, recent or current corticosteroid use [54,55] cost, the need for lifestyle adjustments to accommodate certain antibiotics and patient preferences. Variations in patient-specific details and the limitations of the evidence imply that clinicians may, in a variety of circumstances, need to select therapeutic regimens utilizing higher doses, longer durations or combinations of first-line agents...
Recommendation 2d
Clinicians should continue antibiotic therapy for patients who have not fully recovered by the completion of active therapy. Ongoing symptoms at the completion of active therapy were associated with an increased risk of long-term failure in some trials and therefore clinicians should not assume that time alone will resolve symptoms. There is a wide range of options and choices must be individualized, based on the strength of the patient’s initial response.
Strong-to-moderate responses favor extending the duration of therapy of the initial agent; modest responses may prompt an increase in the dose of the original antibiotic or a switch to a different first-line agent or tetracycline.
Minimal or absent responses suggest a need for a combination of first-line agents, which includes at least one that is able to effectively reach intracellular compartments; injectable penicillin G benzathine (Bicillin LA) or intravenous (iv.) ceftriaxone are other options.
Disease progression or recurrence suggests that the iv. antibiotics or injectable penicillin G benzathine, as discussed previously, may be required. For patients requiring antibiotic therapy beyond the initial treatment period, subsequent decisions regarding the modification or discontinuation of treatment should be based on the therapeutic response and treatment goals. Additionally, minimal or absent responses and disease progression require a re-evaluation of the original diagnosis (see remarks following Recommendation 2f).
Recommendation 2e
Clinicians should retreat patients who were successfully treated initially but subsequently relapse or have evidence of disease progression. Therapeutic options include repeating the initial agent, changing to another oral agent or instituting injectable penicillin G benzathine or iv. ceftriaxone therapy. Choices must be individualized and based on several factors, including: the initial response to treatment; the time to relapse or progression; the current disease severity and the level of QoL impairments.
Prior to instituting additional antibiotic therapy, the original diagnosis should be reassessed and clinicians should evaluate patients for other potential causes that would result in the apparent relapse or progression of symptoms and/or findings (see remarks following Recommendation 2f). The presence of other tick-borne diseases, in particular, should be investigated if that had not already been done.
Following a long period of disease latency, minimal manifestations causing little deterioration in the patient’s QoL favor continued observation or repeating therapy with the initial agent; mild manifestations or QoL impairments may prompt a switch to a different first-line agent, tetracycline or the use of a combination of first-line agents.
Disease relapse or progression with mild manifestations or QoL impairments occurring within a few months of treatment suggests a need for longer regimens using either tetracycline, a combination of oral first-line agents, injectable penicillin G benzathine or iv. ceftriaxone.
Regardless of the duration of disease latency, when disease manifestations or QoL impairments are significant or rapidly progressive, injectable penicillin G benzathine or iv. ceftriaxone may be required. Subsequent decisions regarding the modification or discontinuation of a patient’s treatment should be based on individual therapeutic response and preferences...
THE ABOVE ARE A FEW SELECTED QUOTES.
PLEASE SEE THE GUIDELINES IN FULL FOR MORE DETAILED INFORMATION
For a one page handout with treatment recommendations that you can print and take to your doctor with you, please go to the Treat The Bite website.
TRANSMISSION TIME
Regarding the time it takes to transmit Lyme disease once a tick bites you- that information has also been discredited.
Michael Cook reports- "The claims that removal of ticks within 24 hours or 48 hours of attachment will effectively prevent LB are not supported by the published data, and the minimum tick attachment time for transmission of LB in humans has never been established."
Literature published by the Infectious Diseases Society of America (IDSA) and CDC continues to claim it takes over 24/48 hours (or more) for a tick to transmit the spirochetes that cause Lyme disease to human hosts. This theory, along with much of their Lyme related literature, has been proven to be inaccurate.
A newly released study by Michael Cook, Lyme borreliosis: a review of data on transmission time after tick attachment, who reviewed scientific literature published over the past century, indicates a tick can be attached for much less than 24/48 hours and still transmit Lyme disease, something many people bitten by ticks already, unfortunately, learned from experience. Cook's report supports what countless patients have experienced.
Below are quotes from Cook's very interesting article; however, it is well worth reading his entire article that is linked below.
~ ~ ~
QUOTES
"Studies have found systemic infection and the presence of spirochetes in the tick salivary glands prior to feeding, which could result in cases of rapid transmission. Also, there is evidence that spirochete transmission times and virulence depend upon the tick and Borrelia species. These factors support anecdotal evidence that Borrelia infection can occur in humans within a short time after tick attachment."
~ ~ ~
"Tick blood feeding behavior includes engagement, the adherence to the host; exploration, the search for a suitable site for attachment; and penetration, where the tick inserts the mouthparts in preparation for feeding.60
During the process of exploration when the tick is searching for a suitable site, temperature increase will activate OspA/OspC regulation and begin the process of increased motility and infectivity [of the spirochetes].
Exploration time will be highly variable and depend on how quickly the tick migrates to an optimal site. This time could vary with host animal size, the presence of competing ticks, or rejection of a site as unsuitable.
Unattached and un-engorged ticks are routinely observed by deer hunters and pet owners. Hence, exploration time must be included with attachment time to more accurately reflect “time for transmission”.
~ ~ ~
"Although LB receives considerable attention and is the focus of this study, ticks transmit many diseases with 12 viral infections discussed by Lani et al including tick-borne encephalitis, Louping-ill, Colorado tick fever, and Alkhurma hemorrhagic fever, which has a mortality rate of 25%.11
Hard-bodied ticks of the genus Ixodes also carry bacterial and parasitic diseases including: anaplasmosis, babesiosis, ehrlichiosis, rickettsiosis, and bartonellosis. Zhang et al investigated the microbiome of Ixodes persulcatus using rRNA sequencing and found 237 bacteria genera suspected of being pathogens to vertebrates.12
Many studies have found ticks infected with two or more of these pathogens and this increase in pathogen burden can result in more serious symptoms and post-treatment sequelae.13–16
An important emerging pathogen is Candidatus neoehrlichia mikurensis,17and in a survey of Canadian residents, 62% of respondents reported at least one coinfection and 15% reported three coinfections with Bartonella and Babesia the most common.18
The attachment time for transmission of almost all of these pathogens is unknown; however, there are studies that indicate rapid transmission of some. Ebel and Kramer demonstrated Powassan virus infection with 15 minutes of tick attachment19 and although Saraiva et al found that transmission of Rickettsia rickettsii by unfed Amblyomma aureolatum ticks required >10 hours attachment time, they found that transmission could occur in as little as 10 minutes with fed ticks.20"
~ ~ ~
"After transferring to the host, the tick searches for a suitable attachment site. With natural hosts, this is typically in the head area giving access to the ears and neck region or groin area.27
Tick attachment starts by inserting the saw-like chelicerae into the epidermis to create an entrance wound.
Then using the leverage from the chelicerae the barbed hypostome mouthpart is pulled in. This process is continued in a ratchet-like fashion until the tick is fully attached, with the process complete within 10 minutes.
This is described by Richter et al,28 and demonstrated in a video.29 The multiple barbs of the hypostome lock the tick into the epidermis and help prevent host activities, for example, grooming, from detaching the tick, and in some species, a cement plug is created to further ensure firm attachment."
~ ~ ~
"During attachment, ticks inject a complex mixture of bioactive chemicals into the host including histamine binders and cytokine inhibitors to mediate host response, complement inhibitors to suppress the host immune response, and anticoagulants to facilitate the blood meal. 30,31
"This results in a painless “bite” and usually prevents an inflammatory response.
[MY NOTE- An inflammatory response at the tick bite site (not an EM rash) could possibly indicate the inhibitors used to suppress the host immune response were not fully functioning, or in varying species of ticks are more/less viable than others?]
Injection of saliva occurs over a major part of the attachment time with the blood meal occurring late in the process.32 Approximately 75% of the water taken up during feeding is returned to the host.33 "
~ ~ ~
"The potential for pathogen transmission by regurgitation was considered; however visual and microscopic observation of post feeding saliva found no evidence of this. 34"
~ ~ ~
"This indicates that the probability of transmission within 24 hours could be as high as 20.37%.
Similarly, the probability of infection within 48 hours has a confidence interval of ±24.63% with a probability of transmission up to 57.63%. "
~ ~ ~
"Shih and Spielman, also using animal models reported in 1993 that infection occurred mainly after 2 days of feeding; however, they indicated that in one experiment, 100% of the mice became infected within 48 hours.
It was also found that partially fed ticks would efficiently re-attach to a new host, and in these new hosts transmission occurred in 83% of cases within 24 hours. 36"
~ ~ ~
"Histological studies reported by Gern et al in 1990 found that when I. ricinus ticks acquired infection during feeding, the spirochetes multiplied in the midgut, but they noted that some spirochetes penetrated the gut wall of the ticks and caused systemic infection. 41"
~ ~ ~
"A study by Piesman et al found infected ticks with bacteria in their salivary glands and other organs at the onset of feeding, and even before feeding began. 26
Lebet and Gern demonstrated that 11% of field-collected unfed nymphal ticks had systemic infection,42 and Leuba-Garcia et al found that 36% of unfed adult I. ricinus ticks collected in two districts of Switzerland had systemic infection, and they commented that this could impact transmission time in humans.43
These results suggest that in cases where the spirochetes are present in the tick salivary glands, they can be injected into the host during the preparatory transfers of antihistamines and anticoagulants prior to the commencement of feeding, ie, immediately after attachment of the tick to the host."
~ ~ ~
"An extensive study using a total of 1962 I. persulcatus ticks infected with B. garinii and B. afzelii found that Borrelia were frequently found in the salivary glands of unfed ticks and that during the early stage of feeding, the proportion of ticks with spirochetes in the salivary glands did not increase, nor the concentration of spirochetes. The authors concluded that Borrelia migration from the tick gut to the salivary glands during feeding is not necessary for pathogen transmission. 45"
~ ~ ~
"As a tick takes a blood meal, the body becomes engorged and the change in body length has been suggested as a method to estimate the time of attachment. Falco et al studied this in 1996 and used the scutal index, which is the ratio of the length of the hard body plate to the tick body length.24
Their published graphical data indicate that the method cannot discriminate between attachment times <24 hours, it is poor up to 36 hours, and there is large variability thereafter. This is explained by the blood meal and engorgement taking place during the later stage of attachment.
Meiners et al62 found that the scutal index estimate for attachment time had poor correlation with the attachment time estimated by the patients. ... This poor correlation indicates that neither the scutal index nor the coxal index is useful as a risk indicator."
~ ~ ~
"A European study documented six cases of culture-confirmed infection where tick attachment was <6 hours and nine cases where transmission occurred in <24 hours.64 Angelov reported a case based on clinical symptoms and positive serology, where infection was transmitted in <24 hours and a second case where a patient’s conjunctiva was infected by the intestinal contents of a tick. 65"
~ ~ ~
"The claims that removal of ticks within 24 hours or 48 hours of attachment will effectively prevent LB are not supported by the published data, and the minimum tick attachment time for transmission of LB in humans has never been established."
~ ~ ~
"Therefore, LB infection can never be excluded after a tick bite irrespective of the estimated duration of attachment time."
Int J Gen Med. 2015; 8: 1–8.
Published online 2014 Dec 19. doi: 10.2147/IJGM.S73791
PMCID: PMC4278789
Lyme borreliosis: a review of data on transmission time after tick attachment
Link Here- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278789/
Lucy Barnes