The drugs DO work...the evidence

Apologies to that mannie from 'The Verve', but in my case, the drugs do indeed work. 

Yesterday I walked up a hill! Now, admittedly, it was a mild-mannered amble up a fairly teensy hummock, but I got to the top (and back down again with the aid of crutches) with no real problems. I was walking like  Andy Pandy on beta blockers for the rest of the afternooon, but no long term fallout, I'm not shattered or anything today. Yay! This wouldn't have been possible a couple of months ago, when just getting upstairs was a real challenge.

... but do they really work? Could this just be me, getting better anyway- might I have improved without the antibiotics? Is is not just a placebo effect? Are the antibiotics just making me feel better by reducing inflammation? (I will post more about this persistence v's post-infective inflammation another day)

Well...I know personally many people who have chronic Lyme and have recovered most or all of their health with long-term antibiotic use. There are thousands of people worldwide who can tell the same tale- long term antibiotics DO work- and I know from personal experience that they worked for me. I was ill with Lyme for 19 months in 2008/2009. I had various antibiotics for most of this time  and I got better- completely well - for 2.5 years. I tried to stop the antibiotics a few times and relapsed each time, only when I had been symptom free for 2 months on antibiotics could I stop them and remain symptom free. Yes, I have now relapsed, but that just goes to show how it is very very difficult (impossible?) to fully eradicate the Lyme bacteria once it has spread. I am very thankful for those 2.5 years, and can get there again, with the right drugs.

Those personal tales are all very well, but WHERE IS THE SCIENTIFIC EVIDENCE? 

There is a lack of research in this area. In particular, there is a lack of good quality European trials (European Lyme is often caused by different genospecies of the bacteria, so may be subtly different to American Lyme). The papers allegedly showing long term antibiotics have no effect have been heavily criticised in numerous other publications (I will post links at a later date)

However, the following studies show longer courses of antibiotics can be beneficial for Chronic Lyme:

1)Fallon B et al., “A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy” Neurology 2008;70;992-1003

Methods: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics,
current positive IgG Western blot, and objective memory impairment. Healthy individuals
served as controls for practice effects. Patients were randomly assigned to 10 weeks of double masked
treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary
outcome was neurocognitive performance at week 12—specifically, memory. Durability of benefit
was evaluated at week 24. Group differences were estimated according to longitudinal mixedeffects
models.
Results: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals
enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of
fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant
treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement
was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to
week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical
functioning who received antibiotics were improved at week 12, and this was sustained to week
24 for pain and physical functioning. Adverse events from either the study medication or the PICC
line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%)
patients given IV placebo; these resolved without permanent injury.
Conclusion: IV ceftriaxone therapy results in short-term cognitive improvement for patients with
posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued.
Treatment strategies that result in sustained cognitive improvement are
needed. 

 

 n.b. The Fallon study gave 10 weeks IV ceftriaxone (or placebo) to patients with fairly severe disease, who had already had at least 3 weeks prior IV therapy- so these were quite sick individuals that seemed to have fairly treatment-resistant Lyme. I think most Lyme-specialist doctors (ones who do not follow IDSA guidelines) would give follow-up oral antibiotics of various types to fully treat these kind of patients.

2)   Stricker RB, DeLong AK, Green CL, Savely VR, Chamallas SN, Johnson L Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease. International Journal of General Medicine, 2011 Volume 4 Pages 639 – 646.

Conclusion: Prolonged intravenous antibiotic therapy is associated with improved cognition,
fatigue, and myalgias in patients referred for treatment of neurologic Lyme disease. Treatment
for 25–52 weeks may be necessary to obtain symptomatic improvement in these patients.

N.B. this was not a double-blind placebo controlled trial, but instead looked at patients receiving extended courses of intravenous Ceftriaxone.

3) Clarissou J, et al. “Efficacy of a long-term antibiotic treatment in patients with a chronic Tick Associated Poly-organic Syndrome (TAPOS).” Med Mal Infect (2008), doi:10.1016/j.medmal.2008.11.012

SETTINGS:Despite a now codified antibiotic treatment for Lyme disease, a significant proportion of patients treated according to recommendations complain of persistent signs and symptoms. The pathophysiological mechanisms which underlie this syndrome of post-treatment chronic systemic illness remain unclear. For some physicians post-treatment symptoms indicate a persistent infection requiring prolonged antibiotic therapy. For others, there is no benefit from antimicrobial therapy. The difficulty of assessment encountered in studies is significant because many symptoms are subjective. We think that the term "chronic Lyme disease" is not appropriate and should be replaced by chronic "tick associated poly-organic syndrome" (TAPOS).

OBJECTIVE:This open-label prospective study was made on a group of 100 patients having followed a medical treatment for a chronic TAPOS and to evaluate their evolution under prolonged antibiotic treatment.

RESULTS:The medical management was found to be effective for symptoms, especially for patients with a high probability of chronic TAPOS (NEJM score). Patients with post tick-bite symptoms, which often worsens their quality of life, deserve particular attention.

CONCLUSION:This study had methodological limitations but could help in terms of feasibility, choice of inclusion criteria, and design of follow-up for a future randomized, double blind study to test for an optimal management of TAPOS.

I could not get the full text to this Clarissou paper, so cannot comment on it but I will update this page if I get hold of it.

4) Sam T. Donta, Tetracycline Therapy for Chronic Lyme Disease. Clin Infect Dis. (1997) 25(Supplement 1): S52-S56 

Two hundred seventy-seven patients with chronic Lyme disease were treated with tetracycline
for 1 to 11 months (mean, 4 months); the outcomes for these patients were generally good. Overall,
20% of the patients were cured; 70% of the patients’ conditions improved, and treatment failed for
10% of the patients. Improvement frequently did not take place for several weeks; after 2 months
of treatment, 33% of the patients’ conditions were significantly improved (degree of improvement,
75%–100%), and after 3 months of treatment, 61% of the patients’ conditions were significantly
improved. Treatment outcomes for seronegative patients (20% of all patients) were similar to those
for seropositive patients. Western immunoblotting showed reactions to one or more Borrelia burgdorferi–
specific proteins for 65% of the patients for whom enzyme-linked immunosorbent assays
were negative. Whereas age, sex, and prior erythema migrans were not correlated with better or
worse treatment outcomes, a history of longer duration of symptoms or antibiotic treatment was
associated with longer treatment times to achieve improvement and cure. These results support the
use of longer courses of treatment in the management of patients with chronic Lyme disease.
Controlled trials need to be conducted to validate these observations.

Again, this is not a controlled or blinded trial, but the results are encouraging nonetheless.  

5). Sam T. Donta. Macrolide therapy of Chronic Lyme disease. Med Sci Monit. 2003 Nov;9(11):PI136-42.

MATERIAL/METHODS:235 patients with a multi-symptom complex typical of chronic Lyme disease, ie fatigue, musculoskeletal pain, and neurocognitive dysfunction and with serologic reactivity against B.burgdorferi were treated with a macrolide antibiotic (eg clarithromycin) and hydroxychloroquine. Patients were treated with hydroxychloroquine, 200 mg twice daily, and a macrolide antibiotic (clarithromycin 500 mg twice daily, azithromycin 250–500 mg daily, or erythromycin 500 mg three times daily). The treatment was continued until patients’ symptoms were resolved or improved.

RESULTS:Eighty % of patients had self-reported improvement of 50% or more at the end of 3 months. After 2 months of treatment, 20% of patients felt markedly improved (75-100% of normal); after 3 months of treatment, 45% were markedly improved. Improvement frequently did not begin until after several weeks of therapy. There were no differences among the three macrolide antibiotics used. Patients who had been on hydroxychloroquine or macrolide antibiotic alone had experienced little or no improvement. Compared to patients ill for less than 3 years, the onset of improvement was slower, and the failure rate higher in patients who were ill for longer time periods.

CONCLUSIONS:These results support the hypothesis that the Lyme borrelia reside in an acidic endosome and that the use of a lysosomotropic agent augments the clinical activity of macrolide antibiotics in the treatment of patients with chronic Lyme Disease. In contrast, the efficacy of tetracycline in such patients is not affected by hydroxychloroquine. 

Again, not a controlled or blinded study, but results seem good. Macrolides (Clarithromycin, Azithromycin or Erythromycin) are often used successfully by LLMD's and they do sometimes combine them with Hydroxychloroquine to make them more effective.

The following references are taken from the DBG guidelines. I have not checked these through, but they apparently provide evidence of the positive effect of long term antibiotic therapy:

6) CIMMINO, M. A.; ACCARDO, S.: Long term treatment of chronic Lyme arthritis with benzathine penicillin. Ann Rheum Dis 51 (1992), 1007–1008

The cases are reported of two patients with chronic Lyme arthritis resistant to the recommended
antibiotic regimens who were cured by long term treatment with benzathine penicillin.
 

7) DATTWYLER, R. J.; HALPERIN, J. J.; PASS, H.; LUFT, B. J.: Ceftriaxone as effective therapy in refractory Lyme disease. J Infect Dis 155 (1987), 1322–1325

8) FALLON, B. A.; LIPKIN, R. B.; CORBERA, K. M.; YU, S.; NOBLER, M. S.; KEILP, J. G.; PETKOVA, E.; LISANBY, S. H.; MOELLER, J. R.; SLAVOV, I.; HEERTUM, R. V.; MENSH, B. D.; SACKEIM, H. A.: Regional cerebral blood flow and metabolic rate in persistent Lyme encephalopathy. Arch Gen Psychiatry 66 (2009), 554–563. http://dx.doi.org/10.1001/-archgenpsychiatry.2009.29

9) GASSER, R.; DUSLEAG, J.: Oral treatment of late borreliosis with roxithromycin plus co-trimoxazole. Lancet 336 (1990), 1189–1190

10) GASSER, R.; REISINGER, E.; EBER, B.; POKAN, R.; SEINOST, G.; BERGLÖFF, J.; HORWARTH, R.; SE-DAJ, B.; KLEIN, W.: Cases of Lyme borreliosis resistant to conventional treatment – Improved symptoms with cephalosporin plus specific beta-lactamase inhibition. Microb Drug Resist 1 (1995), 341–344

11) KLEMANN, W.; HUISMANS, B.-D.: Patienten mit Erreger-Direktnachweis bei chronischer Lyme-Borreliose – Klinik, Labordiagnostik, Antibiotika-Therapie und Krankheitsver-lauf. Eine retrospektive Studie. Umwelt-Medizin-Gesellschaft 2 (2009), 132–138 

It should be said that probably part of the reason that there are so few good, large, double-blinded controlled trials is that they are very difficult to do. Ethically, they are difficult- to give seriously ill patients a placebo when there is data suggesting further antibiotics could be helpful is questionable. Getting big enough cohorts of patients to take part is very tricky- the Fallon trial used only 1% of screened patients as they were very strict about eligibility criteria. I imagine the funding is hard to get since the big players in infectious diseases do not seem to believe chronic Lyme is a treatable disease.There is a lot of Lyme in mainland Europe, but not as much as the US, so perhaps that is hampering the development of European trials? There is currently a study ongoing at a University in the Netherlands though-see this link: 

http://www.nhs.uk/Conditions/Lyme-disease/Pages/clinical-trial-details.aspx?TrialId=NCT01207739&Condition=Lyme%20disease&pn=1&Rec=0&CT=0 

After an initial course of IV Ceftriaxone, they are comparing 3 months follow-up treatment with either placebo, Doxycycline (100mg twice a day) or Clarithromycin (500mg twice a day) combined with Hydroxychloroquine (200mg twice a day).

This should be an interesting study, and I look forward to the results. I know Clarithromycin and Hydroxychloroquine is used by some LLMD's in the states and 12 weeks is decent treatment duration (although maybe not long enough for some cases).

  In the meantime, I'll just keep taking the tablets!

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