Re: Invincible borrelia?
Posted: Sun 31 Jul 2016 16:39
Duncan: Just as I thought -- you assume too much and don't know what you are talking about.
LymeNet Europe Forum
Any more recent studies undertaken on treatment in patients with PTLDS also require that no objective evidence of infection be found in patients, as outlined in the "proposed" definition for 'PLDS' in the 2006 IDSA Lyme guidelines.Patients were excluded if they had hypersensitivity to the study medications, had previously received parenteral antibiotic therapy for 60 days or more for their current symptoms, had active inflammatory synovitis, had a coexisting condition that could have accounted for their symptoms, or were unable to discontinue medications that could interfere with the evaluation of their response to the treatment regimen (e.g., narcotic analgesics or prednisone in a dose of 10 mg per day or more). Patients with a positive polymerase-chain-reaction (PCR) test for B. burgdorferi DNA in plasma or cerebrospinal fluid at base line were also excluded.
Dealing with these one by one.......Among Lyme activists, these are some of the evolving reasons for treatment failures:
1. Treatment was too short
3. Physical seclusion (e.g., intracellular, which Bb doesn’t do)
4. Toxins (which Bb doesn’t produce)
5. Morphological changes (i.e., round bodies)
6. Antigenic variation of surface proteins
7. Antibiotic resistance (not seen in Bb)
8. Immunosuppression by Bb products
10. Persister cells following antibiotic treatment
Did I forget any? Of course, most bacterial and parasitic pathogens employ one or more of the above strategies, and yet remain susceptible to antimicrobial drugs and adaptive immune responses.
Pharmacodynamics of doxycyclineTwelve months after therapy began, we noted that the serum concentration of doxycycline varied from 0.06 to 12.92 μg/mL. This wide heterogeneity in doxycycline levels was also found in patients with small, asymptomatic, abdominal aortic aneurysms . This marked interpatient variation is difficult to explain, although low serum doxycycline concentrations might occur with the use of some psychotropic drugs and/or alcohol. Moreover, because doxycycline was administered orally, it is also possible that, for some patients, certain foods or drugs, such as antacids, inhibited the bioavailability of doxycycline [12, 13]. Because doxycycline can cause various adverse effects, such as epigastric burning, nausea, vomiting, or hyperpigmentation of the skin after exposure to the sun, lack of compliance of patients may also explain the wide variation in serum doxycycline concentrations. Moreover, one may hypothesize that bioavailability of the drug differs from patient to patient because of weight or clearance of the drug and, thus, that dosage of doxycycline needs to be adjusted for each patient. In our experience, the same standard dose of doxycycline was given to all patients whether they weighed 50 or 110 kg. Interestingly, we found that the mean serum doxycycline concentration in our patients increased during long-term administration of drugs 
It is possible to speculate that patients with higher serum doxycycline concentrations were treated more efficiently. The positive correlation between serum doxycycline concentrations and decreases in C. burnetii phase 1 antibody titers found in this study is in accordance with this hypothesis. A decrease in phase 1 IgG antibody titers <1:800 remains the main predictive criterion of clinical cure . In general, the antibody titers decrease slowly with treatment . However, the kinetics of antibody titer decrease in patients treated with doxycycline may vary, suggesting that some patients should be treated for >18 months to be cured. Moreover, the differences found in the present study show that patients with serum doxycycline concentrations <5 μg/mL had a lessened decreases in antibody titers, suggesting that treatment was not sufficiently effective. One may hypothesize that higher doses of doxycycline would be more effective in the treatment of Q fever endocarditis. Forslin et al.  have demonstrated that, when the oral dose of doxycycline increases, the serum concentration increases accordingly.
Considering the low and erratic levels produced by the usual 200-mg dose of doxycycline, it is possible that higher doses (400 mg) may be justified in the treatment of some cases of Q fever endocarditis, especially for patients who are infected with strains with higher MICs against doxycycline.
Tetracycline and glycylcycline pharmacokinetics and pharmacodynamics represent a relatively under-investigated but interesting area of antimicrobial chemotherapy. Until recently our understanding was poor and little progress had been made until tigecycline entered clinical development. We are still unclear as to the relative importance of serum versus tissue levels in predicting outcomes for the tetracyclines and glycylcyclines but this may be important given their large volumes of distribution. Much work could be done to improve our pharmacokinetic/pharmacodynamic knowledge of these agents, and as tigecycline enters clinical use it is to be hoped that this experience will add to our knowledge in the area.
So, in this case, 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery. Does anyone actually think those are very good results????? Seems to me that they are both highly "inefficient"!!!Findings
Of 118 patients who underwent randomization, 102 completed the study (mean clinical score at baseline 8·5 [SD 4·1]). 4 months after the start of treatment, mean score improvement in the doxycycline group (n=54) was 4·5 (95% CI 3·6 to 5·5) points and that in the ceftriaxone group (n=48) was 4·4 (3·4 to 5·4) points (95% CI for difference between groups −0·9 to 1·1; p=0·84). 26 (48%) patients in the doxycycline group and 16 (33%) in the ceftriaxone group had total recovery (95% CI for difference between groups −4% to 34%; p=0·13). Side-effects possibly related to treatment were reported in 21 (37%) and 26 (46%) patients in these groups, respectively (−28% to 9%; p=0·30). Three patients discontinued ceftriaxone treatment owing to adverse events.
Oral doxycycline is as efficient as intravenous ceftriaxone for the treatment of European adults with Lyme neuroborreliosis.
Intracellular localization of Borrelia burgdorferi within human endothelial cells.The most active agents in vivo are ceftriaxone, clarithromycin, and the tetracyclines (8,119). The basis for the occasional discrepancy between in vitro and in vivo results of antimicrobial susceptibility tests for B. burgdorferi is unknown. The organism may persist intracellularly where antibiotic agents may vary widely in their effectiveness (53, 111, 117). For example, B. burgdorferi has been shown to persist within fibroblasts where they may avoid the antimicrobial effects of ceftriaxone (53). The organism may also interact with host factors to alter its pathogenicity. For example, addition of cytokines to the culture medium enhances the pathogenicity of B. burgdorferi (60, 61).
Although spirochetes are predominantly extracellular pathogens, they invade endothelial layers to pass into tissues, including the brain .
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4. Toxins (which Bb doesn’t produce)In recent years it has been shown that localization to different cellular compartments plays a significant role in coordinating the activation of innate immune pathways. The broad classification of cell surface being distinct from intracellular receptors is no longer sufficient when describing the complexity of signaling pathways. Although “intracellular” is used to broadly imply endosomal localization it is now known that immune signaling can be orchestrated from intracellular vesicles and organelles (Kagan, 2012). In addition, some immune signaling complexes previously thought to be strictly cytoplasmic may in fact be recruited to specific compartments containing ligands. In support of this hypothesis, recent data has shown that caspase-1 can accumulate at the phagosome, suggesting that molecules of the inflammasome are also recruited to phagosomal compartments.
5. Morphological changes (i.e., round bodies)Beneficial versus Destructive Roles of Macrophages in CNS Injury
After entering the CNS injury site macrophages have several functions, some of them shown to be beneficial and others detrimental (Figure 3). A well-known neurotoxic product of activated microglia and macrophages is glutamate, a primary CNS excitatory neurotransmitter, which is released in large quantities after injury and contributes to both neuronal excitotoxicity and secondary degeneration (Bullock et al., 1995; Doble, 1999; Yawata et al., 2008). Moreover, TNF—a cytokine robustly produced after injury—is a major stimulator of microglial production of glutamate and can further potentiate glutamate-induced killing of neurons (Leonoudakis et al., 2008; Olmos and Llado, 2014). Macrophages also contribute to secondary death through the production of nitric oxide synthase (iNOS) and free radicals.
If I have missed any others, I would refer you to "Survival strategies of Borrelia burgdorferi,Abstract
Pathogenic spirochetes cause clinically relevant diseases in humans and animals, such as Lyme disease and leptospirosis. The causative agent of Lyme disease, Borrelia burgdorferi, and the causative agent of leptospirosis, Leptospria interrogans, encounter reactive oxygen species (ROS) during their enzootic cycles. This report demonstrated that physiologically relevant concentrations of pyruvate, a potent H2O2 scavenger, and provided passive protection to B. burgdorferi and L. interrogans against H2O2. When extracellular pyruvate was absent, both spirochetes were sensitive to a low dose of H2O2 (≈0.6 µM per h) generated by glucose oxidase (GOX). Despite encoding a functional catalase, L. interrogans was more sensitive than B. burgdorferi to H2O2 generated by GOX, which may be due to the inherent resistance of B. burgdorferi because of the virtual absence of intracellular iron. In B. burgdorferi, the nucleotide excision repair (NER) and the DNA mismatch repair (MMR) pathways were important for survival during H2O2 challenge since deletion of the uvrB or the mutS genes enhanced its sensitivity to H2O2 killing; however, the presence of pyruvate fully protected ΔuvrB and ΔmutS from H2O2 killing further demonstrating the importance of pyruvate in protection. These findings demonstrated that pyruvate, in addition to its classical role in central carbon metabolism, serves as an important H2O2 scavenger for pathogenic spirochetes. Furthermore, pyruvate reduced ROS generated by human neutrophils in response to the Toll-like receptor 2 (TLR2) agonist zymosan. In addition, pyruvate reduced neutrophil-derived ROS in response to B. burgdorferi, which also activates host expression through TLR2 signaling. Thus, pathogenic spirochetes may exploit the metabolite pyruvate, present in blood and tissues, to survive H2O2 generated by the host antibacterial response generated during infection.
To fight, flee or hide are the imperatives of long-term survival by an infectious microbe. Active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, and incursion into immune privileged sites are examples of survival strategies of persistent pathogens. Here we critically review the supporting evidence for possible stratagems utilized by Borrelia burgdorferi, the spirochete that causes Lyme disease, to persist in the mammalian host.
Is chronic illness in patients with Lyme disease caused by persistent infection? Three decades of basic and clinical research have yet to produce a definitive answer to this question. This review describes known and suspected mechanisms by which spirochetes of the Borrelia genus evade host immune defenses and survive antibiotic challenge. Accumulating evidence indicates that Lyme disease spirochetes are adapted to persist in immune competent hosts, and that they are able to remain infective despite aggressive antibiotic challenge. Advancing understanding of the survival mechanisms of the Lyme disease spirochete carry noteworthy implications for ongoing research and clinical practice.