So, this is someone's dissertation for their doctoral degree. In 2004.
RESPONSES TO ENVIRONMENTAL STRESS TRIGGERS DIFFERENTIAL EXPRESSION
AND CELLULAR DAMAGE IN BORRELIA BURGDORFERI
A Dissertation Submitted to the Graduate Faculty of the University of Georgia in Partial
Fulfillment of the Requirements for the Degree
DOCTOR OF PHISOLOPHY
Should I forgive the typo, on a dissertation?
Well, I will. Just this once, because I am interested in commenting on more of the content inside and think this is a minor oversight. For all I know, there's a minor typo somewhere in my own publications that will come back to haunt me...
First, this section on serological tests for Lyme disease:
"ELISA assays are the most widely available and commonly performed tests, and have replaced IFA which are both labor intensive and subjective in interpretation (54, 77, 176, 192). However, both ELISA and IFA are prone to both false positives and false negatives. False positives generally result from the cross reactivity of B. burgdorferi proteins with proteins of other infectious agents (spirochetal, bacterial, rickettsial, rocky mountain spotted fever, EBV) (54, 77, 176, 192)."
Yes, it's important to know what you're infected with, but in this case, with the exception of EBV - everything there is a bacterial infection requiring antibiotic treatment. So patient history plus serology is more than likely going to nab this one for treatment.
Next, let's look at this section on antibiotic resistance:
"Antibiotic resistance in B. burgdorferi has been investigated in vivo, in vitro, as well as in clinical reports. B. burgdorferi is resistant to aminoglycosides, ciprofloxacin, rifampin, most first generation cephalosporins and some clinical isolates are erythromycin resistant (40, 134, 136, 138, 154, 192, 199, 220, 293)."
See, that's a lot of different drugs to which it's resistant. Note, please, that aminoglycosides are the first drug mentioned there.
And then we look at which antibiotics affect Borrelia burgdorferi:
"In contrast, it is sensitive to penicillin and penicillin derivatives along with some macrolides and second generation cephalosporins (9, 40, 134, 136, 138, 154, 199, 220, 273, 277, 310). To effectively treat B. burgdorferi located in deep tissue, CNS, eye, and within tendons, higher doses are often required (9, 40, 199, 220, 273, 277, 310)."
Okay, I think you could have expected this... this statement is totally within the standard guidelines and on research done to date on these particular antibiotics in vitro.
But then there's this part of the paper:
"Treatment of disseminated and late Lyme disease is much more difficult. The duration of treatment is longer, the response is often slower and treatment failure is higher due to the presence of B. burgdorferi in the CNS, eye, within tendons and deep tissue (192, 306). For patients with neurological complications, intravenous treatment regimens can last many months and includes 2 grams daily of ceftriaxone or 20 million units per day of penicillin G in divided doses (192, 306, 309). "Hm. Okay. This isn't something that's included in the guidelines. Fascinating. This sounds more like the treatment plan that many Lyme disease patients with persisting symptoms have been taking, and getting some flack for from some medical professionals.
So why? If this is good enough for a doctoral dissertation, why isn't it good enough for patients?
Did something happen in 2004 I don't know about? I'm pretty sure the guidelines for treatment at this point did not include this treatment recommendation.
So what are papers 192, 306, and 309?
192. Nocton, J. J., and A. C. Steere. 1995. Lyme disease. Adv. Intern. Med. 40:68-115
306. Wilson, M. E. 2002. Prevention of tick-borne diseases. Tick-Borne Diseases 86:219-238.
309. Wormser, G., R. Nadelman, J. Dattwyler, D. Dennis, E. Shapiro, A. C. Steere, T.
Rush, D. W. Rahn, P. K. Coyle, D. H. Persing, D. Fish, and B. J. Luft. 2000. Practice
guidelines for the treatment of Lyme disease. Clin. Infect. Dis. 31:S1-S14.
Wait. I'm really seeing this?
I need to go look at these papers and have a stiff drink.
Okay, paper 192 is http://www.ncbi.nlm.nih.gov/pubmed/7747659 on PubMed, but there is no option to view an abstract of it, or pay for full text access through PubMed. Advances in Internal Medicine stopped publishing in 2001, so you'll have to get a hard copy elsewhere (Elsevier doesn't have it, either.)
On to the next paper... http://www.ncbi.nlm.nih.gov/pubmed/11982299 which one has to pay for access online, though there is a limited abstract.
And then 309, which is this http://www.ncbi.nlm.nih.gov/pubmed/10982743 Which is the IDSA Lyme disease guidelines for 2000.
And, well, they say about what I expected:
"Late neuroborreliosis affecting the CNS or peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (B-II).
Alternative parenteral therapy may include administration of cefotaxime (2 g iv every 8 h) (B-II) or iv penicillin G (18–24 million units daily, divided into doses given every 4 h for patients with normal renal function) (B-II). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, a 14–28-day course of treatment with ceftriaxone (75–100 mg/kg/d in a single daily iv dose; maximum, 2 g) is recommended (B-II). An alternative is cefotaxime (150–200 mg/kg/d iv, divided into 3 or 4 doses; maximum, 6 g/d) (B-II). Another alternative is iv penicillin G (200,000–400,000 units/kg/d, divided into doses given every 4 h for those with normal renal function; maximum, 18–24 million units/d) (B-II)."
As has been said other places at other times: Why aren't these "reliable objective measures" spelled out in this document?
And how does one determine whether to dose out 2 weeks, 3 weeks, or 4 weeks of ceftriaxone? What's the objective measurement they use to decide between giving a patient 2 weeks versus 4 weeks of IV?
And the next section is...
"Chronic Lyme disease or post–Lyme disease syndrome..."
Yeah, well, let's not even go there right now. Most people reading along already know what that section says...
I suspect that the 2002 Wilson paper is what mentions long term treatment protocols in the dissertation I began writing about - but I'm going to have to look for it elsewhere and see if I can find access available for all my readers. For what it's worth, there is some mention of Sam Donta in the same publication, so perhaps this is where the extended IV protocol in bold came from?
At any rate, getting back to reading the 2000 guidelines (and I have yet to reread the 2006 ones), it appears that there weren't many studies back then on large numbers of patients with neuroborreliosis and late stage Lyme disease including encephalopathy. We're talking 7 patients for this one case series, 48 for another... small numbers.
And amid all that, there are studies like this which were conducted:
"From 1986 through 1991, 48 adult and pediatric patients with Lyme arthritis were randomly assigned to receive either doxycycline (100 mg orally twice a day) or amoxicillin and probenecid (500 mg of each 4 times a day), in each instance for 30 days . Eighteen of the 20 evaluable patients treated with doxycycline and 16 of the 18 evaluable patients who completed the amoxicillin regimen had resolution of arthritis within 13 months after enrollment in the study. However, neuroborreliosis later developed in 5 patients, 4 of whom were treated with the amoxicillin/probenecid regimen.
The concomitant use of probenecid with amoxicillin may be inadvisable, because probenecid may impair penetration of b-lactam antibiotics into brain parenchyma [72, 88].
In retrospect, it was noted that all 5 patients reported subtle distal paresthesias or memory impairment at the time of enrollment. It was concluded that patients with Lyme arthritis can usually be treated successfully with oral antibiotics, but practitioners must be aware of subtle neurological symptoms that may require treatment with iv antibiotics."
Hope that test got a do-over, and they found out what was wrong with those 5 patients and they got the help they needed. Would you have included patients with that background in this study? I wouldn't have. Their symptoms match those of neuroborreliosis. Why weren't they excluded from the study earlier on?
I underlined "subtle neurological symptoms" to make a point, by the way: The panelists are always mentioning that they need objective evidence of infection, yet here they are urging practitioners to be aware of subtle neurological symptoms. Which are subjective evidence.
So... what else can you look at as objective measurements other than serology? Because after the first two weeks of infection, CSF tests don't have good yields. And if your patient already had some antibiotics but they were undertreated, will they produce a robust ab response on tests? Can someone tell me?
Okay, here's another study from the 2000 guidelines:
"Patients with late Lyme disease associated with prominent neurological features also respond to antibiotic therapy. In trials conducted from 1987 through 1989, 27 adult patients with Lyme encephalopathy, polyneuropathy, or both were treated with iv ceftriaxone (2 g/d for 2 weeks) . In addition to clinical signs and symptoms, outcome measures included CSF analyses and neuropsychological tests of memory. Response to therapy was usually gradual and did not begin until several months after treatment. When response was measured 6 months after treatment, 17 patients (63%) had uncomplicated improvement, 6 (22%) had improvement but then relapsed, and 4 (15%) had no change in their condition."
So right there, the study outcome was that 6 of 27 patients improved but relapsed, and 4 just didn't get any better. In this study, 37% of the patients did not have "uncomplicated improvement". (What does that mean, "uncomplicated improvement"? Why not use the words "were cured"? )
No, in this study, 37% did not improve at all as far as we know. Some followup report here would be good.
Moving on to another study from the 2000 guidelines (are you bored yet?):
"In 1987, a case series of 7 patients with Lyme arthritis or chronic neuroborreliosis, who were refractory to oral or iv penicillin therapy were then treated with iv ceftriaxone (2 or 4 g/d for 2 weeks) . All 5 patients who had arthritis responded to ceftriaxone therapy, and for 5 of the 6 patients with limb paresthesias, a reduction in symptoms and improvement of nerve conduction study ﬁndings were noted."
So here, again, "reduction in symptoms" and "improvement of nerve conduction study findings were noted"... but I'm not seeing the phrase, "resolution of symptoms". Is this the most patients can hope for with these conditions?
I'm hoping I missed something, and just need to find the original case series paper and read it. But I see this as 5-6 people out of 7 did not have resolution of their symptoms. How else can I read it?
More from the 2000 guidelines:
"In a follow-up study, 23 patients with Lyme arthritis or late neuroborreliosis were randomly assigned to receive penicillin (20 million units per day iv for 10 days) or ceftriaxone (4 g/d iv for 14 days) . Of the 13 patients who received ceftriaxone none had objective evidence of persistent disease after treatment, although 3 had mild arthralgias and 1 complained of fatigue and memory difﬁculty. In contrast, 5 of the 10 patients who received iv penicillin continued to have fatigue, memory deﬁcit, or recurrent oligoarthritis. For 4 of these 5 patients, symptoms resolved after repeat treatment with ceftriaxone."
Better outcome. Good. I'm glad they figured out ceftriaxone worked better than penicillin.
Still, what happens if ceftriaxone didn't work? Do you try another antibiotic or say, "that's it"? I'm wondering what happened to that fifth person and how they're doing today. And I do wonder what happened to those 3 patients with mild arthalgias and 1 with fatigue and memory problems... were they followed up later on? Did their symptoms resolve or continue? Do they know what caused them? Unanswered questions.
"In a subsequent study, 31 patients with Lyme arthritis or chronic neuroborreliosis were randomly assigned to receive 2 or 4 g/d of ceftriaxone for 2 weeks . After treatment, 3 of the 31 patients had persistent encephalopathy, 2 had persistent neuropathy, and 3 had no diminishment of their arthritis. The overall frequency of persistent symptoms among patients was 13%, which was similar in both treatment groups."
And... and... oh, here's one with more people, and it's randomized:
"In an open-label, randomized, multicenter study, 143 evaluable patients with manifestations of late Lyme disease, primarily Lyme arthritis, were treated with iv ceftriaxone (2 g/d for either 2 or 4 weeks) . In 76% of those treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved after treatment (the P value was not signiﬁcant). The most common persistent symptoms were arthralgia, pain, weakness, malaise, and fatigue."
Okay, so 76% of patients treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved. Now what about the other 24% and 30% respectively? Their symptoms must not have resolved?
Now I can't keep going on with posting all of these, it's getting tedious - there are more examples of the work they were doing in the guidelines and you can check them out for yourself.
Let's review the treatment recommendation for Late stage Lyme neuroborreliosis, shall we?
"Late neuroborreliosis affecting the CNS or the peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (tables 3 and 4) (B-II). Alternative parenteral therapy may include administration of cefotaxime (B-II) or penicillin G (BII). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, treatment with ceftriaxone is recommended (tables 3 and 4) (BII). Cefotaxime or penicillin G administered iv are alternatives (B-II)."
So this is the recommendation for 2000.
I really need to take a look at the guidelines for 2006 and compare them.
But just looking at the 2000 guidelines as their own sort of universe, what is puzzling me is why they are recommending treatment guidelines which don't lead to resolution of symptoms for everyone. At least a greater number of people?
If the reason these other cases failed - and with the bigger studies, we're looking at 24-37% of patients did not have resolution of their symptoms - was because they had this particular human leukocyte antigen–DR4 speciﬁcity and antibody reactivity with OspA of the spirochete... that isn't stated for ANY of these studies.
It is stated for one study they mentioned later on with 16 patients though - but it's the only one mentioned where they tested for this marker. One study. Sixteen people.
I'm hoping when I look at the next set of guidelines, it will be data rich. Right now, I'm just reeling a bit from this, and wondering if the author of the dissertation saw these results and wondered about them, too.
How do you tell the difference between late stage Lyme disease that relapsed or continued versus what they are calling PLDS?
Getting back to the dissertation (remember the dissertation I first began writing about? It's okay if you don't - I almost forgot it myself):
I found this bit of microbiology trivia for those interested:
"Finally, in contrast to most bacteria, B. burgdorferi phospholipids, lipoproteins and glycolipids contain unsaturated fatty acids, such as linoleic, linolenic, and arachidonic acids, which are derived from the host (35, 38, 121, 171)."
The damned things are just parasites, really.
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