THE NEW LYME DISEASE... I humbly propose we redefine what we have been calling Lyme. A huge body of research and clinical experience has demonstrated the nearly universal phenomenon in Lyme patients of co-infection with multiple tick-borne pathogens. As many have heard me say, coinfection is not surprising, for ticks are arachnids that literally live in dirt and drink the blood of wild animals. To think that a significant tick bite transmits only one infection is narrow minded indeed. Studies have shown that concurrent Borrelial and Ehrlichial and/or Babesial infections result in a change in their individual clinical presentations, with different symptoms, atypical signs, decreased reliability of standard diagnostic tests, and most importantly, the creation of chronic, persistent forms of each of these infections. As time goes by, I am convinced that more pathogens will be found.
Therefore, Lyme, as we had come to know it, probably represents a mixed infection. I will leave to the reader the implications of how this may explain the discrepancy between laboratory study of pure Borrelia infections, and what front line physicians have been seeing for years in real patients.
It is still early in our efforts to sort out the individual contributions of each of these pathogens in the coinfected patient, so the suggestions that follow are quite preliminary. However, I believe this information is so important, I did not want to delay any further this edition of my Guidelines.
I will refer to the general symptom complex as "Lyme", but will refer to the separate entities as Lyme Borreliosis (LB) or Borrelia burgdorferi (Bb), Babesia microti (Bm), and the Ehrlichia species as a group.
In past editions, I mentioned how the diagnosis and treatment of Lyme Disease had entered a new era, as simplistic approaches were being replaced by more modern ones based on better knowledge, more experience, and the application of common sense. Seronegativity, the existence of chronic persistent infection, relapses and treatment failures had all been confirmed, as well as the need for many months of therapy in those ill for a long time. Unfortunately, many health care workers and health reporters have not kept up with these facts. It is only through knowledge that we will be able to conquer this misinformation. Please continue your efforts to educate the unaware.
The concept of a "therapeutic alliance" between the caregiver and patient must again be emphasized. This means that the patient has to work with and become part of the medical team, and must take responsibility for complying with the recommendations given, maintaining the best possible health status, reporting promptly any problems or new symptoms, and especially in realizing that despite all our best efforts, success in diagnosis and treatment is never assured. The medical team must make great efforts to listen carefully to the patient and not be too quick to dismiss seemingly bizarre or illogical complaints.
I extend my best wishes to the many patients and caregivers who deal with Lyme, and a sincere thank you to my colleagues whose endless contributions have helped me shape my approach to tick borne illnesses. I hope that my new approach proves to be useful. Happy reading!
The evaluation of a Lyme patient must begin with testing for all currently known tick borne pathogens. Serological studies for Borrelia, Babesia and Ehrlichia should be combined where appropriate with direct antigen assays. Antigen detection tests (antigen capture and PCR) are especially helpful in evaluating the seronegative patient and those still ill or relapsing after therapy. Unfortunately, over a dozen protozoans other than Babesia microti can be found in ticks, yet commercial tests for only B. microti are available at this time, so as in Borrelia, clinical assessment is the primary diagnostic tool. In Ehrlichiosis, test for both the monocytic and granulocytic forms. Many presently uncharacterized Ehrlichia-like organisms can be found in ticks and may not be picked up by currently available assays, so in this illness too, serologies are only an adjunct in making the diagnosis.
Babesia are parasites, and I suggest that if a coinfection is found involving this organism, treat this first, so that subsequent therapy for Borrelia and Ehrlichia will be more effective.
Experience has shown that collateral conditions exist in those who have been ill a long time. Test B12 levels, and be prepared to aggressively treat with parenteral formulations of the B-vitamins: 100mg each of B1 and B6 and 1000 mcg of B12 IM at least weekly in the more ill patient. Magnesium deficiency is very often present and quite severe. Magnesium is predominantly an intracellular ion, so blood level testing is of little value. Oral preparations are acceptable for maintenance, but most need parenteral dosing: 1 gram IV or IM at least weekly until neuromuscular irritability has cleared. Because the Lyme syndrome has been associated with faulty activation of T4, measure free T3 levels by RIA and basal A.M. body temperatures. If hypothyroidism is found, treat with T3 preparations.
SPECT scanning of the brain, if done by knowledgeable radiologists using high-resolution equipment, will show characteristic abnormalities in Lyme encephalopathy. This not only helps with the differential diagnosis, but if done before and after acetazolamide, it will guide in the use of vasodilators, which may clear some cognitive symptoms. Therapy can also include serotonin agonists, pentoxiphylline and even Ginko biloba. Therapeutic trials may be needed.
Tilt table testing is another powerful tool which, just as in CFIDS, may demonstrate neurally mediated hypotension (NMH). If found, therapy is based on blood volume expansion (increased sodium and fluid intake and possibly Florinef plus potassium). If not sufficient, beta blockade may be added based on response to Isuprel challenge during testing. If NMH is present, treatment can dramatically lessen fatigue and palpitations, and increase stamina.
Lyme is diagnosed clinically, as no currently available tests, no matter the source or type, are definitive in ruling in or ruling out infection with these pathogens, or whether these infections are responsible for the patient's symptoms. The entire clinical picture must be taken into account, including a search for concurrent conditions and alternate diagnoses, and other reasons for some of the presenting complaints. Often, much of the diagnostic process in late, disseminated Lyme involves ruling out other illnesses and defining the extent of damage that might require separate evaluation and treatment.
Consideration should be given to tick exposure, rashes (even atypical ones), evolution of typical symptoms in a previously asymptomatic individual, and results of tests for tick borne pathogens. Another very important factor is response to treatment- presence or absence of Jarisch Herxheimer-like reactions, and improvement with therapy.
Classic teachings state that acute infections are usually only seen in those with some form of immune compromise. Flu-like symptoms rapidly evolve to include shaking chills, high fevers, hemolysis and pancytopenia. Fatalities have been reported. Visualizing Babesial forms on peripheral smears can make the diagnosis in this situation. In those with intact immune systems, a mild flu-like illness appears one to two weeks after exposure and clears without treatment over six to eight weeks. In either case, it is imperative to test for Borrelia and Ehrlichia.
However, when coinfection exists, this acute presentation is much less common, and it is rare to see parasite forms on smear. Signs of coinfection include severe headaches, dizziness and encephalopathy out of proportion to the other Borrelial symptoms. Testing is not at all definitive, yet should include CBC, Babesia smear (very low yield), serologies (IgG and IgM) and if necessary, PCR of peripheral blood. Newer direct assays are currently being researched, as this is an active area of investigation. Always consider coinfection in your current Lyme patients who are not responding fully.
While it is true that this illness can have a fulminant presentation, I am convinced that milder forms do exist especially when other tick-borne organisms were transmitted. When present in a Lyme patient, persistent leucopenia is an important clue. Thrombocytopenia is much less common, but likewise should not be ignored. Headaches, myalgias, and ongoing fatigue seem to relate to this illness, but are extremely difficult to separate from symptoms caused by Bb. At this time, we only have serologies for laboratory diagnosis, as no direct assay currently exists. There is no way at this time to judge the accuracy of these tests, especially since there may be a variety of pathogenic Ehrlichia-like organisms that will not be picked up by current testing technology. Direct visualization of this organism in leukocytes has been reported, but is rare. Again, consider this diagnosis in a LB patient not responding well to therapy.
Erythema migrans (EM) is diagnostic of Bb infection, but is present in fewer than half. Even if present, it may go unnoticed by the patient. It is an erythematous, centrifugally expanding lesion that is raised and warm. Sometimes there is mild stinging or pruritus. The EM rash will begin four days to several weeks after the bite, and may be associated with constitutional symptoms. Multiple lesions are present less than 10% of the time, and represent disseminated disease. Some lesions have an atypical appearance and skin biopsy specimens may be helpful. When an ulcerated or vesicular center is seen, this may represent a mixed infection, involving other organisms besides B. burgdorferi.
After a tick bite, serologic tests (ELISA. IFA, western blots, etc.) are not expected to become positive until several weeks have passed. Therefore, if EM is present, treatment must begin immediately, and one should not wait for results of Borrelia tests. You should not miss the chance to treat early disease, for this is when the success rate is the highest. Indeed, many knowledgeable clinicians will not even order a Borrelia test in this circumstance.
DIAGNOSING LATE DISEASE
When reactive, serologies indicate exposure only and do not directly indicate whether the spirochete is now currently present. Because Bb serologies often give inconsistent results, test at more than one laboratory using if possible different methods. I recommend ordering both ELISAs and western blots. Be aware that in late disease there may be repeatedly peaking IgM's and therefore a reactive IgM may not differentiate early from late disease, but it does suggest an active infection. When late cases of LB are seronegative, 36% will transiently become seropositive at the completion of successful therapy.
Western blots are reported by showing which bands are reactive. 41KD bands appear the earliest but cross react with T. pallidum and several other spirochetes. The 18KD, 23-25KD (Osp C), 31KD (Osp A), 34KD (Osp B), 39KD, 83KD and the 93KD bands are the most specific but appear later or may not appear at all. You need to see at least the 41KD and one of the specific bands. 55KD, 60KD, 66KD, and 73KD are nonspecific and nondiagnostic.
Antigen detection tests including PCR are now available, and although they are very specific, sensitivity remains poor, possibly less than 30%. This is because Bb causes a deep tissue infection and is only transiently found in body humors. Therefore, multiple specimens must be collected to increase yield, and a negative result does not rule out infection, yet a positive one is significant. The patient must be antibiotic free for at least six weeks before testing. Antigen capture can be done on urine, CSF, and synovial fluid. PCR can be done on blood (buffy coat is best), urine, CSF, any other body fluid including breast milk, and on tissue biopsy specimens.
Spinal taps are not routinely recommended, as a negative tap does not rule out Lyme. Antibodies to Bb can be detected in the CSF in just 20% of patients with late disease. Therefore, spinal taps are only performed on patients with pronounced neurological manifesta-tions, if they are seronegative, or are still sig-nificantly symptomatic after completion of treatment. When done, the goal is to rule out other conditions, and to determine if Bb antigens are present. It is especially important to look for elevated protein and mononuclear cells, which would dictate the need for more aggressive therapy, as well as the opening pressure, which can be elevated and add to headaches, especially in children.
To aid the clinician, a workable set of diagnostic criteria were developed with the input of dozens of front line physicians. The resultant document has proven to be extremely useful not only to the clinician, but it also can help clarify the diagnosis for third party payers and utilization review committees. It is important to note that the CDC's published reporting criteria are for surveillance only, not for diagnosis.
LYME BORRELIOSIS DIAGNOSTIC CRITERIA RELATIVE VALUE:
|Tick exposure in an endemic region||1|
|Historical facts and evolution of symptoms consistent with Lyme ||2|
|Systemic signs & symptoms consistent with Bb infection (other potential diagnoses excluded):|
Single system. e.g. monoarthritis
Two or more systems. e.g. monoarthritis and facial palsy
|Erythema migrans, physician confirmed||7|
|Acrodermatitis Chronica Atrophicans, biopsy confirmed||7|
|Seroconversion on paired sera||4|
|Tissue microscopy, silver stain||3|
|Tissue microscopy, monoclonal immunofluorescence||4|
|Culture positivity ||4|
|B. burgdorferi antigen recovery||4|
|B. burgdorferi DNA/RNA recovery ||4|
|Lyme Borreliosis Highly Likely||7 or above|
|Lyme Borreliosis Possible||5-6|
|Lyme Borreliosis Unlikely|| 4 or below|
I suggest that when using these criteria, you state Lyme Borreliosis is "unlikely', "possible", or "highly likely" based upon the following criteria - then list the criteria.
SYMPTOM CHECK LIST
This is not meant to be used as a diagnostic scheme, but is provided to streamline the office interview. Note the format - complaints referable to specific organ systems are clustered to better display multisystem involvement.
NAME _______________ DATE _______________
RISK PROFILE (PLEASE CHECK)
|Tick infested area__|
|Frequent outdoor activities__ |
|Camping ___ |
|Gardening ___ |
|Hunting ___ |
|Ticks noted on pets ___|
|Do you remember being bitten by a tick? No__ Yes__ When? _________|
|Do you remember having the "bull's eye rash"? No__ Yes__ |
|Any other rash? No__ Yes__|
|Have you had any of the following? (CIRCLE ALL YES ANSWERS)|
|1. Unexplained fevers, sweats, chills, or flushing|
|2. Unexplained weight change--loss or gain|
|3. Fatigue, tiredness, poor stamina|
|4. Unexplained hair loss|
|5. Swollen glands: list areas_______________________________|
|6. Sore throat|
|7. Testicular pain/pelvic pain|
|8. Unexplained menstrual irregularity|
|9. Unexplained milk production: breast pain|
|10.Irritable bladder or bladder dysfunction|
|11.Sexual dysfunction or loss of libido|
|13.Change in bowel function-constipation, diarrhea|
|14.Chest pain or rib soreness|
|15.Shortness of breath, cough|
|16.Heart palpitations, pulse skips, heart block|
|17.Any history of a heart murmur or valve prolapse?|
|18.Joint pain or swelling: list joints________________________|
|19.Stiffness of the joints, neck, or back|
|20.Muscle pain or cramps|
|21.Twitching of the face or other muscles|
|23.Neck creeks and cracks, neck stiffness, neck pain|
|24.Tingling, numbness, burning or stabbing sensations, shooting pains|
|25.Facial paralysis (Bell's Palsy)|
|26.Eyes/Vision: double, blurry, increased floaters, light sensitivity|
|27.Ears/Hearing: buzzing, ringing, ear pain, sound sensitivity|
|28.lncreased motion sickness, vertigo, poor balance|
|31.Confusion, difficulty in thinking|
|32.Diffculty with concentration, reading|
|33.Forgetfuiness, poor short term memory|
|34.Disorientation: getting lost, going to wrong places|
|35.Difficulty with speech or writing|
|36.Mood swings, irritability, depression|
|37.Disturbed sleep-too much, too little, early awakening|
|38.Exaggerated symptoms or worse hangover from alcohol|
LYME DISEASE TREATMENT GUIDELINES
Adults: 1g q8h plus probenecid 500mg q8h; doses up to 6 grams daily are often neededPregnancy: 1g q6h and adjust.Children: 50 mg/kg/day divided into q8h doses.
Piroplasms are not bacteria, they are protozoans. Therefore, they will not be eradicated by any of the currently used Lyme treatment regimens. Therein lies the significance of coinfections- If a Lyme patient has been extensively treated yet is still ill, suspect a piroplasm.
Just as in Lyme Borreliosis, the longer one has been infected, the longer the course of therapy must be. Similarly, clinical assessment is the only guide to treatment endpoint.
Treatment choices are limited. Pentamidine is a treatment given as daily IM shots- very painful, they cause sterile abscesses and permanent fibrous scars on the buttocks. More importantly, response is poor, and the patient risks development of glucose intolerance. Clearly, not a first choice.
Clindamycin, 600 mg qid plus Quinine, 650 mg qid has been the published standard but the suggested two week course is nearly impossible to tolerate (hearing loss, rash, fever, headache) and treatment failures have been reported.
Gentamicin in combination with either penicillin or a first generation cephalosporin is used in treating livestock infected with piroplasms. There are only anecdotal reports of efficacy in Humans and the dose and duration of therapy (14+days) has not been well worked out. The main side effect is hearing loss from the gentamicin, and the need for IM or IV doses.
Mepron (atavoquone), 750 mg bid, has demonstrated efficacy, but should be given concurrently with azithromycin, 250 to 600 mg daily, or resistance may develop. Efficacy is by far the best with this combination, but surprisingly, Herxheimer-like reactions are almost always seen at the fourth day, and at the fourth week of therapy. Does this represent a newly described phenomenon in treating Piroplasms, or does this combination have heretofore unrecognized efficacy in killing Bb? Although I do not have the answer, I suspect the latter simply based on the familiar (in Bb) four-week cycle. In late, longstanding cases, one month of treatment is the minimum, and four or more months are often needed. Problems during therapy include diarrhea, mild nausea, the expense of Mepron ($600.00 per bottle- enough for one month of treatment), and rarely, a temporary yellowish discoloration of the vision. Regular blood counts and liver panels are recommended during any prolonged course of therapy.
Treatment recommendations at this time are very preliminary, mainly due to the lack of direct detection methods needed to guide us in developing a solid clinical feel. The mainstay of treatment is doxycycline, either orally or IV, given for at least two weeks for an early infection, or at least four weeks in a longstanding one. Interestingly, the unexpected efficacy of IV doxycycline in treating Lyme cases which had previously responded poorly to cell wall agents, may in fact reflect concurrent therapy of coinfection with Bb and Ehrlichial species. The new concern for Ehrlichia is the main reason that Doxycycline is now the first choice in treating tick bites and early Lyme, before serologies can become positive.
LYME BORRELIOSIS (LB)
After a tick bite, Bb undergoes rapid hematogenous dissemination, and for example, can be found within the central nervous system as soon as twelve hours after entering the bloodstream. This is why even early infections require full dose antibiotic therapy with an agent able to penetrate all tissues in adequate concentrations to be bactericidal to the organism.
It has been shown that the longer a patient had been ill with Bb prior to first definitive therapy, the longer the duration of treatment must be, and the need for more aggressive treatment increases.
Bb contains beta lactamases, which, with some strains, may confer resistance to cephalosporins and penicillins. This is apparently a slowly acting enzyme system, and may be overcome by higher or more continuous drug levels especially when maintained by continuous infusions (cefotaxime) and by depot preparations (benzathine penicillin). Nevertheless, some penicillin and cephalosporin treatment failures do occur and have responded to sulbactam/ampicillin, imipenim, and vancomycin, which act on different cell wall sites than penicillin and the cephalosporins.
There is now evidence that B. burgdorferi can remain viable within cells, such as macrophages, lymphocytes, endothelial cells, neurons, and fibroblasts, and evade the effects of antibiotics in vitro by sequestering in these intracellular niches. In addition, Bb secretes a glycoprotein that can encapsulate the organism (an "S-layer"). This may impair immune recognition and block antibiotic penetration. Because this glycoprotein binds host IgM, it is possible that Borrelial antigens are hidden by host protein, and in theory at least, this will interfere with immune recognition, and cause seronegativity.
There are multiple strains of Borrelia burgdorferi and they vary in their antigen profile and antibiotic susceptibilities. In addition, L-forms exist which do not contain cell walls, and thus cell wall antibiotics will not affect them. Apparently, Bb can shift between the two forms during the course of the infection and cause the varying serologic responses seen over time, including seronegativity. Because of this, it may be necessary to change antibiotic or even prescribe a combination of agents.
Vegetative endocarditis has been associated with Borrelia burgdorferi, but the vegetations may be too small to detect with echocardiography. Keep this in mind when evaluating patients with murmurs, as this may explain why some patients seem to continually relapse after even long courses of antibiotics.
COURSE DURING THERAPY
As the spirochete has a very long generation time (12 to 24 hours in vitro and possibly much longer in living systems) and may have periods of dormancy, during which time antibiotics will not kill the organism, treatment has to be continued for a long period of time to eradicate all the active symptoms and prevent a relapse, especially in late infections. If treatment is discontinued before all symptoms of active infection have cleared, the patient will remain ill and possibly relapse further. In general, early disseminated LB is treated for four to six weeks, and late LB usually requires a minimum of four to six months of continuous treatment. All patients respond differently and therapy must be individualized. It is not uncommon for a patient who has been ill for many years to require open ended treatment regimens; indeed, some patients will require ongoing maintenance therapy to remain well.
It has been observed that symptoms will flare in cycles every four weeks. It is thought that this represents the organism's cell cycle, with the growth phase occurring once per month. As antibiotics will only kill bacteria during their growth phase, therapy is designed to bracket at least one whole generation cycle. This is why the minimum treatment duration should be at least four weeks. If the antibiotics are working, over time these flares will lessen in severity and duration. The very occurrence of ongoing monthly cycles indicates that living organisms are still present and that antibiotics should be continued.
With treatment, these monthly symptom flares are exaggerated and presumably represent recurrent Herxheimer-like reactions as Bb enters its vulnerable growth phase. For unknown reasons, the worst occurs at the fourth week of treatment. Observation is that the more severe this reaction, the higher the germ load, and the more ill the patient. In those with long-standing highly symptomatic disease who are on I.V. therapy, the week-four flare can be very severe, similar to a serum sickness reaction, and be associated with transient leucopenia and/or elevations in liver enzymes. If this happens, decrease the dose temporarily, or interrupt treatment for several days, then resume with a lower dose. If you are able to continue or resume therapy, then patients dramatically improve. Those whose treatment is stopped and not restarted at this point usually will need retreatment in the future due to ongoing or recurrent symptoms. Patients on I.V. therapy who have a strong reaction at the fourth week will need to continue parenteral antibiotics for several months, for when this monthly reaction finally lessens in severity, then oral or IM medications can be substituted. Indeed, it is just this observation that guides the clinician in determining the endpoint of I.V. treatment. In general, I.V. therapy is given until there is a clear positive response, then treatment is changed to IM or po until free of signs of active infection for 4 to 8 weeks. Some patients, however, will not respond to IM or po treatment and I.V. therapy will have to be used throughout. As mentioned earlier, leucopenia may be a sign of persistent Ehrlichiosis, so be sure to look into this.
Repeated treatment failures should alert the clinician to the possibility of an otherwise inapparent immune deficiency, and a workup for this may be advised.
There are three things that will predict treatment failure regardless of which regimen is chosen: Non-compliance, alcohol use on a regular basis, and failure of the patient to obtain proper rest. Advise them to take a break when (or ideally before) the inevitable mid afternoon fatigue sets in.
All patients must keep a carefully detailed daily diary of their symptoms to help us judge the effects of treatment, the presence of the classic four week cycle, and treatment endpoint. One must follow such diaries, temperature readings in late afternoon, physical findings, notes from physical therapists, and cognitive testing to best judge when to change or end antibiotics.
Remember- there currently is no test for cure, so this clinical follow-up assumes a major role in Lyme Disease care.
There is no universally effective antibiotic for treating LB. The choice of medication used and the dosage prescribed will vary for different people based on multiple factors. These include age, weight, gastrointestinal function, blood levels achieved, and patient tolerance. Doses found to be effective clinically are often higher than those recommended in older texts. This is due to deep tissue penetration by Bb, it's presence in the CNS including the eye, within tendons, and because very few of the many strains of this organism now known to exist have been studied for antibiotic susceptibility. In addition, all animal studies to date have only addressed early disease in models that behave differently than human hosts. Therefore, begin with a regimen appropriate to the setting and modify it over time based upon response,s and refer to the suggested reading list and the appendix at the end of this document.
There are four types of antibiotics in general use for Bb treatment. The tetracyclines, including doxycycline and minocycline, are bacteriostatic unless given in high doses. If high blood levels are not attained, treatment failures in early and late disease are common. However, these high doses can be difficult to tolerate. For example, doxycycline can be very effective but only if adequate blood levels are achieved either by high oral doses (300 to 600 mg daily) or by parenteral administration.
Penicillins are bactericidal. As would be expected in managing an infection with a gram negative organism such as Bb, amoxicillin has been shown to be more effective than oral penicillin V. Because of its short half-life and need for high levels, amoxicillin is usually administered along with probenecid. Since blood levels are extremely variable they should be measured.
Cephalosporins must be of ad-vanced generation: first generation drugs are not effective, and second generation drugs are comparable to amoxicillin and doxycycline both in-vitro and in-vivo. Third generation agents are currently the most effective of the cephalosporins because of their very low MBC's (0.06 for ceftriaxone) and have been shown to be effective in penicillin and tetracycline failures. Cefuroxime axetil (Ceftin), a second generation agent, is also effective against staph and thus is useful in treating atypical erythema migrans that may represent a mixed infection, containing some of the more common skin pathogens in addition to Bb. Because this agent 's G.I. side effects and high cost, it is not used as first line drug.
When choosing a third generation cephalosporin, there are several points to remember: Ceftriaxone is administered once daily (an advantage for home therapy), but has 95% biliary excretion and can crystallize in the biliary tree with resultant colic and possible cholecystitis. GI excretion results in a large impact on gut flora. Biliary and superinfection problems with ceftriaxone can be lessened if this drug is given in interrupted courses, such as five days in a row each week. Cefotaxime, which must be given at least every twelve, and preferably every eight hours, is less convenient, but as it has only 5% biliary excretion, it never causes biliary concretions, and may have less impact on gut flora. It is the experience of some clinicians that cefotaxime can be even more efficacious if given as a continuous infusion, rather than in interrupted doses.
Erythromycin has been shown to be almost ineffective as monotherapy. The advanced macrolides and azalides such as azithromycin and clarithromycin can be difficult to tolerate orally due to their tendency to promote yeast overgrowth and poor GI tolerance at the high doses needed. As they have impressively low MBCs and do concentrate in tissues and penetrate cells, they theoretically should be ideal agents. However, initial clinical results were disappointing. It has been suggested that when Bb is within a cell, it is held within a vacuole and bathed in fluid of low pH, and this acidity may inactivate this class of antibiotics. Therefore, they are administered concurrently with hydroxychloroquine or amantadine, which raise vacuolar pH, rendering these agents much more effective. It is not known whether this same technique will make erythromycin a more effective antibiotic in LB. Another alternative is to administer azithromycin parenterally. Results are excellent, but expect to see abrupt Jarisch-Herxheimer reactions.
Other agents with demonstrated in-vitro efficacy have been used successfully in treating patients with Bb and are listed further below.
Drug levels are measured until the most acceptable dose is found, and then at any time major changes in the treatment regimen occur. With parenteral therapy, CBC and chem/liver panels are done at least twice each month during symptom flares, with urinalysis and prothrombin time monitored monthly.
ORAL THERAPY: Always check blood levels when using agents marked with an *, and adjust dose to achieve a peak level in the mid- teens and a trough greater than five. Because of this, the doses listed below may have to be raised. Consider Doxycycline first due to concern for Ehrlichia.
DoxycyclineAdults: 100 mg tid with food; doses of up to 600 mg daily are often needed, as doxycycline is only effective at high blood levels.
Not for children or in pregnancy. If levels are too low at tolerated doses, give parenterally
Cefuroxime axetilOral alternative that may be effective in amoxicillin and doxycycline failures. Useful in EM rashes co-infected with common skin pathogens. Adults and pregnancy: 1g ql2h and adjust.Children: 125 to 500 mg ql2h based on weight.
TetracyclineAdults only and not in pregnancy. 500 mg tid to qid
ErythromycinPoor response and not recommended.
AzithromycinAdults: 500 to 1200 mg/d. Adolescents; 250 to 500 mg/d add hydroxychloroquine, 200-400 mg/d or amantadine 100-200 mg/dCannot be used in pregnancy or in younger children.
ClarithromycinAdults: 250 to 500 mg q6h plus hydroxychloroquine 200-400 mg/d or amantadine 100-200 mg/d. Cannot be used in pregnancy or in younger children.
Augmentin Cannot exceed three tablets daily due to the clavulanate, thus is given with amoxicillin.
ChloramphenicolNot recommended as not proven and potentially toxic.
Ceftriaxone: Risk of biliary sludging can be minimized with intermittent breaks in therapy (ie: infuse five days in a row per week).Adults and pregnancy: 2g q24h. For large body habitus or more severe illness: up to 4g dailyChildren: 75 mg/kg/day up to 2g/day
CefotaximeComparable efficacy to ceftriaxone: no biliary complications.Adults and pregnancy: 2g q8h; may dose as high as 12g daily. Consider continuous infusion.Children: 90 to 180 mg/kg/day dosed q6h (preferred) or q8h, not to exceed 12 g daily.
*DoxycyclineRequires central line as is caustic.Surprisingly effective, probably because blood levels are higher when given parenterally.Always measure blood levels.Adults: 400 mg q24h and adjust based on levelsCannot be used in pregnancy or in younger children.
AzithromycinRequires central line as is caustic.Dose: 500 to 1000 mg daily in adolescents and adults.
Penicillin GIV penicillin G is minimally effective and not recommended.
Benzathine penicillinSurprisingly effective IM alternative to oral therapy. May need to begin at lower doses as strong, prolonged (6 or more week) Herxheimer-like reactions have been observed.Adults: 1.2 million U once to twice weeklyAdolescents: 300,000 to 1.2 million U weekly.Should not be used in pregnancy.
Poorly studied but anecdotally effective:
Vancomycinobserved to be one of the best drugs in treating Lyme, but potential toxicity limits its use. It is a perfect candidate for pulse therapy to minimize these concerns. Use standard doses and confirm levels.
Imipenim and Unisynsimilar in efficacy to cefotaxime, but often works when cephalosporins have failed.Must be given q6 to q8 hours.
Cefuroximeuseful but not demonstrably better than ceftriaxone or cefotaxime
Ampicillin IVmore effective than penicillin G. Must be given q6 hours.
PROPHYLAXIS of high risk groups- education and preventive measures. Antibiotics are not given.
TICK BITES - Embedded Deer Tick With No Signs or Symptoms of Lyme (see appendix):
Decide to treat based on the type of tick, whether it came from an endemic area and percent infected, how it was removed, and length of attachment (nymphs: at least one day; adults: anecdotally, as little as four hours). The risk of transmission is greater if the tick is engorged, or of it was removed improperly allowing the tick's contents to spill into the bite wound. High risk bites are treated as follows (remember the possibility of coinfection!):
1) Adults: Oral therapy for 21 days.
2) Pregnancy: Amoxicillin 1000 mg q6h for 6 weeks. Test for Babesia and Ehrlichia.
Alternative: Cefuroxime axetil 1000 mg q12h for 6 weeks.
3) Young Children: Oral therapy for 21 days.
EARLY LOCALIZED - Single erythema migrans with no constitutional symptoms:
1) Adults: oral therapy for 6 weeks.
2) Pregnancy: 1st and 2nd trimesters: I.V. X 21 days then oral X 6 weeks
3rd trimester: Oral therapy X 6 weeks.
Any trimester- test for Babesia and Ehrlichia
3) Children: oral therapy for 6 weeks.
DISSEMINATED DISEASE - Multiple lesions, constitutional symptoms, lymphadenopathy, or any other manifestations of dissemination.
EARLY DISSEMINATED: Milder symptoms present for less than one year and not complicated by immune deficiency or prior steroid treatment:
1) Adults: oral therapy until no active disease for 4 weeks (4-6 months typical)
2) Pregnancy: As in localized disease, but duration as above. Some
experienced clinicians treat throughout pregnancy.
3) Children: Oral therapy with duration based upon clinical response.
PARENTERAL ALTERNATIVES for more ill patients and those unresponsive to or intolerant of oral medications:
1) Adults and children: I.V. therapy for 6 weeks or until clearly improved. Follow with oral therapy
or IM benzathine penicillin until no active disease for 8 weeks. I.V. may have to
be resumed if oral or IM therapy fails.
2) Pregnancy: IV then oral therapy as above.
LATE DISSEMINATED: present greater than one year, more severely ill patients, and those with prior significant steroid therapy or any other cause of impaired immunity:
1) Adults and pregnancy: extended I.V. therapy (6 to 10 or more weeks), then
oral or IM, if effective, to same endpoint.
2) Children: IV therapy for 6 or more weeks, then oral or IM follow up as above.
ALTERNATE SCHEDULING OF ANTIBIOTIC TREATMENT
Pulse therapy consists of administering antibiotics (usually parenteral ones) two to three days in a row per week. This allows for several advantages:
· Dosages are doubled (ie: cefotaxime, 12 g daily), increasing efficacy
· More toxic medications can be used with increased safety (ie: vancomycin)
· May be effective when conventional, daily regimens have failed.
· IV access may be easier or more tolerable
· More agreeable lifestyle for the patient
· Often less costly than daily regimens
Note that this type of treatment is expected to continue for a minimum of ten weeks, and often must continue beyond twenty weeks. The efficacy of this regimen is based on the fact that it takes 48 to 72 hours of continuous bactericidal antibiotic levels to kill the spirochete, yet it will take longer than the four to five days between pulses for the spirochetes to recover. As with all Lyme treatments, specific dosing and scheduling must be tailored to the individual patient's clinical picture based upon the treating physician's best clinical judgment.
This consists of using two or more dissimilar antibiotics simultaneously for antibiotic synergism and to better compensate for differing killing profiles and sites of action of the individual medications. A typical combination is the use of a cell wall agent plus a protein inhibitor (ie: amoxicillin plus clarithromycin). Note that GI intolerance and yeast superinfections are the biggest drawbacks to this type of treatment. However, these complications can often be prevented or easily treated, and the clinically observed benefits of this type of regimen clearly have outweighed these problems in selected patients.
PERSISTENT SIGNS AND SYMPTOMS THAT RESPOND TO ANTIBIOTIC THERAPY
Patients in this group improve on antibiotics yet relapse repeatedly when medications are discontinued. Some patients in this category have been proven, in peer reviewed medical literature, to have persistent infection. The treating physician may decide on chronic therapy in order to avoid clinical deterioration. Recommend you confirm blood levels, and study immune competence. This includes T- and B- cell function and counts, Natural Killer cell functional assays, complement levels, neutrophil function, and vaccine responsiveness.
Options for treatment:
- Longer duration, including open ended maintenance therapy
- Increased dose
- Different drug
- Change method of administration (oral to IV)
- Combination or pulse therapy
- Search for and treat concurrent illnesses
- Supportive therapy as needed
PERSISTENT SIGNS AND SYMPTOMS NOT RESPONSIVE TO ANTIBIOTICS
- Reconsider the diagnosis, and perform specific Bb antigen tests after antibiotic free for 6 to 12 weeks
- Search for and treat concurrent illnesses and coinfections
- Supportive therapy based on symptoms
- NSAIDS and hydroxychloroquine
- Antidepressants, analgesics, muscle relaxants, and amantadine
- Psychiatric/psychometric evaluation and treatment if indicated
- Long-term follow-up
- Consider retreatment if condition changes
RECOMMENDED IN ALL LYME PATIENTS:
- daily yogurt and acidophilus preparations
- multivitamins and B complex 50 mg daily
- Physical therapy, rehabilitation, and a graded exercise program
PRESCRIBE AS NEEDED, especially in more severe cases:
- vitamin and nutritional supplements as listed below
- Psychosocial evaluation and possibly refer for counseling
- NSAIDS and remittive agents
- antidepressants, analgesics, muscle relaxants, and amantadine
- Immune globulins and other immunotherapy if indicated
- Sinequan (DAW) in low doses (5 to 50 mg daily) reportedly improves T-cell function
- alcohol use
- excessive caffeine intake
- any avoidable stresses
- sleep deprivation
Over a decade of experience in treating thousands of patients with Lyme has proven that therapy as described above, although intense, is generally well tolerated. The most common adverse reaction seen is allergy to probenecid. In addition, yeast superinfections are seen, but these are generally easily recognized and managed. The induction of Clostridium difficile toxin production is seen most commonly with ceftriaxone, but can occur with any of the antibiotic regimens mentioned in this document. However, regular use of the lactobacillus preparations seems to be helpful in controlling yeast and antibiotic related colitis, as the number of cases of C. difficile in Lyme patients is low when these guidelines are followed.
When using PICC lines (peripherally inserted central catheters), if ANY line problems arise, it is recommended that the line be pulled for patient safety. Salvage attempts (urokinase, repairing holes) are often ineffective and may not be safe.
Please advise all patients who take the tetracyclines of skin and eye sensitivity to sunlight and the proper precautions. When doxycycline is given parenterally, do not freeze the solution prior to use!
Years of experience with chronic antibiotic therapy in other conditions, including rheumatic fever, acne, recurrent otitis, recurrent cystitis, COPD, bronchiectasis, and others have not revealed any consistent dire consequences as a result of such medication use. Indeed, the very real consequences of untreated, chronic persistent infection by B. burgdorferi can be far worse than the potential consequences of this treatment.
Studies on patients with chronic Lyme Disease and in those with the Chronic Fatigue Syndrome have demonstrated that some of the late symptoms are related to cellular damage and deficiencies in certain essential nutrients. Double blinded, placebo controlled studies, and in one case direct assay of biopsy specimens have proven the value of the supplements listed.
ESSENTIAL FATTY ACIDS:
Studies show that when EFAs are taken regularly, statistically significant improvements in fatigue, aches, weakness, vertigo, dizziness, memory, concentration and depression are likely. There are two broad classes: GLA and EPA, derived respectively from plant and fish oils. The plant sources are many, so choose one from the list below.
Plant Oils: evening primrose oil, black currant seed oil, borage oil (probably the best choice)
Fish oil: "MAX EPA" (or any similar preparation containing 1,000 mg of EPA)
RECOMMENDATION: four plant oil capsules and two to four EPA capsules daily, taken with the largest meal of the day. Benefit begins within several days, but further improvement continues to occur over time. Continue for three to four months.
CO-Q 10 (ubiquinone):
This is a vitamin B- like compound essential to every living cell. Deficiencies have been related to poor function of the heart, limitations of stamina, and poor resistance to infections. Tissue biopsy studies have resulted in the recommendation that a patient with chronic Lyme should take between 200 and 300 mg daily, in two or three equal doses. Improvements in stamina and general well being do not begin for several weeks. The body will manufacture its own Co-Q 10 when the original infection is controlled, but only if stimulated by aggressive exercise. Therefore, use this supplement until the patient is feeling well and is exercising regularly, usually three to four months.
Studies in the 1950s demonstrated the need for supplemental vitamin B in infections with other Borrelia. This enhances clearing of neurological symptoms. I recommend one 50 mg B-complex capsule daily long term.
Magnesium supplementation very helpful for the tremors, twitches, cramps, muscle soreness, arrhythmias and weakness. It may also help in energy level and cognition. Unexplained hyperreflexia is an indicator of Mg deficiency. The best source is magnesium chloride ("Slo-Mag", one or two qid) or magnesium oxide (Mag-Ox, 400 mg one or two daily). DO NOT rely on "cal-mag", calcium plus magnesium combination tablets, as they are not well absorbed. In many cases, I.M. or I.V. magnesium is necessary. Continue long term.
I recommend the LifePak family of supplements- choose LifePak for males under 40, LifePak Women for hormonally active women, and LifePak Prime for post menopausal women and men over 40. These are unique supplements- Pharmaceutical grade and USP certified, and the only products clinically proven to raise antioxidant levels in the blood and lipids.
All of these products are available without a prescription.
Those with long-standing tick borne illnesses end up in poor physical condition. Even with successful treatment of the infections, they will not return to normal unless they take an active role in personal rehabilitation.
In late stage disease, many negative effects to the body are occurring: muscles atrophy, and to some degree, the heart muscle also suffers, as do the joints, tendons, nerves, etc. The per cent fat content of the body as a whole rises, the cholesterol rises, and the balance between HDL and LDL becomes less favorable. In at least 80% of the patients, significant weight gain occurs.
Because of the extreme fatigue and body pain, many Lyme sufferers end up spending inordinate amounts of time in bed, and get far less exercise than they did before they became ill. This begins a debilitating downward spiral that can be very difficult to reverse.
As a result, Lyme patients are stiff, weak, tired, have poor stamina, and are at increased risk for cardiovascular disease and diabetes. Antibiotic treatment alone cannot correct these effects. Therefore, it is necessary to prescribe physical therapy, the extent of which depends on an individual patients' condition, followed by a graded exercise program.
The earliest phase involves multiple modalities (massage, heat, TENS, MENS, ultrasound, etc.) and aggressive range of motion exercises supervised by a physical therapist. The goal is to relieve discomfort and to promote better sleep and flexibility. This then evolves into stretching and mild muscular toning which can lessen joint pain and increase mobility and stamina. Finally, the program must expand to include muscular conditioning and strengthening, ideally under the supervision of a credentialed exercise physiologist. "Body sculpture" classes are ideal. Aerobics are not recommended until the patient has fully recovered.
This is the time for the very best of health habits. I recommend light, low fat food, with high quality nutritional value, minimal amounts of starch and other simple carbohydrates, absolute abstention from alcohol, elimination of caffeine, and if applicable, a serious commitment to weight loss. Consider recommending books that outline "arthritis diets", as they can help some patients.
Cessation of smoking is extremely important and must be addressed immediately.
As written orders for physical therapy are required to initiate the program, an example of the format of a typical prescription for Lyme rehabilitation follows.
LYME REHAB THERAPY PRESCRIPTION
Please enroll this patient in a program of therapy to rehabilitate him/her from the effects of Lyme Disease. If necessary, begin with classic physical therapy, then progress when appropriate to a whole body conditioning program. Such therapy must be graded, carefully individualized, and be performed on a one-on-one basis, at least initially, to ensure the maximal amount of supervision and guidance.
THERAPEUTIC GOALS (to be achieved in order as the patient's ability allows):
1. Relieve pain and muscle spasms utilizing multiple modalities as available and as indicated: massage, heat, ultrasound, TENS, "micro amp", etc.
2. Increase mobility while protecting damaged and weakened joints, tendons, and ligaments, to increase range of motion and relieve stiffness.
EXERCISE Begin with a private trainer for careful direction and education.
PATIENT EDUCATION AND MANAGEMENT (to be done during the initial one-on-one sessions
and reinforced at all visits thereafter):
1. Instruct patients on correct exercise technique, including proper warm-up, breathing, joint protection, proper body positioning during the exercise, and how to cool-down and stretch afterwards.
2. Please work one muscle group at a time and perform extensive and extended stretches to each muscle group immediately after each one is exercised, before moving on to the next muscle group.
3. A careful interview should be performed at the start of each session to make apparent the effects, both good and bad, from the prior visit's therapy, and adjust therapy accordingly.
1. Improve strength and reverse the poor conditioning that results from Lyme, through a whole-body exercise program ("stretch and tone", or "body sculpture" classes). This consists of light calisthenics and weight lifting, using small weights and many repetitions.
2. Exercise no more often than every other day
3. Each session should last one hour. If the patient is unable to continue for the whole hour, then modify the program to decrease the intensity to allow him/her to do so.
4. This is what is required to achieve wellness and is the main focus of rehab. Simply placing the patient on a treadmill or an exercise bike is not acceptable, nor is a simple walking program.
5. Aerobic exercises are not allowed, not even low impact variety, until the patient has fully recovered.
Please feel free to contact my office if you would like to discuss this client's situation in more detail.
MANAGING YEAST INFECTIONS
Many patients with Lyme Disease develop an overgrowth of yeast. Therefore, it is recommended that on a daily basis the patient eat a full container of yogurt that contains active cultures, and take acidophilus, two after each meal. Here are some suggestions on how to control yeast:
MOUTH: A tongue with a beige coating, bad breath, and dysgeusia are signs of thrush. The patient must brush the tongue whenever they brush their teeth, and use antiseptic mouthwashes then. Because the effectiveness of a mouthwash is related to how long it is in contact with the germs, it should be kept in the mouth while brushing.
Since yeast germs feed on sugars, have patients avoid simple carbohydrates, starches, fruits, and juices for at least two weeks, or until the problem is gone.
Prescription medications may be necessary. Mycelex troches and Nystatin liquid are not recommended for they contain large amounts of simple sugars. Nystatin powder is used, mixed with water, to be swished and swallowed qid (pc and hs). Systemic antifungals (Diflucan, Nizoral) may be necessary.
The most effective (and drastic) treatment, employed as a last resort, consists of using "Dakin's Solution" as a mouth rinse. This is a mixture of household liquid bleach (Clorox), one teaspoon in four ounces of water. A small amount is held in the mouth while brushing, then spit out, and repeated until the mouth has cleared. This is usually a one-time treatment, but may have to be repeated every few weeks.
After using an antiseptic to clean the mouth, it is necessary to immediately eat yogurt or liquid acidophilus, or chew an acidophilus capsule to replenish the beneficial flora in the mouth. Because the germ count after such a cleaning will be artificially reduced, and because yeast germs are opportunists, they would be the first to come back. By having the yogurt or acidophilus then, a more normal oral flora will result and thrush will be better controlled.
INTESTINAL TRACT: An overgrowth of yeast here will ferment dietary sugars and starches, forming acids, gas, and alcohols. Symptoms include gas, heartburn and/or pain in the stomach area, and because of the alcohol, there can be headaches, dizziness, lightheadedness, and wooziness. To clear intestinal yeast, first the tongue and mouth must be cleared so yeast does not reenter the system with every swallow. Avoid sweets, starches, fruits and juices for two weeks or longer to starve the germs. Systemic antifungals (Diflucan, Nizoral) usually are needed.
VAGINAL: An occasional vaginal yeast infection can be controlled with products such as Monistat cream or suppositories. If it is a recurrent or ongoing problem, then it often reflects a simultaneous intestinal infection, reinfecting the genital area with every bowel movement. Therefore treat the patient as above for intestinal overgrowth, and prescribe topical preparations such as Monistat concurrently for two weeks.
BITE PREVENTION AND TICK REMOVAL
HOW TO PROTECT YOURSELF FROM TICK BITES
PROPERTY Remove wood piles, rock walls, and bird feeders as these attract tick-carrying small animals and can increase the risk of acquiring Lyme.
INSECTICIDES: Property should be treated with a product called "Damminix". This consists of cardboard tubes containing cotton balls that have been dipped in insecticide. These tubes are placed around the property in the wooded areas and below shrubs. Mice, which are a key link in the propagation of Lyme disease, find the cotton and bring it back to their burrows to be used as nesting material, with the result being a big decrease in the number of ticks in the area. Unfortunately, after two years tick populations may rise again as other small animals that do not gather cotton become hosts to the ticks. Therefore, Damminix alone is not sufficient. Use this product in conjunction with liquid or granular insecticides.
LIQUID & GRANULAR PESTICIDES: Products meant for widespread application include Dursban, Tempo, permethrin, and sevin. They are available as a liquid concentrate and as granules. If liquid insecticides are used, application should be by fogging, not by coarse sprays. Apply these products in a strip a few feet wide at the perimeter of the lawn at any areas adjacent to woods and underbrush. Also treat any ornamental shrubs near the house that may serve as a habitat for small animals. The best time to apply these products is in late Spring and early Fall.
CLOTHING When wearing long pants, tuck the cuffs into the socks so any ticks that get on shoes or socks will crawl on the outside of the pants and be less likely to bite. Also, light colored clothing should be worn so the ticks will be easier to spot. Smooth materials such as windbreakers are harder for ticks to grab onto and are preferable to knits, etc.
Tick repellents that contain "permethrin" (Permanone, Permakill) are meant to be sprayed onto clothing. Spray the clothes before they're put on, and let them dry first. Do not apply this chemical directly to the skin.
Ticks are very intolerant of being dried out. After being outdoors in an infested area, place clothes in the dryer for a few minutes to kill any ticks that may still be present.
SKIN Insect repellents that contain "DEET" are somewhat effective when applied to the arms, legs, and around the neck. Do not use any repellent over wide areas of the body as they can be absorbed causing toxicity. Also, it is inadvisable to use a product that contains more than 50% DEET, and 25% concentrations are preferred. Use repellents cautiously on small children, as they are more susceptible to their toxic effects. Be aware that this repellent evaporates quickly and must be reapplied frequently.
Check carefully for ticks not only when home but frequently while still outside!
HOW TO REMOVE AN ATTACHED TICK
Using a tweezer (not fingers!), grasp the tick as close to the skin as possible and pull straight out. Then apply an antiseptic. Do not try to irritate them with heat or chemicals, or grasp them by the body, as this may cause the tick to inject more germs into your skin. Tape the tick to a card and record the date and location of the bite. Remember, the sooner the tick is removed, the less likely an infection will result.
RATIONALE FOR TREATING TICK BITES
The Medical Advisory Committee of the Lyme Disease Foundation now recommends antibiotic prophylactic treatment upon a known tick bite for:
1. People at higher health risk bitten by an unknown type of tick or tick capable of transmitting Borrelia burgdorferi, e.g., pregnant women, babies and young children, people with serious health problems, and those who are immunodeficient.
2. Persons bitten in an area endemic for Lyme Borreliosis by an unidentified tick or tick capable of transmitting B. burgdorferi.
3. Persons bitten by a tick capable of transmitting B. burgdorferi, where the tick is engorged, or the attachment duration of the tick is greater than four hours, and/or the tick was improperly removed. This means when the tick is squeezed between the fingers, irritated with toxic chemicals in an effort to get it to back out, or disrupted in such a way that it's contents were allowed to contact the bite wound. Such practices increase the risk of disease transmission.
4. A patient, when bitten by a known tick, clearly requests oral prophylaxis and understands the risks. This is a case-by-case decision.
The physician cannot rely on a laboratory test or clinical finding at the time of the bite to definitely rule in or rule out Lyme Disease infection, so must use clinical judgment as to whether to use antibiotic prophylaxis. Testing the tick itself for the presence of the spirochete, even with PCR technology, is not reliable enough to guide your decision to treat, as false positives and false negatives occur.
An established infection by B. burgdorferi can have serious, long-standing or permanent, and painful medical consequences, and be expensive to treat. Since the likelihood of harm arising from prophylactically applied spirochetal antibiotics is low, and since treatment is inexpensive and painless, it follows that the risk benefit ratio favors tick bite prophylaxis.
It is the Medical Advisory Committee's recommendation that antibiotic prophylactic treatment for tick bite in many circumstances is not only justified but warranted. The ultimate decision for treatment on tick bite should be determined jointly between the physician and patient.
RATIONALE FOR TREATMENT RECOMMENDATIONS:
When I began treating Lyme Borreliosis (LB) in the mid 1980s, I recognized that in disseminated disease, the then recommended ten to fourteen day courses of antibiotics would either result in only a lessening of the illness, or an initial good outcome followed by a relapse of symptoms. These patients would then respond again to a repeat course of antibiotics.
Published studies by Steere and others (1) had, at that time, defined success as the elimination of the "major" symptoms of Lyme (arthritis, carditis, and Bell's Palsy) even though they usually resolve over time without treatment. These same studies go on to report the persistence of "minor symptoms" of Lyme even after antibiotic therapy, and the authors call it the "post Lyme syndrome".
In 1987 I participated in a study in which twenty six patients with active disseminated LB, who were culture positive for Borrelia burgdorferi (Bb), were treated with ceftriaxone I.V. for fourteen days, using either two or four grams a day. Although culture negative at the immediate end of therapy, all patients became culture positive again within several weeks, which corresponded to the time when their symptoms recurred. I concluded then that the persistence of symptoms after this type of therapy in fact represented ongoing infection. The results of this study were presented in 1989 at the national meeting of the Lyme Borreliosis Foundation.
Upon the advice of colleagues who for years have been involved in seminal LB research (2), I then studied the effects of lengthened duration of treatment. I found a direct correlation between treatment duration and the ultimate outcome of patients' symptoms. Using amoxicillin 3g/day plus probenecid 1.5g/day in divided doses, the per cent success was tabulated for therapies lasting for from one through six months. Success here is defined as the elimination of all LB symptoms, both major and minor, without a relapse by three months after completion of treatment.
The data clearly demonstrated a direct relationship between duration and success, starting at 17% for one month of therapy, and reaching a plateau at 67% at five months duration. These data were also presented at the 1989 meeting mentioned above.
Next, using ceftriaxone, results of therapy were tabulated based on duration. Even with 45 days of continuous antibiotic, none of the patients returned to or maintained their well, pre-Lyme state. However, if oral medications were continued after ceftriaxone, to the endpoint of being free of signs and symptoms of active disease, then relapses did not occur. Again, the average duration of antibiotic treatment necessary to achieve this was at least four months.
Further culture studies involving 74 patients confirmed that the patients had to be free of signs and symptoms of active Borreliosis before antibiotics were discontinued in order to be both culture negative, and not experience a relapse during three months of follow up.
There are now a growing number of published reports utilizing various forms of Bb antigen detection that demonstrate the persistence of infection in antibiotically treated patients (3,4,5,6,7,8), confirming my earlier work. Even Steere has proposed this as a mechanism for chronic arthritis in Lyme (9).
Although syphilis perhaps is not a synonymous spirochetosis to Lyme, similar findings of organism persistence despite presumed adequate (short course) therapy has been reported in those who later became immune deficient (10). Indeed, Wassermann in 1936 recommended a minimum of twenty six weeks of treatment for established infection, based upon generation-time studies.
I had participated in an NIH study utilizing the antigen detection method of Dorward et al (11). In testing over 130 patients with Chronic Persistent LB, in whom symptoms of active disease continued despite even prolonged treatment (indeed, some would describe as excessive the treatment given to several participants), Bb could be recovered from blood, CSF, urine, and tears. Indeed, many of these patients had received months to years of aggressive, often parenteral therapy for LB. For example, one had received continual antibiotics for three years, while another was treated for 18 months with repeated courses of parenteral therapy. As a matter of record, neither one was a patient of mine.
These examples clearly indicate what researchers have recognized as the ability of Bb to evade host defenses (1,12,13,14,15) even in the presence of antibiotics (5,6,7,8).
I do not now recommend treatment forever, but I point out the above results to be able to make several points:
1. There has never been a study in the history of this illness that even in the simplest way proves that currently recognized short-course (two to four week) therapy results in a bacteriologic cure.
2. There has never been a consensus in patients still symptomatic after short treatment courses as to what constitutes the post Lyme syndrome, how Bb induces it, and what perpetuates it if bacteriologic cure is indeed presumed.
3. Patients must be kept on therapy until free of active symptoms or they either will never recover fully, or suffer a relapse.
4. Extended durations of antibiotic therapy clearly have helped literally thousands of patients who were not helped by short courses of treatment.
5. Finally, we have to recognize that in some patients, LB may not be curable in a strict bacteriologic sense.
Until sensitive and specific antigen detection tests become widely available, treatment of LB will remain difficult, controversial, and the subject of much discussion.
J.J. Burrascano, Jr., M.D.
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2. Berger, B.W., Johnson, R. C., Schwann, T.G. Clinical and microbiologic findings in six patients with erythema migrans of Lyme Disease. Am J Acad Dermatol 1989: 21:1186-91
3. Cimmino, M.A., Azzolini, A., Tobia, F., Pesce, C.M. Spirochetes in the spleen of a patient with chronic Lyme Disease. Am J Clin Pathol 1989; 91:95-97
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14. Musher, D.M. Syphilis, Neurosyphilis, Penicillin, and AIDS. J Infect Dis 1991; 163:1201-1206
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16. Pfister, H.W., Preac-Mursic, V., Wilske, B. Latent Lyme neuroborreliosis: Presence of Borrelia burgdorferi in the CSF without concurrent inflammatory signs. Neurology 1989: 39:1118-20
17. Preac-Mursic, V., Marget, W., Busch, U., Pleterski-Rigler, D., Hagl, S. Kill kinetics of Borrelia burgdorferi and bacterial findings in the relation to the treatment of Lyme borreliosis. Infection 1996; 24(1):11-18
18. Preac-Mursic, V., Wanner, G., Reinhardt, S., Wilske, B., Marget, W. Formation and cultivation of Borrelia burgdorferi spheroplast L-form variants. Infection 1996; 24(3):218-225
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