200 mg of Doxy as Prophylactic May Not Work
This Lancet article that I have enclosed debunks single dose doxy. That's why they tried topical azithromycin. I would like to highlight the section on page 2 of 8 which states "Evidence before this study: We searched PubMed for all papers published up to July 18, 2016, with the keywords “Lyme borreliosis”, “Lyme disease”, and “prophylactic antibiotic treatment”, and reviewed previous studies on antibiotic prophylaxis after tick bite. A broadly applicable pharmacological strategy to prevent the onset of Lyme borreliosis is not available. Four previous studies involving 1082 patients assessed a prevention strategy of single-dose oral doxycycline and treatment for 10 days with oral penicillin, amoxicillin, or tetracycline after tick bite. Although the single-dose doxycycline strategy provided some evidence of inhibiting the onset of Lyme borreliosis, the evidence in total is limited and has not led to a recommendation to use any of the explored preventive steps in clinical practice."
Prior studies also found no help with prophylactic doxy. This is stated in the NEJM article on the use of single dose doxy (Prophylaxis with Single-Dose Doxycycline for the Prevention of Lyme Disease after an Ixodes scapularis Tick Bite. July 12, 2001. N Engl J Med 2001; 345:79-84. DOI: 10.1056/NEJM200107123450201) and they reference in the article prior studies showing no help: "previous studies,6-8 showed no clear protection attributable to antimicrobial prophylaxis given after a tick bite: 6. Costello CM, Steere AC, Pinkerton RE, Feder HM Jr. A prospective study of tick bites in an endemic area for Lyme disease. J Infect Dis 1989;159:136-1397. Agre F, Schwartz R. The value of early treatment of deer tick bites for the prevention of Lyme disease. Am J Dis Child 1993;147:945-9478. Shapiro ED, Gerber MA, Holabird ND, et al. A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites. N Engl J Med 1992;327:1769-1773
There was no long term follow-up of patients in the NEJM article. That is why it was not recommended by ILADS and many other physicians. There was also no recommendation regarding use of single dose doxy for prophylaxis made by our HHS TBDWG . Many different options were discussed, but not advising single dose doxy.
Here are the reports. The last link also has an overview of neurological Lyme disease:
Finally, the ILADS guidelines published in 2014 address the science behind prophylaxis with single dose doxy. Those peer reviewed guidelines, which meet IOM and GRADE guideline development, state on page 8-9 :
Bias
The single-dose doxycycline trial was designed using prevention of an EM rash at the bite site as a surrogate for the prevention of Lyme disease [62]. This surrogate has not been validated. Although 15 years of CDC surveillance data documented that 31% of reported surveillance cases lacked an EM rash [63], the single-dose doxycycline trial was not designed to detect cases of Lyme disease in which the rash was absent. Instead, the trial design regarded all subjects lacking an EM as disease negative, thus biasing the trial in favor of finding treatment effective. It should be noted that the single-dose doxycycline trial identified three subjects with clinical and laboratory evidence (seroconversion) of early Lyme disease who lacked an EM at the bite site, thus demonstrating that the prevention of an EM rash at the bite site is not an appropriate surrogate for prevention of Lyme disease [62]. Later manifestations of Lyme disease may take months or years to develop [64–68]. The trial’s 6-week observation period was therefore insufficient to detect treatment failure and thus biased the trial toward finding treatment to be effective [62]. Investigators neglected to state that failed treatment resulted in seronegative disease as exhibited by one subject in the study [62]. This unfavorable outcome was not included in the risk–benefit assessment, biasing the study in favor of treatment.
Precision
The single-dose doxycycline trial was incapable of measuring the effectiveness of a single 200 mg dose of doxycycline for Lyme disease prevention because outcome measurements were limited to documenting the occurrence of an EM rash at the bite site as opposed to all disease manifestations [62]. However, the trial did demonstrate that treatment with doxycycline resulted in fewer EM rashes than placebo, 1 of 235 (0.4%) and 8 of 247 (3.2%), respectively (p < 0.04) [59]. Yet the data here are sparse, coming from a single study with few events, and, thus, imprecise. The corresponding relative treatment effectiveness was reported to be 87%, with a 95% CI of 25–98% [59]. The wide CI indicates that the finding was imprecise. This value, however, appears to be incorrect. Although the authors reported using the Fisher exact test to calculate the odds ratio, by our calculations, the correct CI is 0.003–0.968, corresponding to a 95% CI on the scaled risk difference from 3.2 to 99.7%. This wider 95% CI suggests the study findings are consistent with a much smaller minimum treatment effect, with the lower limit of the CI reflecting the possibility of only a 3.2% reduction in the risk of EM in the antibiotic arm compared with placebo. Thus, the trial was not well powered to precisely measure the treatment effect despite being adequately powered to detect statistical significance. Although the dropout rate was low (11%), the assumption that none of the participants who dropped out developed an EM is unsupported and biased the estimated incidence in each arm downward. Furthermore, had a single EM in the antibiotic arm been missed due to patient dropout, then the statistical significance of the primary outcome would have been lost (p = 0.11). It is unsettling when changing one participant’s outcome can dramatically affect a study’s conclusion.
Consistency
No other clinical trials have evaluated the effectiveness of a single 200 mg dose of doxycycline for the prevention of an EMrash at the bite site; therefore, the consistency of this finding in humans cannot be judged. However, the effectiveness of doxycycline prophylaxis has been studied in a murine model [69,70] and the findings were inconsistent with that of the single-dose doxycycline trial [62]. In contrast to the human trial, which used a surrogate marker, the murine study used tissue cultures and post-treatment necropsy findings to provide direct evidence of treatment effectiveness. In the murine model, single-dose oral doxycycline was 43% effective forpreventing Lyme disease [69]. A second murine study using ticks dually infected with Borrelia burgdorferi and Anaplasma phagocytophilum demonstrated that single-dose oral doxycycline was 20 and 30% effective for preventing B. burgdorferi and A. phagocytophilum infections, respectively [70]. While it has been suggested that the lower efficacy of doxycycline in the murine studies was related to differences between mice and humans with regard to the duration of time that doxycycline levels exceeded the minimal inhibitory concentration for B. burgdorferi following a single oral dose of doxycycline (T > minimal inhibitory concentration) [71], subsequent pharmacodynamic modeling found that other pharmacodynamic parameters correlated better with efficacy [72]. However, these findings were based on flawed assumptions. Thus, the reason for the apparently lower efficacy of single-dose oral doxycycline in mice is unclear. It is worth noting that the 95% CI in the study by Nadelman et al. was quite large, 3.2–99.7% (see precision discussion above), suggesting that true treatment effectiveness was approximately 50% [69], a value comparable tothat of the murine study [69].
Directness (Generalizability)
The directness of the trial is limited to patients bitten by I. scapularis ticks treated with a single-dose doxycycline. The effectiveness of single-dose regimens using other antibiotics and the effectiveness of single-dose doxycycline in other Ixodes species have not been evaluated. Further, animal models suggest single-dose oral doxycycline prophylaxis is less effective when multiple pathogens are simultaneously transmitted to a host[70]; therefore, the findings are not applicable to patients exposed to B. burgdorferi and A. phagocytophilum and the applicability to patients exposed to B. burgdorferi and other co-infecting pathogens cannot be assumed. Evidence quality, in aggregate Overall, the quality of the evidence supporting the use of a single 200 mg dose doxycycline following a tick bite is very low (TABLE 2), implying that the true effectiveness of a single 200 mg dose of doxycycline is likely to be substantially different from the trial’s reported effectiveness rate [6].
Benefits
The single 200 mg dose doxycycline trial design employed an unvalidated and inappropriate surrogate and the duration of the observation period was inadequate. The reported 87%efficacy of single-dose doxycycline therapy was with regard to the observed reduction in the incidence of an EM rash at the bite site in the doxycycline subjects compared with the placebo subjects (TABLE 3) [59], but the reliability of this finding is diminished by its imprecision and its clinical significance is questionable (see quality of evidence discussion above). Therefore, the trial’s significant design deficiencies prohibit conclusions regarding the efficacy and, thus, the benefits of single-dose doxycycline therapy for the prevention of Lyme disease.