Identification of FDA-Approved Drugs with Activity against Stationary Phase Bartonella henselae
Tingting Li, Jie Feng, Shuzhen Xiao, Wanliang Shi, David Sullivan, Ying Zhang  – https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31035691/
Bartonella henselae can cause various infections in humans, ranging from benign and self-limiting diseases to severe and life-threatening diseases as well as persistent infections that are difficult to treat. To develop more effective treatments for persistent Bartonella infections, in this study, we performed a high-throughput screen of an FDA-approved drug library against stationary phase B. henselae using the SYBR Green I/propidium iodide (PI) viability assay. We identified 110 drug candidates that had better activity against stationary phase B. henselae than ciprofloxacin, and among the top 52 drug candidates tested, 41 drugs were confirmed by microscopy to have higher activity than the current frontline antibiotic erythromycin. The identified top drug candidates include pyrvinium pamoate, daptomycin, methylene blue, azole drugs (clotrimazole, miconazole, sulconazole, econazole, oxiconazole, butoconazole, bifonazole), aminoglycosides (gentamicin and streptomycin, amikacin, kanamycin), amifostine (Ethyol), antiviral Lopinavir/ritonavir, colistin, nitroxoline, nitrofurantoin, verteporfin, pentamidine, berberine, aprepitant, olsalazine, clinafloxacin, and clofoctol. Pyrvinium pamoate, daptomycin, methylene blue, clotrimazole, and gentamicin and streptomycin at their respective maximum drug concentration in serum (Cmax) had the capacity to completely eradicate stationary phase B. henselae after 3-day drug exposure in subculture studies. While the currently used drugs for treating bartonellosis, including rifampin, erythromycin, azithromycin, doxycycline, and ciprofloxacin, had very low minimal inhibitory concentration (MIC) against growing B. henselae, they had relatively poor activity against stationary phase B. henselae, except aminoglycosides. The identified FDA-approved agents with activity against stationary phase B. henselae should facilitate development of more effective treatments for persistent Bartonella infections.

Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease.

Daniel J Cameron, Lorraine B. Johnson, and Elizabeth L Maloney. Informa Healthcare, September 2014, Vol. 12, No. 9 , Pages 1103-1135.
ILADS is the first organization to issue guidelines on Lyme disease that were developed in accordance with the IOM standards. The document provides a detailed review of the pertinent medical literature and contains the first set recommendations for Lyme disease based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. This rigorous review format is also used by many other well-respected medical organizations including the World Health Organization (WHO), the American College of Physicians, and the National Institute for Health and Clinical Excellence (NICE) in the UK.

Analysis of Overall Level of Evidence Behind Infectious Diseases Society of America Practice Guidelines
Dong Heun Lee, MD; Ole Vielemeyer, MD
Archives of Internal Medicine. 2011;171(1):18-22. January 10, 2011
We analyzed the strength of recommendation and overall quality of evidence behind 41 Infectious Diseases Society of America (IDSA) guidelines released between January 1994 and May 2010. Individual recommendations were classified based on their strength of recommendation (levels A through C) and quality of evidence (levels I through III). Guidelines not following this format were excluded from further analysis. Evolution of IDSA guidelines was assessed by comparing 5 recently updated guidelines with their earlier versions. In the 41 analyzed guidelines, 4218 individual recommendations were found and tabulated. Fourteen percent of the recommendations were classified as level I, 31% as level II, and 55% as level III evidence. Among class A recommendations (good evidence for support), 23% were level I (> or = 1 randomized controlled trial) and 37% were based on expert opinion only (level III). Updated guidelines expanded the absolute number of individual recommendations substantially. However, few were due to a sizable increase in level I evidence; most additional recommendations had level II and III evidence. More than half of the current recommendations of the IDSA are based on level III evidence only. Until more data from well-designed controlled clinical trials become available, physicians should remain cautious when using current guidelines as the sole source guiding patient care decisions.

The Management of Ixodes scapularis Bites in the Upper Midwest
Elizabeth L. Maloney, MD
Wisconsin Medical Journal, Volume 110, Issue 2 (April 2011), pp. 78-81.
This paper reviews the prevailing antibiotic prophylaxis recommendation for Lyme disease and the evidence supporting it. Given the additional risk of acquiring anaplasmosis from an I scapularis bite in the upper Midwest, this paper proposes an alternative regimen for antibiotic prophylaxis in this region.

Standardized Symptom Measurement of Individuals with Early Lyme Disease Over Time
Kathleen T. Bechtold, Alison W. Rebman, Lauren A. Crowder, Doug Johnson-Greene and John N. Aucott
Archives of Clinical Neuropsychology, online first, November 23, 2016. http://acn.oxfordjournals.org/content/early/2016/11/23/arclin.acw098.abstract
Understanding the Lyme disease (LD) literature is challenging given the lack of consistent methodology and standardized measurement of symptoms and the impact on functioning. This prospective study incorporates well-validated measures to capture the symptom picture of individuals with early LD from time of diagnosis through 6-months post-treatment. Overall, the findings suggest that ideally-treated early LD patients recover well and experience symptom resolution over time, though a small subgroup continue to suffer with symptoms that lead to functional decline. The authors discuss use of standardized instruments for identification of individuals who warrant further clinical follow-up.

Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis.
Department of Medicine, Turku University Central Hospital, Finland. jarmo.oksi@utu.fi
Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK.
A total of 165 patients with disseminated Lyme borreliosis (diagnosed in 1990-94, all seropositive except one culture-positive patient) were followed after antibiotic treatment, and 32 of them were regarded as having a clinically defined treatment failure. Of the 165 patients, 136 were tested by polymerase chain reaction (PCR) during the follow-up. PCR was positive from the plasma of 14 patients 0-30 months after discontinuation of the treatment, and 12 of these patients had a clinical relapse. In addition, Borrelia burgdorferi was cultured from the blood of three patients during the follow-up. All three patients belonged to the group with relapse, and two of them were also PCR positive. This report focuses on the 13 patients with clinical relapse and culture or PCR positivity. Eight of the patients had culture or PCR-proven initial diagnosis, the diagnosis of the remaining five patients was based on positive serology only. All 13 patients were primarily treated for more than 3 months with intravenous and/or oral antibiotics (11 of them received intravenous ceftriaxone, nine for 2 weeks, one for 3 weeks and one for 7 weeks, followed by oral antibiotics). The treatment caused only temporary relief in the symptoms of the patients. All but one of them had negative PCR results immediately after the first treatment. The patients were retreated usually with intravenous ceftriaxone for 4-6 weeks. None of them was PCR positive after the retreatment. The response to retreatment was considered good in nine patients. We conclude that the treatment of Lyme borreliosis with appropriate antibiotics for even more than 3 months may not always eradicate the spirochete. By using PCR, it is possible to avoid unnecessary retreatment of patients with ‘post-Lyme syndrome’ and those with ‘serological scars’ remaining detectable for months or years after infection.

Hide and Seek: How Lyme Disease Spirochetes Overcome Complement Attack
Peter Kraiczy
Frontiers in Immunology, online first September 26, 2016.
Overcoming the first line of the innate immune system is a general hallmark of pathogenic microbes to avoid recognition and to enter the human host. In particular, spirochetes belonging to the Borrelia burgdorferi sensu lato complex have developed various means to counter the immune response and to successfully survive in diverse host environments for a prolonged period of time.

Something to Grapple with: How Wily Lyme Disease Prowls the Body
The sneaky germ uses a mechanism like that of white blood cells to reach vulnerable tissues and hide from antibiotics
By Knvul Sheikh, ScientificAmerican.com, Armonk, New York, August 25, 2016
Lyme disease is an incredibly evasive adversary. No one is entirely sure how the bacterium that causes it spreads so widely throughout the body or why symptoms sometimes persist after the infection has been treated with antibiotics. Now researchers at the University of Toronto may finally have an explanation: The tiny, spiral-shaped bacterium called Borrelia burgdorferi can quickly grapple along the inner surfaces of blood vessels to get to vulnerable tissues or to hiding places where it can hole up beyond the reach of drugs.

Immune escape strategies of Borrelia burgdorferi
Aslam B, Nisar MA, Khurshid M, Farooq Salamat MK.
Future Microbiology, 2017 Oct;12:1219-1237.
B. burgdorferi faces diverse environmental conditions of its vector and host during its life cycle. To circumvent the host immune system is a prominent feature of B. burgdorferi. To date, numerous studies have reported on the various mechanisms used by this pathogen to evade the host defense mechanisms. This current review attempts to consolidate this information to describe the immunological and molecular methods used by B. burgdorferi for its survival.

Molecular testing of serial blood specimens from patients with early Lyme disease during treatment reveals changing co-infection with mixtures of Borrelia burgdorferi genotypes
Mosel MR, Carolan HE, Rebman AW, Castro S, Massire C, Ecker DJ, Soloski MJ, Aucott JN, Eshoo MW.
Antimicrobial Agents and Chemotherapy, online first 2019 Apr 29.
Borrelia burgdorferi is the etiological agent of Lyme disease. In the current study, we used direct detection PCR and electrospray ionization mass spectrometry to monitor and genotype B. burgdorferi from serially collected whole blood specimens from clinically diagnosed early Lyme disease patients before and during 21 days of antibiotic therapy.
B. burgdorferi was detected up to three weeks after the initiation of antibiotic treatment with ratios of co-infecting B. burgdorferi genotypes changing over time.

A Chromosomally Encoded Virulence Factor Protects the Lyme Disease Pathogen against Host-Adaptive Immunity.
Yang X, Coleman AS, Anguita J, Pal U (2009)
PLoS Pathog 5(3): e1000326. Public Library of Science Pathogens
These data identify the existence of a surface-located antigen of B. burgdorferi that helps the pathogen evade host-acquired immune defense and establish persistent infection and disease in mammals.

Protective value of prophylactic antibiotic treatment of tick bite for Lyme disease prevention: An animal model
Joseph Piesman, Andrias Hojgaard
Ticks and Tick-borne Diseases, Volume 3, Issue 3, June 2012, Pages 193–196.
Although the dynamics of antibiotic treatment in mice may differ from humans, and translation of animal studies to patient management must be approached with caution, we believe our results emphasize the point that antibiotic prophylactic treatment of tick bite to prevent Lyme disease is more likely to be efficacious if delivered promptly after potentially infectious ticks are removed from patients. There is only a very narrow window for prophylactic treatment to be effective post tick removal.

Treatment of Erythema Migrans With Doxycycline for 10 Days Versus 15 Days.
Stupica D, Lusa L, Ruzic-Sabljic E, Cerar T, Strle F.
Clinical Infectious Diseases, online before print, 2012 Apr 20.
117 (52%) patients were treated with doxycycline for 15 days and 108 (48%) with doxycycline for 10 days. At 12 months post-enrollment, 85/91 (93.4%) patients in the 15-day group and 79/86 (91.9%) in the 10-day group had complete response.

Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells.
Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K.
Antimicrobial Agents And Chemotherapy, pii: AAC.00864-15. Online first, 2015 May 26.
In this study, we examined the ability of B. burgdorferi to form persisters. Killing of growing cultures of B. burgdorferi with antibiotics used to treat the disease was distinctly biphasic, with a small subpopulation of surviving cells. Upon regrowth, these cells formed a new subpopulation of antibiotic-tolerant cells, indicating that these are persisters rather than resistant mutants. The level of persisters increased sharply as the culture transitioned from exponential to stationary phase. Combinations of antibiotics did not improve killing.

Persister mechanisms in Borrelia burgdorferi: implications for improved intervention
Jie Feng, Wanliang Shi, Shuo Zhang and Ying Zhang
Emerging Microbes & Infections, 4: e51; Published online, August 19, 2015.
Consistent with the persisting organisms not killed by current antibiotics, experiments in various animal models such as mice, dogs and monkeys have shown B. burgdorferi could still be detected after treatment with different Lyme antibiotics though viable organisms could not be cultured. In vitro studies also demonstrated that B. burgdorferi could develop antibiotic tolerant persisters. Although persister mechanisms have been reported in the model organism E. coli, the mechanisms of B. burgdorferi persisters remain unknown.

Doctor says you are cured, but you still feel the pain. Borrelia DNA persistence in Lyme disease
Jorge Cervantes
Microbes and Infection, Volume 19, Issues 9-10, September-October 2017, Pages 459-463.
Lyme disease is a zoonosis caused by infection with Borrelia burgdorferi (Bb). A great amount of research has attempted to elucidate the mechanisms by which Bb causes inflammation and chronic symptomatology in some patients. Patients often seek unconventional treatments that lack scientific evidence, as medical care is unable to effectively explain and treat their illness. Bb-DNA can persist for long periods of time in some individuals, even after antibiotic therapy. Herein, scientific rationale is presented for a new therapeutic approach against remaining bacterial DNA, and/or increasing the ability of human macrophages to remove extracellular Bb DNA.

Review of evidence for immune evasion and persistent infection in Lyme disease
Berndtson K
International Journal of General Medicine, April 2013,
Volume 2013:6, Pages 291-306.
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.

Borrelia burgdorferi Aggrecanase Activity: More Evidence for Persistent Infection in Lyme Disease
Raphael B. Stricker and Lorraine Johnson
Frontiers in Cellular and Infection Microbiology, online before print July 23, 2013.
Lyme disease is the most common tickborne illness in the world today. A recent study describes for the first time an enzyme produced by the spirochetal agent of Lyme disease, Borrelia burgdorferi, that cleaves aggrecan, a proteoglycan found in joints and connective tissue. Discovery of the spirochetal aggrecanase raises many questions about the pathogenesis of Lyme arthritis and lends support to the concept of persistent B. burgdorferi infection in patients with chronic Lyme disease symptoms.

Persistent infection in chronic Lyme disease: does form matter?
Stricker RB and Johnson L
Research Journal of Infectious Diseases 2013, 1:2
Lyme disease remains a controversial illness. The controversy is based on a profound disagreement over the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, and the ability of this persistent infection to cause chronic symptoms in patients who are untreated or undertreated for the initial spirochetal disease. In this article, we summarize evidence from animal models, human studies and in vitro experiments that support persistent spirochetal infection as the cause of chronic Lyme disease. Specifically, the role of cysts and biofilms in this process is outlined, and the need for better treatment options for patients with chronic Lyme disease is defined.

DNA persistence after treatment of Lyme borreliosis
D. Pícha, L. Moravcová, D. Vanousová, J. Hercogová, Z. Blechová
Folia Microbiologica, August 2013
In 124 patients, The frequency of PCR positives was comparable in CSF and urine, and it was lower by approximately 50 % in plasma. Specific DNA was also found in a significant number of patients in later testing periods: 48 patients after treatment, 29 patients after 3 months, and 6 patients after 6 months. The prolonged PCR positivity was not explainable by persistent infection according to the clinical manifestations of the disease. Possible explanations of the problem are discussed.

Sleeper cells: The stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle.
Cabello FC, Godfrey HP, Bugrysheva J, Newman SA.
Environmental Microbiology, online first, 2017 Aug 24.
Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them.

Dynamic Longitudinal Antibody Responses during Borrelia burgdorferi Infection and Antibiotic Treatment of Rhesus Macaques.
Clinical and Vaccine Immunology, online before print, 2012 Jun 20.
Embers ME, Hasenkampf NR, Jacobs MB, Philipp MT.
Infection with B. burgdorferi elicits robust, yet disparate antibody responses in infected individuals. A longitudinal assessment of antibody responses to multiple diagnostic antigens following experimental infection and treatment has not previously been reported. Because the rhesus macaque recapitulates the hallmark signs and disease course of human Lyme disease, we examined the specific antibody responses to multiple antigens of B. burgdorferi following infection of macaques.

Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection.
Embers ME, Barthold SW, Borda JT, Bowers L, Doyle L, et al.
(2012) PLoS ONE 7(1): e29914.
Rhesus macaques were infected with B. burgdorferi and a portion received aggressive antibiotic therapy 4-6 months later. Multiple methods were utilized for detection of residual organisms, including the feeding of lab-reared ticks on monkeys (xenodiagnosis), culture, immunofluorescence and PCR. Antibody responses to the B. burgdorferi-specific C6 diagnostic peptide were measured longitudinally and declined in all treated animals. B. burgdorferi antigen, DNA and RNA were detected in the tissues of treated animals. Finally, small numbers of intact spirochetes were recovered by xenodiagnosis from treated monkeys.

Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Treatment in Rhesus Macaques.
Crossland NA, Alvarez X, Embers ME.
The American Journal of Pathology, online first, 2017 Dec 11.
Rare morphologically intact spirochetes were observed in the brains of two treated Rm, the heart of one treated Rm, and adjacent to a peripheral nerve of an untreated animal. Borrelia antigen staining of probable spirochete cross-sections was also observed in heart, skeletal muscle, and near peripheral nerves of both treated and untreated animals. These findings support the notion that chronic Lyme disease symptoms can be attributable to residual inflammation in and around tissues that harbor a low burden of persistent host-adapted spirochetes and/or residual antigen.

Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding.
Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, Hodzic E.
PLoS One. 2017 Dec 13;12(12):e0189071. (eCollection 2017)
Our results demonstrate host-dependent signs of infection and variation in antibody responses. In addition, we observed evidence of persistent, intact, metabolically-active B. burgdorferi after antibiotic treatment of disseminated infection and showed that persistence may not be reflected by maintenance of specific antibody production by the host.

Xenodiagnosis Using Ixodes scapularis Larval Ticks in Humans
Turk SP, Williams C, Marques A.
Methods in Molecular Biology. 2018;1690:337-346.
Part of the Methods in Molecular Biology book series (MIMB, volume 1690).
Xenodiagnosis is the use of a natural vector to detect the presence of an organism, and xenodiagnosis using Ixodes ticks has long been used by entomologists in Lyme disease research to provide evidence of the host’s infectious status with Borrelia burgdorferi. We developed the methodology and performed the first human research study using uninfected larval Ixodes scapularis ticks to assess evidence of B. burgdorferi infection.

Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy
Linda K. Bockenstedt, David G. Gonzalez, Ann M. Haberman and Alexia A. Belperron
Journal of Clinical Investigation, 2012;122(7): 2652-2660.
This is the first direct demonstration that inflammatory B. burgdorferi components can persist near cartilaginous tissue after treatment for Lyme disease.

Persistence of borrelial DNA in the joints of Borrelia burgdorferi-infected mice after ceftriaxone treatment
Heta Yrjanainen, Jukka Hytonen, Pauliina Hartiala, Jarmo Oksi and Matti K. Viljanen
APMIS, (Acta Pathologica, Microbiologica et Immunologica Scandinavica, official journal of the Scandinavian Societies for Medical Microbiology and Pathology), online in advance of print July 2, 2010.
All samples of ceftriaxone-treated mice were culture negative, whereas all untreated controls were culture positive. Importantly, B. burgdorferi DNA was detected in the joints of 30-100% of the treated mice. In conclusion, these results combined with earlier results suggest that the joint or a tissue adjacent to the joint is the niche of persisting B. burgdorferi in ceftriaxone-treated mice.

Characterization of Biofilm Formation by Borrelia burgdorferi In Vitro.
Sapi E, Bastian SL, Mpoy CM, Scott S, Rattelle A, et al. (2012) PLoS ONE 7(10): e48277.
In summary, we have found substantial evidence that Borrelia burgdorferi is capable of forming biofilm in vitro. Biofilm formation by Borrelia species might play an important role in their survival in diverse environmental conditions by providing refuge to individual cells.

Biofilm formation by Borrelia sensu lato
Arun Timmaraju, Priyanka A.S. Theophilus, Kunthavai Balasubramanian, Shafiq Shakih, David F. Leucke, and Eva Sapi
FEMS Microbiology Letters, online first, 24 July 2015.
Using various histochemistry and microscopy techniques, we show that Borrelia afzelii and Borrelia garinii form biofilms, which resemble biofilms formed by Borrelia burgdorferi sensu stricto. High-resolution atomic force microscopy revealed similarities in the ultra-structural organization of the biofilms form by three Borrelia species.

Adaptive immunity to Anaplasma pathogens and immune dysregulation: Implications for bacterial persistence
Wendy C. Brown
Comparative Immunology, Microbiology and Infectious Diseases, published online before print, January 4, 2012.
Anaplasma phagocytophilum infects neutrophils and causes disease in many mammals, including ruminants, dogs, cats, horses, and humans. Both bacteria cause persistent infection – infected cattle never clear A. marginale and A. phagocytophilum can also cause persistent infection in ruminants and other animals for several years. This review describes correlates of the protective immune response to these two pathogens as well as subversion and dysregulation of the immune response following infection that likely contribute to long-term persistence.

Statistical analysis questions evidence discouraging retreatment, coverage
Published on August 31, 2012 at 9:50 AM
Most doctors treat Lyme disease with antibiotics for two to four weeks after diagnosis, but if symptoms persist after that, medical guidelines recommend against antibiotic retreatment. That recommendation may not be warranted. A newly published statistical review of the four studies upon which those guidelines are based reports flaws in design, analysis, and interpretation that call into question the strength of the evidence against retreatment.

Medical guidance on retreatment of persistent Lyme disease may be flawed
Brown University, Providence, Rhode Island Contact: David Orenstein, 401-863-1862
A new statistical review calls into question studies that have been taken as proof that antibiotic retreatment for chronic Lyme disease is futile. That misunderstanding has led to medical guidance that discourages retreatment and insurance coverage for it. Instead, the authors of the review suggest, the proper reading of the studies and their data is that they prove nothing. “The goal of the paper is to clarify what was actually found from these clinical trials and what could be said and what couldn’t be said,” DeLong said. “A lack of evidence should not be used to deny treatment when the studies have serious flaws.”

Doxycycline-mediated effects on persistent symptoms and systemic cytokine responses post-neuroborreliosis: a randomized, prospective, cross-over study
Johanna Sjowall, Anna Ledel, Jan Ernerudh, Christina Ekerfelt, Pia Forsberg
BMC Infectious Diseases 2012, 12:186 (10 August 2012)
Persistent symptoms after treatment of neuroborreliosis (NB) are well-documented, although the causative mechanisms are mainly unknown. The effect of repeated antibiotic treatment has not been studied in detail. The aim of this study was to determine whether: (1) persistent symptoms improve with doxycycline treatment; (2) doxycycline has an influence on systemic cytokine responses, and; (3) improvement of symptoms could be due to doxycycline-mediated immunomodulation. No doxycycline-mediated improvement of post-treatment symptoms or quality of life was observed. Nor could any doxycycline-mediated changes in systemic cytokine responses be detected. Accordingly, doxycycline does not seem to be the optimal treatment of diverse persistent symptoms post-NB.

Potential Benefits of Retreatment Highlight the Need for Additional Lyme Disease Research
Allison K., DeLong, MS, Barbara, Blossom, BA, Elizabeth Maloney, MD, Steven E. Phillips, MD
The American Journal of Medicine, Volume 127, Issue 2, Pages e9-e10, February 2014.
We are responding to Klempner etal regarding our statistical review of the National Institutes of Health-sponsored antibiotic retreatment trials for Lyme disease. Our primary finding is that the trials did not prove retreatment is ineffective. A basic concept in statistical science regarding randomized controlled trials is that one can only??conclude treatment is ineffective when the treatment effect and confidence interval exclude and are below the minimum clinically important difference. None of the trials showed this.

Sixteenth Edition, Copyright October, 2008
A very important issue is the definition of “Chronic Lyme Disease”. Based on my clinical data and the latest published information, I offer the following definition. To be said to have chronic LB, these three criteria must be present:
1. Illness present for at least one year (this is approximately when immune breakdown attains clinically
significant levels).
2. Have persistent major neurologic involvement (such as encephalitis/encephalopathy, meningitis, etc.)
or active arthritic manifestations (active synovitis).
3. Still have active infection with B. burgdorferi (Bb), regardless of prior antibiotic therapy (if any).

One-year follow-up of tick-borne central nervous system infections in childhood
Engman ML, Lindstrom K, Sallamba M, Hertz C, Sundberg B, Hansson ME, Lindquist L, Orvell C, Lidefelt KJ, Sundin M.
Pediatric Infectious Disease Journal, June 2012, Volume 31, Issue 6, p 570-574.
Children diagnosed with TBE displayed significantly more long-term subjective complaints (ie, fatigue, headache and irritability) compared with the NB and control groups. Significantly higher frequency of disabilities was also detected by the Five-to-Fifteen Questionnaire in the TBE group. Both TBE and NB cause consequences (eg, prolonged convalescence, worries and financial loss) for the families. Markers for genetic susceptibility and brain damage had no prognostic values in this cohort. Pediatric TBE results in long-lasting residual symptoms and neurologic deficits affecting daily life. Vigilance for TBE-related morbidity among pediatricians and long-term clinical follow-up with assessment of cognitive dysfunctions and appropriate interventions seems reasonable for these children.

Resurgence of Persisting Non-Cultivable Borrelia burgdorferi following Antibiotic Treatment in Mice.
Hodzic E, Imai D, Feng S, Barthold SW
PLoS ONE 9(1): e86907. (2014)
Results confirmed previous studies, in which B. burgdorferi could not be cultured from tissues, but low copy numbers of B. burgdorferi flaB DNA were detectable in tissues at 2, 4 and 8 months after completion of treatment, and the rate of PCR-positive tissues appeared to progressively decline over time. However, there was resurgence of spirochete flaB DNA in multiple tissues at 12 months, with flaB DNA copy levels nearly equivalent to those found in saline-treated mice.

The diagnostic spectrum in patients with suspected chronic Lyme neuroborreliosis – the experience from one year of a university hospital’s Lyme neuroborreliosis outpatients clinic.
Djukic M, Schmidt-Samoa C, Nau R, Von Steinbuchel N, Eiffert H, Schmidt H.
European Journal of Neurology, online before print, October 27, 2010.
Conclusion: Patients with persistent symptoms with elevated serum antibodies against BB but without signs of cerebrospinal fluid inflammation require further diagnostic examinations to exclude ongoing infection and to avoid co-infections and other treatable conditions (e.g. autoimmune diseases). One patient with acute LNB, who was treated with ceftriaxone for 3 weeks suffered from LNB with new headaches and persistent symptoms 6 months later. These data should encourage further studies with new experimental parameters.

Antibiotics, Acne, and Staphylococcus aureus Colonization
Matthew Fanelli, MD; Eli Kupperman, BA; Ebbing Lautenbach, MD, MPH; Paul H. Edelstein, MD;
Archives of Dermatology, published online before print, April 11, 2011.
Unlike current dogma about the long-term use of antimicrobial agents, the prolonged use of tetracycline antibiotics commonly used to treat acne lowered the prevalence of colonization by S aureus and did not increase resistance to the tetracycline antibiotics.

Risk factors for a non-favorable outcome after treated European neuroborreliosis
Eikeland R, Mygland A, Herlofson K, Ljostad U.
Acta Neurologica Scandinavica, online before print, 2012 Jun 12.
Delayed treatment start, more symptoms and findings before treatment, and non-complete recovery at 4 months after treatment are possible predictors of a poorer HRQoL and more fatigue 30 months after treated LNB. We did not find age, gender, educational level, involvement of the central nervous system, coexisting diseases, or cerebrospinal fluid findings to be associated with reduced HRQoL or fatigue.

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library
Jie Feng, Wanliang Shi, Shuo Zhang, David Sullivan, Paul Auwaerter and Ying Zhang
Frontiers in Microbiology, 7:743 2016. Online first, May 3, 2016.
Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA) drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI) viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies.

Azithromycin is Equally Effective as Amoxicillin in Children with Solitary Erythema Migrans.
Arnež M, Ružic-Sabljic E.
The Pediatric Infectious Disease Journal, Online first, 2015 Jul 16.
Comparison of azithromycin and amoxicillin for the treatment of children with solitary EM revealed comparable efficacy and adverse effects of treatment.

Minocycline as A Substitute for Doxycycline in Targeted Scenarios: A Systematic Review
Carris NW, Pardo J, Montero J, Shaeer KM.
Open Forum Infectious Diseases. 2015 Nov 25;2(4):ofv178. eCollection 2015.
Doxycycline, a commonly prescribed tetracycline, remains on intermittent shortage. We systematically reviewed the literature to assess minocycline as an alternative to doxycycline in select conditions, given doxycycline’s continued shortage. We identified 19 studies, 10 of which were published before 2000. Thirteen of the studies were prospective, but only 1 of these studies was randomized. Based on the available data, we found minocycline to be a reasonable substitute for doxycycline in the following scenarios: skin and soft-tissue infections and outpatient treatment of community-acquired pneumonia in young, otherwise healthy patients or in patients with macrolide-resistant Mycoplasma pneumoniae, as well as Lyme disease prophylaxis and select rickettsial disease should doxycycline be unavailable.

Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi In Vitro
Feng J, Zhang S, Shi W, Zhang Y.
Antibiotics, 2017 Mar 22;6(1). pii: E10.
Lyme disease is a most common vector-borne disease in the US. Although the majority of Lyme patients can be cured with the standard two- to four-week antibiotic treatment, at least 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs, sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four-drug combinations dapsone + minocycline + cefuroxime + azithromycin and dapsone + minocycline + cefuroxime + rifampin showed the best activity against stationary phase B. burgdorferi in these sulfa drug combinations.

Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi
Written by: Lorraine Johnson, JD, MBA and Executive Director of the California Lyme Disease Association
December 15, 2009
An important study by Dr. Stephen Barthold and Dr. Ben Luft was recently published. The title sounds a bit bleak, but this study is about how the little guy (Borrelia burgdorferi) always wins and survives despite antibiotic treatment – here tigecycline. To my mind, the findings on persistence are much more important than the finding that tigecycline doesn’t do the job. When one antibiotic doesn’t work, you try another, and if that one doesn’t work, well, you try another or you kick it up a notch and start trying combination antibiotics, like they do with tuberculosis. You don’t fold up the tent and go home because active infection requires antibiotic treatment. And, you won’t ever find out which antibiotic or combinations of antibiotic work, until you try them. So, roll up your sleeves, we have some work to do here.

Benefits of repeated IV Antibiotics: A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy
Fallon et al, Neurology, March 25, 2008, vol. 70 no. 13, 992-1003.
Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models.

Benefit of intravenous antibiotic therapy in patients referred for treatment of neurologic Lyme disease
Stricker et al, Int J Gen Med. 2011; 4: 639–646. Published online 2011 September 6.
Prolonged intravenous antibiotic therapy is associated with improved cognition, fatigue, and myalgias in patients referred for treatment of neurologic Lyme disease. Treatment for 25-52 weeks may be necessary to obtain symptomatic improvement in these patients.

A Reappraisal of the U.S. Clinical Trials of Post-Treatment Lyme Disease Syndrome
Brian A. Fallon, Eva Petkova, John G Keilp, Carolyn Barley Britton
Published 2012 in The open neurology journal
DOI: 10.2174/1874205X01206010079
Four federally funded randomized placebo-controlled treatment trials of post-treatment Lyme syndrome in the United States have been conducted. Most international treatment guidelines summarize these trials as having shown no acute or sustained benefit to repeated antibiotic therapy. The goal of this paper is to determine whether this summary con-clusion is supported by the evidence. The methods and results of the 4 U.S. treatment trials are described and their critiques evaluated. 2 of the 4 U.S. treatment trials demonstrated efficacy of IV ceftriaxone on primary and/or secondary outcome measures.

Oral antibiotic treatment and long-term outcomes of Lyme facial nerve palsy.
Kowalski TJ, Berth WL, Mathiason MA, Agger WA.
Infection, online before print April 27, 2011.
Lyme facial nerve palsy patients were treated with oral antibiotics for a median duration of 21 days (range 7-30 days). Only three patients underwent lumbar puncture and each demonstrated lymphocytic pleocytosis. Fourteen of 15 patients with Lyme facial nerve palsy completely regained nerve function. The long-term outcomes were similar between patients with Lyme facial nerve palsy and controls after a median follow-up duration of 4.6 years. Patients with Lyme facial nerve palsy had significantly higher reported rates of fatigue (60%) than controls (27%) (p = 0.019), but similar energy and vitality scores on the SF-36 questionnaire (55.0 vs. 58.4, p = 0.621). SF-36 social functioning domain scores were significantly lower in patients with Lyme facial nerve palsy (77.5) than in controls (88.6) (p = 0.044).

Progression of Lyme disease to Bell’s Palsy despite treatment with doxycycline
Luis A. Marcos, Zengmin Yan
International Journal of Infectious Diseases, online first July 10, 2017
On day #10 of doxycycline, she woke up and noticed that her right face was paralyzed and unable to close the right eye so she went to the local emergency department. The EM was improved from 4 to 2 cm residual rash. Because of her headaches, a lumbar puncture and brain MRI were recommended. Cerebrospinal spinal fluid analysis revealed only 3 WBCs, protein 30.2 g/dL, glucose 62 mg/L, Lyme serology pair CSF fluid O.D. = 0.114 (borderline), serum Lyme serology pair O.D. = 0.409 (reactive), serum IgM western blot was positive (bands present: 23 and 41 kDa), serum IgG western blot was indeterminate (bands: 41,58 and 93 kDa), CRP remained less than 0.1 mg/dL. MRI of brain showed new increased enhancement involving right facial nerve.

Benefit of Courses of Antibiotics Beyond Two Months
Macrolide therapy of chronic Lyme Disease
Donta ST. Med Sci Monit .2003 Nov ;9 (11):PI136-42. PMID : 14586290
235 patients with a multi-symptom complex typical of chronic Lyme disease, ie fatigue, musculoskeletal pain, and neurocognitive dysfunction and with serologic reactivity against B.burgdorferi were treated with a macrolide antibiotic (eg clarithromycin) and hydroxychloroquine. Eighty % of patients had self-reported improvement of 50% or more at the end of 3 months. After 2 months of treatment, 20% of patients felt markedly improved (75–100% of normal); after 3 months of treatment, 45% were markedly improved. Improvement frequently did not begin until after several weeks of therapy. There were no differences among the three macrolide antibiotics used. Patients who had been on hydroxychloroquine or macrolide antibiotic alone had experienced little or no improvement. Compared to patients ill for less than 3 years, the onset of improvement was slower, and the failure rate higher in patients who were ill for longer time periods.

Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases
Kenneth B. Liegner
Antibiotics 2019, 8, 72.
Three patients, each of whom had required intensive open-ended antimicrobial therapy for control of the symptoms of chronic relapsing neurological Lyme disease and relapsing babesiosis, were able to discontinue treatment and remain clinically well for periods of observation of 6–23 months following the completion of a finite course of treatment solely with disulfiram.
One patient relapsed at six months and is being re-treated with disulfiram.

Maternal Lyme borreliosis and pregnancy outcome
Lakos A, Solymosi N.
International Journal of Infectious Diseases, published online 19 November 2009.
Treatment was administered parenterally to 66 (69.5%) women and orally to 19 (20%). Infection remained untreated in 10 (10.5%) pregnancies. Adverse outcomes were seen in 8/66 (12.1%) parentally treated women, 6/19 (31.6%) orally treated women, and 6/10 (60%) untreated women. In comparison to patients treated with antibiotics, untreated women had a significantly higher risk of adverse pregnancy outcome (odds ratio (OR) 7.61, p=0.004). While mothers treated orally had an increased chance (OR 3.35) of having an adverse outcome compared to those treated parenterally, this difference was not statistically significant (p=0.052). Erythema migrans did not resolve by the end of the first antibiotic course in 17 patients. Adverse pregnancy outcome was more frequent among these ‘slow responder’ mothers (OR 2.69), but this was not statistically significant (p=0.1425). Loss of the pregnancy (n=7) and cavernous hemangioma (n=4) were the most prevalent adverse outcomes in our series. The other complications were heterogeneous.

Congenital Babesiosis After Maternal Infection With Borrelia burgdorferi and Babesia microti
Saetre K, Godhwani N, Maria M, Patel D, Wang G, Li KI, Wormser GP, Nolan SM.
Journal of the Pediatric Infectious Diseases Society, online first 2017 Sep 16.
We describe the cases of 2 infants with congenital babesiosis born to mothers with prepartum Lyme disease and subclinical Babesia microti infection. The infants both developed anemia, neutropenia, and thrombocytopenia, and 1 infant required red blood cell transfusion. Both infants recovered with treatment. Additional studies are warranted to define the optimal management strategy for pregnant women with early Lyme disease in geographic areas in which B microti infection is endemic.

Long term antibiotic therapy may be an effective treatment for children co-morbid with Lyme disease and Autism Spectrum Disorder.
Kuhn M, Grave S, Bransfield R, Harris S.
Medical Hypotheses, online before print, February 21, 2012.
The five children tested positive for Lyme disease and their SAP-O score was evaluated before and after 6 months of antibiotic therapy. Each child was prescribed 200 mg of amoxicillin three times per day and three of the five children were prescribed an additional 50 mg of Azithromycin once per day. All of the children’s scores on the SAP-O assessment improved after 6 months of antibiotic therapy. The assessors also reported anecdotal data of improved speech, eye contact, sleep behaviors, and a reduction of repetitive behaviors.

Intravenous Immunoglobulin for the treatment of autoimmune encephalopathy in children with autism
Connery et al.
Translational Psychiatry (2018)8:1-48
DOI 10.1038/s41398-018-0214-7
The identification of brain-targeted autoantibodies in children with autism spectrum disorder (ASD) raises the possibility of autoimmune encephalopathy (AIE). Intravenous immunoglobulin (IVIG) is effective for AIE and for some children with ASD.

Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library
Jie Feng, Megan Weitner, Wanliang Shi, Shuo Zhang, David Sullivan and Ying Zhang
Antibiotics 2015, 4(3), 397-410.
Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved.

Evaluation of in-vitro antibiotic susceptibility of different morphological forms of Borrelia burgdorferi
Sapi E, Kaur N, Anyanwu S, Luecke DF, Datar A, Patel S, Rossi M, Stricker RB
Infection and Drug Resistance, May 2011, Volume 4, pp. 97 – 113.
Doxycycline reduced spirochetal structures ~90% but increased the number of round body forms about twofold. Amoxicillin reduced spirochetal forms by ~85%-90% and round body forms by ~68%, while treatment with metronidazole led to reduction of spirochetal structures by ~90% and round body forms by ~80%. Tigecycline and tinidazole treatment reduced both spirochetal and round body forms by ~80%-90%. When quantitative effects on biofilm-like colonies were evaluated, the five antibiotics reduced formation of these colonies by only 30%-55%. In terms of qualitative effects, only tinidazole reduced viable organisms by ~90%. Following treatment with the other antibiotics, viable organisms were detected in 70%-85% of the biofilm-like colonies. Antibiotics have varying effects on the different morphological forms of B. burgdorferi. Persistence of viable organisms in round body forms and biofilm-like colonies may explain treatment failure and persistent symptoms following antibiotic therapy of Lyme disease.

Inhibitory effects of 19 antiprotozoal drugs and antibiotics on Babesia microti infection in BALB/c mice.
Yao JM, Zhang HB, Liu CS, Tao Y, Yin M.
Journal of Infection in Developing Countries. 2015 Sep 27;9(9):1004-1010.
The results showed that 15 of the 19 drugs had little or no in vivo effect against B. microti. The inhibitory rates of atovaquone and azithromycin were high at all doses, but the microscopy-negative blood of recovered mice was still infectious. Similar to robenidine hydrochloride at 25 and 50 mg/kg, primaquine at 100 mg/kg had a 100% inhibitory rate. Robenidine hydrochloride achieved a 100% inhibitory rate at 100 mg/kg, and the blood of recovered mice did not result in parasitemia in subpassage experiments. Parasite-negative blood from mice treated with antimalarial drugs (clinically used for babesiosis) still caused parasitemia in subpassage experiments. This suggests that these drugs cannot eradicate the parasites.

In vitro susceptibility of the relapsing fever spirochete Borrelia miyamotoi to antimicrobial agents
Koetsveld J, Draga ROP, Wagemakers A, Manger A, Oei A, Visser CE, Hovius JW.
Antimicrobial Agents and Chemotherapy, online first 2017 Jul 3.
We were able to show that both B. miyamotoi strains and B. hermsii demonstrated greater susceptibility to doxycycline and azithromycin, equal susceptibility to ceftriaxone and proved to be resistant to amoxicillin in vitro as compared to the B. burgdorferi s.l. isolates. The MIC and MBC of amoxicillin for B. miyamotoi evaluated by microscopy were 16-32 mg/L and 32-128 mg/L, respectively. Since B. miyamotoi is susceptible to doxycycline, azithromycin and ceftriaxone in vitro, our data suggests that these antibiotics can be used for treatment of HTBRF.

Pathogenicity and treatment of Bartonella infections.
Angelakis E, Raoult D.
International Journal of Antimicrobial Agents. 2014 Jul;44(1):16-25.
To date, no single treatment is effective for all Bartonella-associated diseases. In the absence of systematic reviews, treatment decisions for Bartonella infections are based on case reports that test a limited number of patients. Antibiotics do not significantly affect the cure rate in patients with Bartonella lymphadenopathy. Patients with Bartonella spp. bacteraemia should be treated with gentamicin and doxycycline, but chloramphenicol has been proposed for the treatment of B. bacilliformis bacteraemia. Gentamicin in combination with doxycycline is considered the best treatment regimen for endocarditis, and erythromycin is the first-line antibiotic therapy for the treatment of angioproliferative lesions. Rifampicin or streptomycin can be used to treat verruga peruana.

Successful Treatment of Human Monocytic Ehrlichiosis with Rifampin
Abusaada K, Ajmal S, Hughes L.
Cureus. 2016 Jan 1;8(1):e444.
Currently recommended treatment regimens for human monocytic ehrlichiosis (HME) include doxycycline or tetracycline. Antibiotic susceptibility studies demonstrate that rifampin has in vitro bactericidal activity against Ehrlichia. Case reports have suggested clinical response with rifampin treatment of human granulocytic anaplasmosis (HGA). We report the first case of HME successfully treated with rifampin.

Researchers investigate four promising new treatments for Lyme disease
By Thea Singer, news@Northeastern, Northeastern University, Boston, Massachusetts March 29, 2016
or http://tinyurl.com/zrmvgj8
The ticks that transmit Lyme dis­ease have mul­ti­plied aggres­sively over the past 20 years, and now thrive in half of all coun­ties in the U.S., according to a recent study in the Journal of Med­ical Entomology. So it’s no sur­prise that when North­eastern researchers reported last May how the bac­terium that causes the dis­ease evades antibi­otics, sug­gesting new treat­ments, the media and the gen­eral public took notice.

In vitro evaluation of antibacterial activity of phytochemicals and micronutrients against Borrelia burgdorferi and Borrelia garinii
Goc A, Niedzwiecki A, Rath M.
Journal of Applied Microbiology, online first, 2015 Oct 12.
Little is known about the effects of phytochemicals against Borrelia sp. causing Lyme disease. Current therapeutic approach to this disease is limited to antibiotics. This study examined the anti-borreliaea efficacy of several plant-derived compounds and micronutrients. The most effective antimicrobial compounds against all morphological forms of the two tested Borrelia sp. were baicalein and monolaurin. This might indicate that the presence of fatty acid and phenyl groups is important for comprehensive antibacterial activity.

The anti-borreliae efficacy of phytochemicals and micronutrients: an update
Anna Goc and Matthias Rath
Therapeutic Advances in Infectious Disease, first published on July 4, 2016.
Naturally occurring substances have been used for centuries to fight against various pathogens. They serve as a source for new chemical entities or provide options to already existing therapeutics.

Cooperation of Doxycycline with Phytochemicals and Micronutrients Against Active and Persistent Forms of Borrelia sp.
Goc A, Niedzwiecki A, Rath M.
International Journal of Biological Sciences. 2016 Jul 22;12(9):1093-103. eCollection 2016.
Phytochemicals and micronutrients represent a growing theme in antimicrobial defense; however, little is known about their anti-borreliae effects of reciprocal cooperation with antibiotics. A better understanding of this aspect could advance our knowledge and help improve the efficacy of current approaches towards Borrelia sp. This data revealed the intrinsic anti-borreliae activity of doxycycline with tested phytochemicals and micronutrients indicating that their addition may enhance efficacy of this antibiotic in combating Borrelia sp. Especially the addition of flavones balcalein and luteolin to a doxycycline regimen could be explored further in defining more effective treatments against these bacteria.

Reciprocal cooperation of phytochemicals and micronutrients against typical and atypical forms of Borrelia spp.
Goc A, Niedzwiecki A, Rath M.
Journal of Applied Microbiology, online first 2017 Jun 23.
We tested 28 combinations of phytochemicals such as polyphenols (baicalein, luteolin, rosmarinic acids), fatty acids (monolaurin, cis-2-decenoic acid), and micronutrients (ascorbic acid, cholecalciferol, and iodine). The results showed that the combinations of baicalein with luteolin as well as monolaurin with cis-2-decenoic acid expressed synergistic anti-spirochetal effects. Moreover, baicalein and luteolin, when combined with rosmarinic acid or iodine, produced additive bacteriostatic and bactericidal effects against typical corkscrew motile spirochetes and persistent knob/round-shaped forms, respectively. An additive anti-biofilm effect was noticed between baicalein with luteolin as well as monolaurin with cis-2-decenoic acid. Finally, application of the combination of baicalein with luteolin increased cytoplasmic permeability of Borrelia spp. but did not cause DNA damage.

Treatment-Related Complications in Children Hospitalized With Disseminated Lyme Disease
Chang C, Feemster KA, Coffin S, Handy LK.
Journal of the Pediatric Infectious Diseases Society, 2017 Sep 1;6(3):e152-e154.
We describe here treatment approaches and treatment-related complications in 138 hospitalized children with disseminated Lyme disease.The patients who received parenteral antibiotics had a higher rate of complications than those who received oral therapy (15.4 vs 4.2 per 1000 days of therapy, respectively; P < .05).

No Visible Dental Staining in Children Treated with Doxycycline for Suspected Rocky Mountain Spotted Fever
Suzanne R. Todd, DVM, F. Scott Dahlgren, MSPH, Marc S. Traeger, MD, Eugenio D. Beltrán-Aguilar, DMD, DrPH, Donald W. Marianos, DDS, Charlene Hamilton, MPH, Jennifer H. McQuiston, DVM, Joanna J. Regan, MD
The Journal of Pediatrics, May 2015;166:1246-51.
Fifty-eight children who received an average of 1.8 courses of doxycycline before 8 years of age and who now had exposed permanent teeth erupted were compared with 213 children who had never received doxycycline. No tetracycline-like staining was observed in any of the exposed children’s teeth.

Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-like Microcolony B. burgdorferi Persisters Which Are Sterilized by Daptomycin/Doxycycline/Cefuroxime Drug Combination without Pulse Dosing
Feng Jie, Zhang Shuo, Shi Wanliang, Zhang Ying
Frontiers in Microbiology, online first 19 October 2016.
Although the majority of Lyme disease patients can be cured, at least 10-20% of the patients continue to suffer from persisting symptoms such as fatigue, muscular and joint pain, and neurologic impairment after standard 2-4 week antibiotic treatment. While the causes for this post-treatment Lyme disease symptoms are unclear, one possibility is due to B. burgdorferi persisters that are not effectively killed by current antibiotics such as doxycycline or amoxicillin used to treat Lyme disease.

Vancomycin Reduces Cell Wall Stiffness and Slows Swim Speed of the Lyme Disease Bacterium
Harman MW, Hamby AE, Boltyanskiy R, Belperron AA, Bockenstedt LK, Kress H, Dufresne ER, Wolgemuth CW.
Biophysical Journal. 2017 Feb 28;112(4):746-754.
We found that in the presence of vancomycin, cell wall stiffness gradually decreased over time, with a 40% reduction in the bending stiffness after 36 h. Under the same conditions, the swimming speed of wild-type B. burgdorferi slowed by ~15%, with only marginal changes to cell morphology. Interestingly, our biophysical model for the swimming dynamics of B. burgdorferi suggested that cell speed should increase with decreasing cell stiffness.

Effects of intravenous ketamine in a patient with post-treatment Lyme disease syndrome
Hanna AF, Abraham B, Hanna A, Smith AJ.
International Medical Case Reports Journal, 2017 Aug 18;10:305-308. eCollection 2017.
Post-treatment Lyme disease syndrome (PTLDS) is a pain disorder for which there remains no gold standard treatment option. Here, we report a case of PTLDS in a female patient whose pain was refractory to treatment options such as radiofrequency ablation, vitamin infusion therapy, opioid analgesics, and other pharmacotherapies.The patient commenced an experimental intravenous ketamine infusion therapy at the Florida Spine Institute (Clearwater, FL, USA) and achieved relief from her chronic pain, an improved quality of life, reduced depression and suicidal ideation, and reduced opioid consumption.

Novel Diamidines with Activity against Babesia divergens In Vitro and Babesia microti In Vivo.
Nehrbass-Stuedli A, Boykin D, Tidwell RR, Brun R.
Antibacterial Agents and Chemotherapy, online before print, ay 2, 2011.
Dicationic diamidines, such as diminazene and pentamidine, are well-studied chemotherapeutic agents with significant activity against parasitic diseases. The in vitro activity of novel diamidine compounds was investigated against the Babesia divergens strains 1903B and 4201. The most potent compound, a diphenyl furan, had an IC(50) of 1.5 ng/ml.

Cat-scratch disease: a wide spectrum of clinical pictures
Katarzyna Mazur-Melewska, Anna Mania, Pawel Kemnitz, Magdalena Figlerowicz, and Wojciech Sluzewski
Advances in Dermatology and Allergology/Postepy Dermatologii i Alergologii, 2015 Jun; 32(3): 216-220.
The aim of this review is to present an emerging zoonotic disease caused by Bartonella henselae. The wide spectrum of diseases connected with these bacteria varies from asymptomatic cases, to skin inflammation, fever of unknown origin, lymphadenopathy, eye disorders, encephalitis and endocarditis. If an antibiotic is chosen, however, azithromycin has been shown to speed recovery.

Neurological Manifestations of Bartonellosis in Immunocompetent
Patients: A Composite of Reports from 2005–2012
E. B. Breitschwerdt,1 S. Sontakke,1,2 and S. Hopkins3
Received 8 October 2012; Revised 2 November 2012; Accepted 4 November 2012
For severe or persistent neurobartonellosis, there is minimal evidence upon which to base treatment decisions. Expert opinion often recommends a combination of doxycycline plus rifampin for 10 to 14 days [8,62]. Based upon in vitro testing, numerous antibiotics appear to be effective for the treatment of Bartonella infections [8]. However, as Bartonella spp. induce both intracellular, as well as extracellular infection, in vitro test results can identify antibiotics that are not effective and can also be used to select antibiotics that should be tested in clinical trials of in vivo efficacy. Doxycycline, erythromycin, and rifampin are the most frequently recommended antibiotics for treating Bartonella spp. infection in people, but clinical improvement has been reported following the use of penicillin, gentamicin, ceftriaxone, ciprofloxacin, and azithromycin.

The Jarisch–Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis
Thomas Butler
The American Journal of Tropical Medicine and Hygiene, Volume 96, Issue 1, Jan 2017, p. 46-52.
Within 24 hours after antibiotic treatment of the spirochetal infections syphilis, Lyme disease, leptospirosis, and relapsing fever (RF), patients experience shaking chills, a rise in temperature, and intensification of skin rashes known as the Jarisch–Herxheimer reaction (JHR) with symptoms resolving a few hours later. Case reports indicate that the JHR can also include uterine contractions in pregnancy, worsening liver and renal function, acute respiratory distress syndrome, myocardial injury, hypotension, meningitis, alterations in consciousness, seizures, and strokes. Experimental evidence indicates it is caused by nonendotoxin pyrogen and spirochetal lipoproteins.

Controversies in Persistent (Chronic) Lyme Disease
Maloney EL.
Journal of Infusion Nursing, online first, 2016 Oct 13.
The Centers for Disease Control and Prevention estimates that more than 300 000 new cases of Lyme disease occur each year in the United States and that 10% to 20% of these patients will remain symptomatic despite receiving appropriate antibiotic therapy.Many elements of the disease are poorly understood and have generated considerable controversy.This paper discusses the medical controversies related to posttreatment manifestations and their potential impact on infusion nurses.

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways
GB Rogers, DJ Keating, RL Young M-L Wong, J Licinio and S Wesselingh
The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association betweenenteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies. Molecular Psychiatry (2016) 21, 738–748; doi:10.1038/mp.2016.50; published online 19 April 2016

Steroid use in Lyme disease-associated facial palsy is associated with worse long-term outcomes
Jowett, N., Gaudin, R. A., Banks, C. A. and Hadlock, T. A.
The Laryngoscope, online first September 6, 2016.
The purpose of this study was to determine whether differences in long-term facial function outcomes following acute Lyme disease-associated facial palsy (LDFP) exist between patients who received antibiotic monotherapy (MT); dual therapy (DT) with antibiotics and corticosteroids; and triple therapy (TT) with antibiotics, corticosteroids, and antivirals. An association between corticosteroid use in acute LDFP and worse long-term facial function outcomes has been demonstrated. Care should be taken in differentiating viral or idiopathic facial palsy (e.g., Bell palsy) from LDFP.

Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?
Richard I. Horowitz and Phyllis R. Freeman
JSM Arthritis, online first, July 16, 2016.
PTLDS/chronic Lyme disease may cause disabling symptoms with associated overlapping autoimmune manifestations, with few clinically effective published treatment options. We recently reported on the successful use of a mycobacterium drug, Dapsone, for those with PTLDS. We now report on the novel use of another mycobacterium drug, pyrazinamide, (PZA), in relieving resistant symptomatology secondary to Lyme disease and associated co-infections, while decreasing autoimmune manifestations with Behçet’s syndrome.

Intrathecal Th17- and B cell-associated cytokine and chemokine responses in relation to clinical outcome in Lyme neuroborreliosis: a large retrospective study.
Gyllemark P, Forsberg P, Ernerudh J, Henningsson AJ.
Journal of Neuroinflammation, 2017 Feb 1;14(1):27.
B cell immunity, including the chemokine CXCL13, has an established role in Lyme neuroborreliosis, and also, T helper (Th) 17 immunity, including IL-17A, has recently been implicated. By using a set of markers in addition to CXCL13 and IL-17A, we confirm that B cell- and Th17-associated immune responses are involved in Lyme neuroborreliosis pathogenesis with different patterns in subgroups. Furthermore, IL-17A, APRIL and BAFF may be associated with time to recovery after treatment.

Persistence of babesiosis for >2 years in a patient on rituximab for rheumatoid arthritis
Raffalli J, Wormser GP
Diagnostic Microbiology & Infectious Disease, online first, 2016 Feb 21.
We report a patient who was being treated with rituximab for rheumatoid arthritis who developed Babesia microti infection that persisted for 26 months despite prolonged anti-babesia drug therapy. The explanation for the persistence was likely to have been the long-term immunocompromising effects of rituximab, as evidenced by seronegativity for B. microti antibodies that lasted for more than 1 year after onset of infection.

A longitudinal study of Babesia microti infection in seropositive blood donors.
Leiby DA, Johnson ST, Won KY, Nace EK, Slemenda SB, Pieniazek NJ, Cable RG, Herwaldt BL.
Transfusion, online before print, 2014 Mar 28.
Three of nine persons who had more than one specimen with evidence of parasitemia had nonconsecutive positives. Several enrollees likely had been infected at least 1 year when their last positive specimen was collected. The final three specimens for seven persons tested negative by all study methods, including IFA. Seropositive blood donors can have protracted low-level parasitemia that is variably and intermittently detected by parasitologic and molecular methods.

The effect of artesunate on short-term memory in Lyme borreliosis
Puri BK, Hakkarainen-Smith JS, Monro JA.
Medical Hypotheses, 2017 Aug; 105: 4-5.
Lyme borreliosis is associated with memory deficits. While this may be related to cerebral infection by Borrelia bacteria, it may also be caused by concomitant co-infection by Babesia protozoa. The anti-malarial artemisinin-derivative artesunate has been shown to be effective against a number of Babesia species and to have efficacy against human cerebral malaria.

Treatment outcomes of human bartonellosis: a systematic review and meta-analysis
Prutsky G, Domecq JP, Mori L, Bebko S, Matzumura M, Sabbouni A, Shahrour A, Erwin PJ, Boyce TG, Montori VM, Malaga G, Murad MH.
International Journal of Infectious Diseases, online before print, 2013 Apr 17.
We found two randomized and seven non-randomized studies at high risk of bias. For cat scratch disease, antibiotics did not significantly affect the cure rate or time to achieve cure. In chronic bacteremia, gentamicin and doxycycline significantly increased the resolution rate. The recommended treatment was not better than other regimens for infectious endocarditis and bacillary angiomatosis.

Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review
R. Dersch, H. Sommer, S. Rauer, J. J. Meerpohl
Journal of Neurology, online first, 12 October 2015.
Controversy exists about residual symptoms after pharmacological treatment of Lyme neuroborreliosis. Reports of disabling long-term sequels lead to concerns in patients and health care providers. Cranial neuropathy, pain, paresis, cognitive disturbances, headache, and fatigue were statistically significantly lower in studies using the “probable/definite” case definition. LNB patients may experience residual symptoms after treatment with a prevalence of approximately 28%. The prevalence and spectrum of residual symptoms differ according to the applied case definition. Symptoms like fatigue are not reported in studies using the “probable/definite” case definition.

Vitamin C Protects Chondrocytes against Monosodium Iodoacetate-Induced Osteoarthritis by Multiple Pathways
Pu-Rong Chiu, Yu-Chen Hu, Tzu-Ching Huang, Bau-Shan Hsieh, Jou-Pei Yeh, Hsiao-Ling Cheng, Li-Wen Huang, and Kee-Lung Chang, David Arráez-Román, Academic Editor and Ana Maria Gómez Caravaca, Academic Editor
Int J Mol Sci. 2017 Jan; 18(1): 38.
Published online 2016 Dec 27. doi: 10.3390/ijms18010038 PMCID: PMC5297673
Osteoarthritis (OA) is the most prevalent joint disease. Dietary intake of vitamin C relates to a reduction in cartilage loss and OA. This study examined the efficacy of vitamin C to prevent OA with the in vitro chondrosarcoma cell line (SW1353) and the in vivo monosodium iodoacetate (MIA)-induced OA rat. Results demonstrated that, in SW1353 cells, treatment with 5 μM MIA inhibited cell growth and increased oxidative stress, apoptosis, and proteoglycan loss. In addition, the expression levels of the pro-inflammatory cytokines IL-6, IL-17A, and TNF-α and matrix metalloproteinases (MMPs) MMP-1, MMP-3, and MMP-13 were increased. All of these MIA-induced changes could be prevented with treatment of 100 μM vitamin C. In an animal model, intra-articular injection of MIA-induced cartilage degradation resembled the pathological changes of OA, and treatment of vitamin C could lessen these changes. Unexpectedly, vitamin C’s effects did not strengthen with the increasing dosage, while the 100 mg/kg dosage was more efficient than the 200 or 300 mg/kg dosages. Vitamin C possessed multiple capacities for prevention of OA progress, including a decrease in apoptosis and in the expression of pro-inflammatory cytokines and MMPs in addition to the well-known antioxidation.

Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function
R Sinha1, I Sinha, A Calcagnotto, N Trushin, J S Haley, T D Schell and J P Richie Jr
European Journal of Clinical Nutrition advance online publication 30 August 2017
GSH levels were elevated after 1 week with maximum increases of 40% in whole blood, 25% in erythrocytes, 28% in plasma and 100% in PBMCs occurring after 2 weeks (P<0.05). GSH increases were accompanied by reductions in oxidative stress biomarkers, including decreases of 35% in plasma 8-isoprostane and 20% in oxidized:reduced GSH ratios (P<0.05). Enhancements in immune function markers were observed with liposomal GSH administration including Natural killer (NK) cell cytotoxicity, which was elevated by up to 400% by 2 weeks (P<0.05), and lymphocyte proliferation, which was elevated by up to 60% after 2 weeks (P<0.05). Collectively, these preliminary findings support the effectiveness of daily liposomal GSH administration at elevating stores of GSH and impacting the immune function and levels of oxidative stress.

Does phytoestrogen supplementation improve cognition in humans? A systematic review.
Ann N Y Acad Sci. 2017 Sep;1403(1):150-163. doi: 10.1111/nyas.13459.
Thaung Zaw JJ1, Howe PRC1,2, Wong RHX1.
Recent evidence indicates that resveratrol, a phytoestrogen, can improve cognitive function in postmenopausal women by enhancing cerebral vasodilator responsiveness. We examine the effects of phytoestrogen supplementation on cognition and compare resveratrol with other phytoestrogens.

Hyperbaric oxygen therapy as an effective adjunctive treatment for chronic Lyme disease.
Huang CY, Chen YW, Kao TH, Kao HK, Lee YC, Cheng JC, Wang JH.
Journal of the Chinese Medical Association, pii: S1726-4901(14)00042-2. Online before print, 2014 Apr 9.
The mechanisms of CLD remain unclear and the symptoms related to CLD are difficult to manage. Hyperbaric oxygen therapy (HBOT) was applied in CLD therapy in the 1990s. However, reported information regarding the effectiveness of HBOT for CLD is still limited. Here, we present a patient with CLD who was successfully treated with HBOT.

Treatment of Lyme neuroborreliosis with plasmapheresis
Çelik, T., Çelik, Ü., Kömür, M., Tolunay, O., Dönmezer, Ç. and Yildizdas, D.
Journal of Clinical Apheresis, online before print, September 10, 2015.
The effect of plasmapheresis in pediatric neuroborreliosis has not been documented before. This study highlights that plasmapheresis could be a useful alternative for pediatric neuroborreliosis cases.

Inhibitory effect of allicin on the growth of Babesia and Theileria equi parasites.
Salama AA, Aboulaila M, Terkawi MA, Mousa A, El-Sify A, Allaam M, Zaghawa A, Yokoyama N, Igarashi I.
Parasitology Research, online before print, 2013 Oct 31.
Allicin is an active ingredient of garlic that has antibacterial, antifungal, antiviral, and antiprotozoal activity. These results indicate that allicin might be beneficial for the treatment of babesiosis, particularly when used in combination with diminazene aceturate.

Selective Essential Oils from Spice or Culinary Herbs Have High Activity against Stationary Phase and Biofilm Borrelia burgdorferi
Feng J, Zhang S, Shi W, Zubcevik N, Miklossy J, Zhang Y.
Frontiers in Medicine, 2017 Oct 11;4:169. eCollection 2017.
Although the majority of patients with acute Lyme disease can be cured with the standard 2-4 week antibiotic treatment, about 10-20% of patients continue suffering from chronic symptoms described as posttreatment Lyme disease syndrome. While the cause for this is debated, one possibility is that persister bacteria are not killed by the current Lyme antibiotics and remain active in the system. It has been reported that essential oils have antimicrobial activities and some have been used by patients with persisting Lyme disease symptoms. However, the activity of essential oils against the causative agent Borrelia burgdorferi (B. burgdorferi) has not been well studied. Here, we evaluated the activity of 34 essential oils against B. burgdorferi stationary phase culture as a model for persister bacteria. We found that not all essential oils had activity against the B. burgdorferi stationary phase culture, with top five essential oils (oregano, cinnamon bark, clove bud, citronella, and wintergreen) at a low concentration of 0.25% showing high anti-persister activity that is more active than the known persister drug daptomycin. Interestingly, some highly active essential oils were found to have excellent anti-biofilm ability as shown by their ability to dissolve the aggregated biofilm-like structures. The top three hits, oregano, cinnamon bark, and clove bud completely eradicated all viable cells without any regrowth in subculture in fresh medium, whereas but not citronella and wintergreen did not have this effect. Carvacrol was found to be the most active ingredient of oregano oil showing excellent activity against B. burgdorferi stationary phase cells, while other ingredients of oregano oil p-cymene and α-terpinene had no apparent activity.

In Vitro Effectiveness of Samento and Banderol Herbal Extracts on the Different Morphological Forms of Borrelia Burgdorferi
by Akshita Datar, Navroop Kaur, Seema Patel, David F. Luecke, and Eva Sapi, PhD
Lyme Disease Research Group, University of New Haven
Townsend Letter for Doctors & Patients, July 2010
Our results demonstrated that both herbal agents, but not doxycycline, had very significant effects on all forms of B. burgdorferi, especially when used in combination, suggesting that herbal agents could provide an effective therapeutic approach for Lyme disease patients.

Effectiveness of Stevia rebaudiana whole leaf extract against the various morphological forms of Borrelia burgdorferi in vitro
P. A. S. Theophilus, M. J. Victoria, K. M. Socarras, K. R. Filush, K. Gupta, D. F. Luecke, E. Sapi
European Journal of Microbiology and Immunology, online first, November 12, 2015.
Lyme disease is a tick-borne multisystemic disease caused by Borrelia burgdorferi. Administering antibiotics is the primary treatment for this disease; however, relapse often occurs when antibiotic treatment is discontinued. The reason for relapse remains unknown, but recent studies suggested the possibilities of the presence of antibiotic resistant Borrelia persister cells and biofilms. In this study, we evaluated the effectiveness of whole leaf Stevia extract against B. burgdorferi spirochetes, persisters, and biofilm forms in vitro. The susceptibility of the different forms was evaluated by various quantitative techniques in addition to different microscopy methods. The effectiveness of Stevia was compared to doxycycline, cefoperazone, daptomycin, and their combinations. Our results demonstrated that Stevia had significant effect in eliminating B. burgdorferi spirochetes and persisters.

Polyphenolic Extract from Maple Syrup Potentiates Antibiotic Susceptibility and Reduces Biofilm Formation of Pathogenic Bacteria.
Maisuria VB, Hosseinidoust Z, Tufenkji N.
Applied & Environmental Microbiology, pii: AEM.00239-15. Online first, 2015 Mar 27.
Phenolic compounds are believed to be promising candidates as complementary therapeutics. Maple syrup, prepared by concentrating the sap from the North American maple tree, is a rich source of natural and process-derived phenolic compounds.

Antimicrobial Activity of Bee Venom and Melittin against Borrelia burgdorferi
Socarras, K.M.; Theophilus, P.A.S.; Torres, J.P.; Gupta, K.; Sapi, E.
Antibiotics 2017; 6(4):31. Online first, November 29, 2017.
Our findings showed that both bee venom and melittin had significant effects on all the tested forms of B. burgdorferi. In contrast, the control antibiotics when used individually or even in combinations had limited effects on the attached biofilm form.  These findings strongly suggest that whole bee venom or melittin could be effective antimicrobial agents for B. burgdorferi; however, further research is necessary to evaluate their effectiveness in vivo, as well as their safe and effective delivery method for their therapeutic use.

Apheresis for babesiosis: Therapeutic parasite reduction or removal of harmful toxins or both?
Saifee NH, Krause PJ, Wu Y.
Journal of Clinical Apheresis, online first, 2015 Oct 20.
Babesiosis is a potentially life-threatening illness caused by intraerythrocytic protozoan parasites of the genus Babesia that are transmitted most commonly by Ixodes ticks, and rarely from blood transfusion or congenitally. Clinical presentations of babesiosis include asymptomatic infection, mild to moderate disease, or severe disease. Antibiotics such as atovaquone plus azithromycin or clindamycin and quinine can be used effectively to treat this disease in most cases, however in high risk populations, the mortality rate can be as high as 20% despite therapy.

Massage therapy for lyme disease symptoms: a prospective case study.
Thomason MJ, Moyer CA.
International Journal of Therapeutic Massage and Bodywork. 2012;5(4):9-14. Online before print, 2012 Dec 19.
LD symptoms decreased during treatment periods and increased during nontreatment periods. Positive affect was increased at every MT session. MT is a promising treatment for the symptoms pain, fatigue, and impaired concentration associated with LD.

A case report of human granulocytic anaplasmosis (ehrlichiosis) in pregnancy and a literature review of tick-borne diseases in the United States during pregnancy.
Qasba N, Shamshirsaz AA, Feder HM, Campbell WA, Egan JF, Shamshirsaz AA.
Obstetrical & Gynecological Survey, 2011 Dec;66(12):788-96.
There is paucity of data regarding tick-borne diseases during pregnancy. Here, we report a case of human granulocytic anaplasmosis during pregnancy with successful treatment and a favorable neonatal outcome. We also review diagnosis, treatment, and outcomes of published case reports from 1983 to 2010 of human granulocytic anaplasmosis, Lyme disease, babesiosis, and human monocytic ehrlichiosis in the United States.

Medical Biomagnetism tested in 265 patients at clinic in Spain on May 2009.
Centro Médico Hilu ( Hilu Stem Center) and Biomagnetic Pair Therapy:
Sra. Julia Anuna, the therapists Juan Carlos Albendea from Madrid and Agueda from Pamplona, Dra Mary Staggs.
According to Dr. Isaac Goiz’s theory, the fundamental elements on which the bio magnetic pair treatment is based are the following: the pH of the organism, the role played by the micro organisms in the production of illness, the presence of a series of energy points in the body related between one another (like the two poles of a battery), the use of magnetic fields produced by magnets with a power greater than 1.000 gauss, creating a magnetic current, which pushes the positive poles against the negative ones, the pH is neutralised and thus instantaneously eliminating all the micro organisms which produce disease.

A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis.
Trock DH , Bollet AJ , Dyer RH Jr , Fielding LP , Miner WK , Markoll R
The Journal of Rheumatology [01 Mar 1993, 20(3):456-460]
Further evaluation of pulsed electromagnetic fields (PEMF), which have been observed to produce numerous biological effects, and have been used to treat delayed union fractures for over a decade. The decreased pain and improved functional performance of treated patients suggests that this configuration of PEMF has potential as an effective method of improving symptoms in patients with OA. This method warrants further clinical investigation.

Outcome of facial palsy from Lyme disease in prospectively followed patients who had received corticosteroids
Wormser GP, McKenna D, Scavarda C, Karmen C.
Diagnostic Microbiology & Infectious Disease, online first 2018 Apr 4.
Although a short course of corticosteroid therapy has been shown to improve the outcome of idiopathic facial nerve palsy (Bell’s palsy), it is unclear whether corticosteroids, in addition to antibiotic therapy, are beneficial, are harmful, or have no impact on the outcome of facial palsy from Lyme disease (LDFP).
From 2011 through 2016, 14 patients with LDFP were enrolled into a prospective study to determine the outcome of Lyme disease over the ensuing 12?months. Eleven (78.6%) had received corticosteroids in addition to oral antibiotics and entered the study within 24? days after onset of the LDFP (median 14? days, range 2–24? days).
Overall, 6 of the corticosteroid-treated patients (54.5%, 95% C.I.: 28.0% to 78.7%) had evidence of residual dysfunction of the facial nerve at the last evaluation, which occurred at a mean of 13.1? months after the baseline visit (range 9.6–19.6? months).
In conclusion, although corticosteroids are frequently prescribed for LDFP, the efficacy of this therapy has not been established. Like another recent report, our study raises concern about the safety of adjunctive corticosteroid treatment for LDFP. A well-designed, prospective clinical trial is needed to determine the risk-to-benefit ratio of corticosteroid therapy for LDFP.

Persistent Borrelia Infection in Patients with Ongoing Symptoms of Lyme Disease
Middelveen MJ, Sapi E, Burke J, Filush KR, Franco A, Fesler MC, Stricker RB.
Healthcare 2018, 6(2), 33. Online first April 14, 2018.
Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borrelia burgdorferi by three distinct polymerase chain reaction (PCR)-based approaches. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods.
Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates. The optimal treatment for persistent Borrelia infection remains to be determined.

UMD Researcher Uncovers Protein Used to Outsmart the Human Immune System
Findings have major implications for tick-borne diseases like Lyme disease
Press Release By Samantha Watters
University of Maryland, College of Agriculture & Natural Resources
College Park, Maryland
April 2, 2018
or http://agnr.umd.edu/node/2449
A UMD researcher has uncovered a mechanism by which the bacteria that causes Lyme disease persists in the body and fights your early, innate immune responses. Dr. Utpal Pal, Professor in Veterinary Medicine, has been studying the Borrelia burgdorferi bacteria throughout his twelve years with UMD, and his work has already produced the protein marker used to identify this bacterial infection in the body. Now, Dr. Pal and his team have isolated a protein produced by the bacteria that disables one of the body’s first immune responses, giving insight into mechanisms that are largely not understood. He has also observed a never-before-seen phenomena demonstrating that even without this protein and with the immune system responding perfectly, the bacteria can spring back in the body weeks later. Understanding this bacteria, which is among only a few pathogens that can actually persist in the body for long periods of time, has major implications for the treatment of tick-borne diseases like Lyme disease, which is an increasingly chronic and consistently prevalent public health issue.
“Most people don’t realize that they actually are walking around with more bacterial cells in their bodies than their own cells, so we are really bags of bacteria,” explains Pal. “Most are good, but the second your body detects something that is a pathogen and can cause disease, your immune system starts to work.” The body sends a first, nonspecific wave of attack to kill the bacteria detected that doesn’t belong. This happens within a few hours to days. If this doesn’t work, it takes seven to ten days to learn about the enemy and send a large second wave of reinforcements to kill what is left. “Lyme disease is actually caused by your immune system,” explains Pal. “This bacteria wins the first battle, and your body overreacts so much that it causes intense inflammation in all the joints and areas that the bacteria spreads by sending so many reinforcements to kill it. Borrelia is then killed, but the inflammation remains and causes many of your symptoms for Lyme disease. That is why killing Borrelia in the first wave of immunity is so important.”
The Centers for Disease Control and Prevention (CDC) estimate about 300,000 cases of Lyme disease annually in the United States. However, these cases are largely underestimated and reported due to the attention given to mosquito-transmitted diseases like malaria. “The majority of all vector-borne diseases in the US are actually tick-borne, and 6 of the 15 distinct tick diseases are transmitted by the Ixodes tick we study in our lab,” says Pal. “The symptoms of these diseases present similarly to many other illnesses and are hard to pin down, so they are vastly underreported and an even bigger public health concern locally and globally than people realize.” Now, chronic Lyme disease is a growing concern. Six to twelve months after traditional antibiotic therapy, many people have non-objective symptoms that return with varying intensity and no current treatment strategy, known as Post-Treatment Lyme Disease Syndrome.
Dr. Pal’s research has shed some light on this issue and paved the way for future research and treatment options by discovering that even without the protein used to beat the first wave of immune defense, infection can reoccur in the body weeks later. “This means there is a second line of defense for Borrelia just like for our body’s immune system. This had never been observed before and gives us insight into what could be causing these chronic Lyme disease cases,” explains Pal.
Dr. Pal is frequently consulted for his expertise and has written books on this highly versatile bacteria. The federal government has recently put more emphasis on tick-borne disease research and a major public health issue with the passage of the 21st Century Cures Act. As part of this, Dr. Pal was asked to serve on a Tick-Borne Disease Working Group Subcommittee for the U.S. Department of Health & Human Services (DHHS) focused on vaccines and therapeutics for tick-borne diseases, driving future research in the field. Dr. Pal currently holds two concurrent multi-million dollar RO1 grants from the National Institutes of Health (NIH) for this work, only granted for highly important and influential research. “I am fascinated by Borrelia, and this discovery will open the door for much more work to treat and control important diseases like Lyme disease,” says Pal.

Recognizing maternal-fetal transmission of Lyme disease
Blog: Touched By Lyme, published by LymeDisease.org/
Written by: Dorothy Kupcha Leland, Vice President for Education and Outreach for LymeDisease.org/
October 8, 2018
Good news: According to the advocacy organization LymeHope, top Canadian health officials have acknowledged the reality of maternal-fetal transmission of Lyme disease.
This is a huge step forward, in terms of proper care for pregnant women and their offspring. (At least in Canada! The US is far from any similar declaration.)
Advocates Sue Faber, Jennifer Kravis and Tamara House (known affectionately to thousands as “the Lyme moms,” last week continued their on-going discussion officials of the Federal Public Health Agency of Canada.

Better drugs for Lyme disease: focus on the spirochete
Stricker RB, Middelveen MJ.
Infection and Drug Resistance, 2018 Sep 7;11:1437-1439. eCollection 2018.
Twenty-five years ago, the AIDS epidemic was wreaking havoc around the world. Although “HIV denialists” threatened to undermine research efforts to combat the epidemic, development of targeted antiviral therapy eventually provided effective treatment for the disease.
Now the Lyme disease epidemic is wreaking havoc around the world, and “Lyme denialists” are undermining efforts to combat the epidemic. Drawing on our experience with the AIDS epidemic, there is a significant need to develop targeted therapy to control the Lyme disease epidemic.

Oral Management for Pediatric Lyme Meningitis
Lopez SMC, Campfield BT, Nowalk AJ.
Journal of the Pediatric Infectious Diseases Society, online first 2018 Aug 28.
Guidelines for pediatric Lyme meningitis recommend treatment with parenteral therapy. Adult studies suggest that Lyme meningitis can be successfully treated with oral therapy. Our objective was to evaluate the clinical response, side effects and outcome of oral therapy for Lyme meningitis in the pediatric population compared with parenteral therapy in an area endemic for Lyme disease.
We identified 38 patients diagnosed with Lyme meningitis. Thirty-two patients were discharge with exclusively oral therapy with: doxycycline and amoxicillin. We had only 2 patients developed potential adverse effects from oral doxycycline therapy. All patients treated with oral antibiotics had resolution of symptoms on follow up appointments.
Oral therapy for Lyme meningitis yields no serious adverse events, was well tolerated and showed resolution of symptoms.

Identifying vancomycin as an effective antibiotic for killing Borrelia burgdorferi
Wu X, Sharma B, Niles S, O’Connor K, Schilling R, Matluck N, D’Onofrio A, Hu LT, Lewis K.
Antimicrobial Agents and Chemotherapy, online first 2018 Aug 20.
Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10-20% go on to develop Post-Treatment Lyme Disease Syndrome. The nature of PTLDS remains unknown, but currently approved antibiotics for treatment of Lyme disease do not appear to impact these symptoms after they have developed.
We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection.
In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi. Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria.
We found that peptidoglycan synthesis continues in stationary cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary phase culture of B. burgdorferi. Examination of the action of antibiotics in immune-deficient SCID mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. By contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining early use of more potent antibiotics on development of PTLDS may be warranted.

The Emerging Role of Microbial Biofilm in Lyme Neuroborreliosis
Enea Gino Di Domenico, Ilaria Cavallo, Valentina Bordignon, Giovanna D’Agosto, Martina Pontone, Elisabetta Trento, Maria Teresa Gallo, Grazia Prignano, Fulvia Pimpinelli, Luigi Toma, Fabrizio Ensoli
Frontiers in Neurology, online first December 3, 2018.
It has been observed that the antibiotic resistance and the reoccurrence of Lyme disease are associated with biofilm-like aggregates in B. burgdorferi, B. afzelii, and B. garinii, both in vitro and in vivo, allowing Borrelia spp. to resist to adverse environmental conditions. Indeed, the increased tolerance to antibiotics described in the persisting forms of Borrelia spp., is strongly reminiscent of biofilm growing bacteria, suggesting a possible role of biofilm aggregates in the development of the different manifestations of Lyme disease including LNB.

Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1
Horowitz RI, Freeman PR
International Journal of General Medicine, Volume 12, Pages 101-119.
DDS CT statistically improved the eight major Lyme symptoms. We found multiple species of intracellular bacteria including rickettsia, Bartonella, Mycoplasma, Chlamydia, Tularemia, and Brucella contributing to the burden of illness and a high prevalence of Babesia complicating management with probable geographic spread of Babesia WA1/duncani to the Northeast. Borrelia, Bartonella, and Mycoplasma species, as well as Babesia microti had variable manifestations and diverse seroreactivity, with evidence of persistence despite commonly prescribed courses of anti-infective therapies. Occasional reactivation of viral infections including human herpes virus 6 was also seen in immunocompromised individuals. DDS CT decreased eight major Lyme symptoms severity and improved treatment outcomes among patients with chronic Lyme disease/PTLDS and associated coinfections.

Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2
Horowitz RI, Freeman PR. Healthcare. 2018 Nov 5;6(4). pii: E129. 
We present a precision medical perspective to assist in the definition, diagnosis, and management of Post Treatment Lyme Disease Syndrome (PTLDS)/chronic Lyme disease. PTLDS represents a small subset of patients treated for an erythema migrans (EM) rash with persistent or recurrent symptoms and functional decline. The larger population with chronic Lyme disease is less understood and well defined. Multiple Systemic Infectious Disease Syndrome (MSIDS) is a multifactorial model for treating chronic disease(s), which identifies up to 16 overlapping sources of inflammation and their downstream effects. 
A patient symptom survey and a retrospective chart review of 200 patients was therefore performed on those patients with chronic Lyme disease/PTLDS to identify those variables on the MSIDS model with the greatest potential effect on regaining health. Results indicate that dapsone combination therapy decreased the severity of eight major Lyme symptoms, and multiple sources of inflammation (other infections, immune dysfunction, autoimmunity, food allergies/sensitivities, leaky gut, mineral deficiencies, environmental toxins with detoxification problems, and sleep disorders) along with downstream effects of inflammation may all affect chronic symptomatology. In part two of our observational study and review paper, we postulate that the use of this model can represent an important and needed paradigm shift in the diagnosis and treatment of chronic disease.

Establishment of a Continuous In Vitro Culture of Babesia duncani in Human Erythrocytes Reveals Unusually High Tolerance to Recommended Therapies
Abraham A, Brasov I, Thekkiniath J, et. al.
Journal of Biological Chemistry, online first 2018 Nov 21. 
These data suggest that current practices are of limited effect in treating the disease. We anticipate this new disease model will set the stage for a better understanding of the biology of this parasite and will help guide better therapeutic strategies to treat B. duncani-associated babesiosis.

Effectiveness of antibiotic therapy in pediatric patients with cat scratch disease
Shorbatli LA, Koranyi KI, Nahata MC.
International Journal of Clinical Pharmacy, online first 2018 Nov 16. 
Azithromycin and TMP/SMX were most frequently prescribed antibiotics. Azithromycin appeared to be an appropriate option for the treatment of CSD. TMP/SMX may be considered as an alternative antibiotic when azithromycin cannot be used.

Long Term Antibiotic Therapy may be an Effective Treatment for Children Co-Morbid with Lyme Disease and Autism Spectrum Disorder
Kuhn, Mason & Grave, Shannon & Bransfield, Robert & Harris, Steven. (2012)
Patients diagnosed with Lyme disease share many of the same physical manifestations as those diagnosed with an Autism Spectrum Disorder (ASD). In this study four male children (ages 26-55 months) who have an ASD diagnosis and one male child (age -O meets state and federal requirements for providing a comprehensive, ongoing assessment of a child with an ASD [33]. The SAP-O form measures children’s abilities using observational, authentic assessment procedures in the domains of joint attention, symbol use, mutual regulation, and self regulation via observations of specific behaviors in familiar settings [33]. The five children tested positive for Lyme disease and their SAP-O score was evaluated before and after 6 months of antibiotic therapy. Each child was prescribed 200mg of amoxicillin three times per day and three of the five children were prescribed an additional 50mg of Azithromycin once per day. All of the children’s scores on the SAP-O assessment improved after 6 months of antibiotic therapy. The assessors also reported anecdotal data of improved speech, eye contact, sleep behaviors, and a reduction of repetitive behaviors.

Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease?
Horowitz, Richard & Freeman, Phyllis R. (2016)
https://www.researchgate.net/publication/324978706_Are_Mycobacterium_Drugs_Effective_for_Treatment_Resistant_Lyme_Disease_Tick-Borne_Co Infections_and_Autoimmune_Disease
PTLDS/chronic Lyme disease may cause disabling symptoms with associated overlapping autoimmune manifestations, with few clinically effective published treatment options. We recently reported on the successful use of a mycobacterium drug, Dapsone, for those with PTLDS. We now report on the novel use of another mycobacterium drug, pyrazinamide, (PZA), in relieving resistant symptomatology secondary to Lyme disease and associated co-infections, while decreasing autoimmune manifestations with Behçet’s syndrome.

An Update on the Appropriate Role for Hyperbaric Oxygen: Indications and Evidence
Caroline E. Fife, MD,corresponding author Kristen A. Eckert, MPhil, and Marissa J. Carter, PhD, MA
Among advanced therapeutic interventions for wounds, hyperbaric oxygen therapy (HBOT) has the unique ability to ameliorate tissue hypoxia, reduce pathologic inflammation, and mitigate ischemia reperfusion injury. Most of the conditions for which it is utilized have few successful alternative treatments, and the morbidity and mortality associated with treatment failure are significant. Data on the efficacy and effectiveness of HBOT were reviewed, comparative effectiveness research of HBOT was explained, and a new paradigm for the appropriate use of HBOT was described.

Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo
Chen Q., Espey M.G., Sun A.Y., Lee J.H., Cherukuri M.K., Shacter E, Choyke P.L., Pooput C., Kirk K.L., Buettner G.R., Levine M.
Treatment of cells with high doses of vitamin C resulted in an immediate increase in intracellular total glutathione content and glutathione-S transferase activity that was accompanied by the uptake of cysteine. These results suggest a new role for high concentrations of vitamin C in modulation of intracellular sulfur containing compounds, such as glutathione and cysteine. This review, discussing biochemical pharmacologic studies, including pharmacogenomic and pharmacoproteomic studies, presents the different pharmacological effects of vitamin C currently under investigation.

Intravenous Nutrient Therapy: the “Myers’ Cocktail”
Alan R. Gaby, MD
Alternative Medicine Review, Volume 7, Number 5, 2002
Building on the work of the late John Myers, MD, the author has used an intravenous vitamin-and-mineral formula for the treatment of a wide range of clinical conditions. The modified “Myers’ cocktail,” which consists of magnesium, calcium, B vitamins, and vitamin C, has been found to be effective against acute asthma attacks, migraines, fatigue (including chronic fatigue syndrome), fibromyalgia, acute muscle spasm, upper respiratory tract infections, chronic sinusitis, seasonal allergic rhinitis, cardiovascular disease, and other disorders. This paper presents a rationale for the therapeutic use of intravenous nutrients, reviews the relevant published clinical research, describes the author’s clinical experiences, and discusses potential side effects and precautions.

Stationary Phase Persister/Biofilm Microcolony of Borrelia burgdorferi Causes More Severe Disease in a Mouse Model of Lyme Arthritis: Implications for Understanding Persistence, Post-Treatment Lyme Disease Syndrome (PTLDS), and Treatment Failure
Jie Feng, Tingting Li, Rebecca Yee, Yuting Yuan, Chunxiang Bai, Menghua Cai, Wanliang Shi, Monica Embers, Cory Brayton, Harumi Saeki, Kathleen Gabrielson, Ying Zhang
Discovery Medicine, online first March 28, 2019, Volume 27, Number 148, March 2019.
Our studies demonstrate that varying levels of persistence and pathologies of Borrelia infection can be established with heterogeneous inocula with different morphologies and have different treatment responses. These observations may have broad implications for understanding pathogenesis and treatment of not only persistent Lyme disease but also other persistent infections in general and call for treatment of persistent infections with persister drug combination regimens that are more effective than the current often single-antibiotic monotherapy treatment.

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