LYME DISEASE TREATMENT GUIDELINES PIROPLASMOSIS (BABESIOSIS) 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. EHRLICHIOSIS 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) GENERAL INFORMATION 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. TREATMENT INFORMATION 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. ANTIBIOTICS 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. MONITORING THERAPY 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. ANTIBIOTIC CHOICES 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. Amoxicillin Adults: 1g q8h plus probenecid 500mg q8h; doses up to 6 grams daily are often needed Pregnancy: 1g q6h and adjust. Children: 50 mg/kg/day divided into q8h doses. Doxycycline Adults: 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 axetil Oral 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. Tetracycline Adults only and not in pregnancy. 500 mg tid to qid Erythromycin Poor response and not recommended. Azithromycin Adults: 500 to 1200 mg/d. Adolescents; 250 to 500 mg/d add hydroxychloroquine, 200-400 mg/d or amantadine 100-200 mg/d Cannot be used in pregnancy or in younger children. Clarithromycin Adults: 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. Chloramphenicol Not recommended as not proven and potentially toxic. PARENTERAL THERAPY 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 daily Children: 75 mg/kg/day up to 2g/day Cefotaxime Comparable 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. *Doxycycline Requires 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 levels Cannot be used in pregnancy or in younger children. Azithromycin Requires central line as is caustic. Dose: 500 to 1000 mg daily in adolescents and adults. Penicillin G IV penicillin G is minimally effective and not recommended. Benzathine penicillin Surprisingly 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 weekly Adolescents: 300,000 to 1.2 million U weekly. Should not be used in pregnancy. Poorly studied but anecdotally effective: Vancomycin observed 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 Unisyn similar in efficacy to cefotaxime, but often works when cephalosporins have failed. Must be given q6 to q8 hours. Cefuroxime useful but not demonstrably better than ceftriaxone or cefotaxime Ampicillin IV more effective than penicillin G. Must be given q6 hours..