Here's the latest from the Annals of Internal Medicine. The reason for rejection was that the letter was "too detailed".

Please feel free to use this as you wish.


html-editing and additions in (( )) by Joachim Gruber (July 19, 2012)

Endorsement of Inadequate Treatment for Lyme Disease.

Raphael B. Stricker, M.D.*, and Steven E. Phillips, M.D.**

*Department of Medicine, California Pacific Medical Center, San Francisco, CA., **Department of Medicine, Greenwich Hospital, Greenwich, CT.

Address all correspondence to:

    Raphael B. Stricker, M.D.
    California Pacific Medical Center
    450 Sutter Street, Suite 1504
    San Francisco, CA  94108
    Phone:  (415) 399-1035
    Fax:  (415) 399-1057

Key Words: Lyme disease, Borrelia burgdorferi, erythema migrans, doxycycline, coinfections.

To the Editor:

In your recent "Update on Infectious Diseases”, the Annals has republished, without critical evaluation or rebuttal, the results of two controversial articles on the treatment of Lyme disease by Nadelman et al. and Klempner et al. (1). The first article endorses a questionable prophylactic regimen for acute Borrelia burgdorferi infection, while the second article undercuts effective therapy for chronic Lyme disease.

Nadelman et al. endorsed a single dose of doxycycline for the prevention of Lyme disease following a tickbite.  Since the primary endpoint of the study, an erythema migrans rash, may be absent in up to 50% of patients who develop Lyme disease (2), the results of the prophylactic trial are highly questionable because roughly half of the patients at risk were not evaluable under the treatment protocol.  Furthermore, the single-dose antibiotic regimen threatens to add to the growing risk of tetracycline resistance (3), and this risk is not outweighed by the possible benefit of treatment given the wide margin of error of the study results (95% confidence interval of 25-98%).  Compounding the insensitive endpoint and perilous treatment protocol of the study, the six-week evaluation period was far too short to assess the development of later-stage Lyme disease due to persistent infection with resistant microorganisms.

Klempner et al. demonstrated that an inadequate antibiotic regimen was no better than placebo for the treatment of chronic Lyme disease [Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D, Levy L, Wall D, McCall J, Kosinski M, Weinstein A., Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001 Jul 12;345(2):85-92.]. Of significance, the study found that roughly two-thirds (64%) of patients with chronic Lyme disease had persistent symptoms after standard treatment for the disease.  This alarming observation underscores the inadequate "standard of care” for Lyme disease in our country, and it emphasizes that this "standard” is completely out of touch with the clinical reality of Lyme symptomatology for many patients (4).  The persistence of neurocognitive symptoms also raised technical questions about the study’s problematic screening and randomization techniques (5).

In this setting, a combination of intravenous ceftriaxone for one month followed by low-dose oral doxycycline for two months cannot be considered additive or adequate therapy for chronic Lyme disease. If patients are sick enough to merit intravenous antibiotic treatment, clinical experience supports the use of longer intravenous regimens in these cases (2, ,6, 7, 8).  Conversely, if patients fail to respond to one month of intravenous therapy, adding a dose of doxycycline that does not penetrate the central nervous system will not benefit these patients with neurocognitive symptoms (2, 6, 8). Thus the treatment protocol was doomed to failure because of its poor design, and it is misleading to characterize the study’s ill-conceived antibiotic regimen as "long-term treatment”. Furthermore, the conclusion that subjects were no longer infected with B. burgdorferi based on plasma and cerebrospinal fluid testing was spurious, since persistent infection can be demonstrated by tissue biopsy in seronegative animals and humans with chronic Lyme disease despite "appropriate” antibiotic therapy (9 10, 11).  Finally, the authors failed to consider coinfections with Babesia, Ehrlichia and Bartonella species in their patients, and these tickborne coinfections may have contributed to patient morbidity when left undiagnosed and untreated (4).

Coming on the heels of an excellent discussion of the complexity of Lyme disease diagnosis and treatment (4), it is disappointing that the Annals has now chosen to disseminate flawed treatment information about a controversial illness without any warning to your readers.


1. Lorber B.  Update in infectious diseases.  Ann Intern Med 2002;137:974-80.

2. Doherty A. Lots of links on Lyme Disease 2003; accessible on the Internet at (link is no longer active).

3. Chopra I, Roberts M.  Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance.  Microbiol Mol Biol Rev 2001;65:232-60.

4. Comments by Lautin A, by McNeil EL, by Liegner KB, and by Stricker RB,   Lyme disease controversy: Use and misuse of language.  Ann Intern Med 2002;137:775-7 on Sigal LH., Misconceptions about Lyme disease: confusions hiding behind ill-chosen terminology. Ann Intern Med 2002 Mar 5;136(5):413-9,

5. Bransfield R, Brand S, Sherr V.  Treatment of patients with persistent symptoms and a history of Lyme disease.  N Engl J Med 2001;345:1424-5.

6. Burrascano JJ.  Lyme disease.  In Conn’s Current Therapy.  Philadelphia:  WB Saunders Company, 1997, pp 140-3 ((latest edition of this paper is Diagnostic hints and treatment guidelines for Lyme and other tick borne illnesses, 14. Edition November, 2002))

7. Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK.  Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med  1999;31:225-32

8. Stricker RB, Winger EE.  Normalization of the CD57 natural killer cell subset associated with prolonged antibiotic therapy in patients with chronic Lyme disease   Clin Immunol 2002;103:S117-8.

9. Frey M, Jaulhac B, Piemont Y, Marcellin L, Boohs PM, Vautravers P, Jesel M, Kuntz JL, Monteil H, Sibilia J.  Detection of Borrelia burgdorferi DNA in muscle of patients with chronic myalgia related to Lyme disease.  Am J Med 1998;104:591-4.

10. Straubinger RK.  PCR-based quantification of Borrelia burgdorferi organisms in canine tissues over a 500-day postinfection period.  J Clin Microbiol 2000;38:2191-9.

11. Cadavid D, O'Neill T, Schaefer H, Pachner AR.  Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of Lyme disease.  Lab Invest 2000;80:1043-54.

Literature added by J. Gruber

Review by independent consulting company

Phillips S, Bransfield R, Sherr V, Brand S, Smith H, Dickson K, and Stricker R: Evaluation of Antibiotic Treatment in Patients with Persistent Symptoms of Lyme Disease, An ILADS Position Paper, April, 2003

Wikipedia review