Eravacycline: a comprehensive review of in vitro activity, clinical efficacy, and real-world applications.

INTRODUCTION: The escalating threat of multidrug-resistant organisms necessitates constant exploration for novel antimicrobial agents. Eravacycline has emerged as a promising solution due to its unique chemical structure, which enhances potency and expands its spectrum of activity. AREA COVERED: This review provides a thorough examination of eravacycline, encompassing its in vitro activity against Gram-positive and Gram-negative aerobes, carbapenem-non-susceptible organisms, anaerobes, and other bacterial strains. Additionally, it evaluates evidence from clinical studies to establish its clinical effect and safety. EXPERT OPINION: Eravacycline, a synthetic fluorocycline, belongs to the tetracyclines class. Similar to other tetracycline, eravacycline exerts its antibacterial action by reversibly binding to the bacterial ribosomal 30S subunit. Eravacycline demonstrates potent in vitro activity against many Gram-positive and Gram-negative aerobes, anaerobes, and multidrug-resistant organisms. Randomized controlled trials and its associated meta-analysis affirm eravacycline's efficacy in treating complicated intra-abdominal infections. Moreover, real-world studies showcase eravacycline's adaptability and effectiveness in diverse clinical conditions, emphasizing its utility beyond labeled indications. Despite common gastrointestinal adverse events, eravacycline maintains an overall favorable safety profile, reinforcing its status as a tolerable antibiotic. However, ongoing research is essential for refining eravacycline's role, exploring combination therapy, and assessing its performance against biofilms, in combating challenging bacterial infections.

Real-world safety profile of tetracyclines in children younger than 8 years old: an analysis of FAERS database and review of case report.

BACKGROUND: The study aims to obtain the real-world safety profile of tetracyclines in children younger than 8 years old and provide reference for clinical drug applications. RESEARCH DESIGN AND METHODS: We made a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database through OpenVigil 2 and conducted a review of case reports regarding adverse drug reactions (ADRs) of tetracyclines in children younger than 8-year-old. RESULTS: FAERS analysis identified 32 ADRs of tetracyclines in children younger than 8-year-old. Respiratory, thoracic, and mediastinal disorders contained the most frequent ADRs among all system organ classes (SOCs). The top three positive signals with the highest proportional reporting ratio (PRR) were laryngeal injury, Horner's syndrome and methaemoglobinaemia. Sixteen published tetracyclines-associated cases in children younger than 8-year-old were identified in the literature, concentrating in three SOCs. Gastrointestinal disorders were the most commonly reported cases (n = 12). CONCLUSIONS: Several ADRs were newly reported only in children younger than 8-year-old in our research, including Horner's syndrome and methemoglobinemia. We recommended that the clinical practitioners should pay attention to the ADRs both in instruction and beyond the label. Take close care of children and timely intervene when the treatment is inevitable.

Efficacy and safety of omadacycline for treating complicated skin and soft tissue infections: a meta-analysis of randomized controlled trials.

OBJECTIVE: In the present study, we aimed to compare the clinical efficacy and safety of omadacycline (OMC) with its comparators for the treatment of complicated skin and soft tissue infections (cSSTIs) in adult patients. METHODS: Randomized controlled trials (RCTs) evaluating OMC for cSSTIs were searched in databases of PubMed, Embase, Cochrane, Web of Science, and Clinical Trial, up to July 2022. The primary outcomes were clinical efficacy and microbiological response, with secondary outcome was safety. RESULTS: Four RCTs consisting of 1,757 patients were included, with linezolid (LZD) as a comparator drug. For clinical efficacy, OMC was not inferior to LZD in the modified intent-to-treat (MITT) (OR: 1.24, 95% Cl: [0.93, 1.66], P = 0.15) and clinically evaluable (CE) populations (OR: 1.92, 95% Cl: [0.94, 3.92], P = 0.07). For microbiological response, OMC was numerically higher than LZD in the microbiologically evaluable (ME) (OR: 1.74, 95% Cl: [0.81, 3.74], P = 0.16) and microbiological MITT (micro-MITT) populations (OR: 1.27, 95% Cl: [0.92, 1.76], P = 0.14). No significant difference was found in subpopulations of monomicrobial or polymicrobial mixed infection populations. The mortality and adverse event rates were similar between OMC and LZD. CONCLUSIONS: OMC was as good as LZD in terms of clinical efficacy and microbiological response, and has similar safety issues in treating cSSTIs. OMC might be a promising option for treating cSSTIs in adult patients.

Rhabdomyolysis Suspected to be Caused by Eravacycline Therapy: A Case Report.

Eravacycline is approved by the U.S. Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal infections. It is a novel, fully synthetic fluorocycline antibiotic belonging to the tetracycline class with a broad-spectrum of activity and an appealing side effect profile. This report describes a 74-year-old female who presented to the hospital with non-ST-elevation myocardial infarction (NSTEMI) requiring coronary artery bypass graft surgery. After surgery, she developed a sternal wound infection that grew multidrug resistant organisms, leading to a much longer than anticipated hospital stay. Eravacycline was eventually added to the antimicrobial regimen for the persistent infection. Shortly after therapy with eravacycline began, the patient started experiencing muscle pain and the creatine phosphokinase (CPK) level was noted to be elevated. Other causes, such as concomitant administration of an HMG-CoA reductase inhibitor, were explored in this case but not thought to be the cause of rhabdomyolysis. The patient's CPK dropped considerably upon discontinuation of the novel antibiotic, and symptoms resolved. The adverse drug event was reported to the drug manufacturer; however, there are no reports up until this time that address a possible relationship between eravacycline administration and the development of rhabdomyolysis.

Prolonged course of eravacycline leading to acute pancreatitis.

Eravacycline is the newest member of the broad-spectrum class of tetracycline antimicrobials. Pancreatitis has been previously associated with the tetracycline class of antibiotics, but, to our knowledge, we believe that this is the first reported case of eravacycline-induced pancreatitis. We describe a 46-year-old male who received eravacycline for treatment of a perirectal abscess. While the patient had slightly elevated lipase levels at baseline post-cardiopulmonary arrest, he developed abdominal pain and a further increase in lipase levels following 10 days of eravacycline, consistent with pancreatitis. Based on the Naranjo adverse drug reaction probability scale, eravacycline was the probable etiology of acute pancreatitis given improvement immediately after discontinuation. Clinicians should be aware of this potential adverse effect of eravacycline and should not initiate eravacycline in those with risk factors for acute pancreatic injury. However, acute pancreatitis should be suspected in all patients complaining of symptoms followed by immediate discontinuation of eravacycline.

Omadacycline for treatment of acute bacterial infections: a meta-analysis of phase II/III trials.

OBJECTIVE: This study aims to assess the clinical efficacy and safety of omadacycline for the treatment of acute bacterial infections. METHODS: A search of PubMed, Embase, Cochrane Library, and Clinical Trials was conducted up to July 1, 2022. We included only randomized controlled trials (RCTs), in which omadacycline and other antibiotics were evaluated for treating acute bacterial infections in adults. The primary outcomes were clinical response and microbiological response, whereas the secondary outcome was the risk of adverse events (AEs). RESULTS: A total of seven RCTs involving 2841 patients with acute bacterial infection were included. Overall, our study illustrated that the clinical cure ratio of omadacycline was similar to the comparators in the treatment of acute bacterial infections (OR = 1.18, 95%CI = 0.96, 1.46, I2 = 29%). Omadacycline had a microbiological eradication rate similar to comparators in the treatment of acute bacterial infections (OR = 1.02, 95%CI = 0.81, 1.29, I2 = 42%). No statistical differences were observed between omadacycline and the comparators in terms of infection caused by Staphylococcus aureus (OR = 1.14, 95%CI = 0.80, 1.63, I2 = 0%), methicillin-resistant S. aureus (MRSA, OR = 1.28, 95%CI = 0.73, 2.24, I2 = 0%), methicillin-susceptible S. aureus (MSSA, OR = 1.12, 95%CI = 0.69, 1.81, I2 = 0%), and Enterococcus faecalis (OR = 2.47, 95%CI = 0.36, 16.97, I2 = 7%). A significant difference was found between omadacycline and the comparators for the risk of any AEs and treatment related AEs. The risk of discontinuation of the study drug due to an AEs was lower for omadacycline than for the comparators. CONCLUSION: Omadacycline is as good as comparators in terms of efficacy and tolerance in the treatment of acute bacterial infections in adult patients. Thus, omadacycline is an appropriate option for antibiotic therapy in adult patients with acute bacterial infections.

Re-establishing the utility of tetracycline-class antibiotics for current challenges with antibiotic resistance.

The progressive increase in antibiotic resistance in recent decades calls for urgent development of new antibiotics and antibiotic stewardship programs to help select appropriate treatments with the goal of minimising further emergence of resistance and to optimise clinical outcomes. Three new tetracycline-class antibiotics, eravacycline, omadacycline, and tigecycline, have been approved within the past 15 years, and represent a new era in the use of tetracyclines. These drugs overcome the two main mechanisms of acquired tetracycline-class resistance and exhibit a broad spectrum of in vitro activity against gram-positive, gram-negative, anaerobic, and atypical pathogens, including many drug-resistant strains. We provide an overview of the three generations of tetracycline-class drugs, focussing on the efficacy, safety, and clinical utility of these three new third-generation tetracycline-class drugs. We also consider various scenarios of unmet clinical needs where patients might benefit from re-engagement with tetracycline-class antibiotics including outpatient treatment options, patients with known ß-lactam antibiotic allergy, reducing the risk of Clostridioides difficile infection, and their potential as monotherapy in polymicrobial infections while minimising the risk of any potential drug-drug interaction. KEY MESSAGESThe long-standing safety profile and broad spectrum of activity of tetracycline-class antibiotics made them a popular choice for treatment of various bacterial infections; unfortunately, antimicrobial resistance has limited the utility of the early-generation tetracycline agents.The latest generation of tetracycline-class antibiotics, including eravacycline, tigecycline, and omadacycline, overcomes the most common acquired tetracycline resistance mechanisms.Based on in vitro characteristics and clinical data, these newer tetracycline agents provide an effective antibiotic option in the treatment of approved indications in patients with unmet clinical needs - including patients with severe penicillin allergy, with renal or hepatic insufficiency, recent Clostridioides difficile infection, or polymicrobial infections, and those at risk of drug-drug interactions.

Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID-19: a critical discussion of recent publications.

INTRODUCTION: Drug repurposing can be a successful approach to deal with the scarcity of cost-effective therapies in situations such as the COVID-19 pandemic. Tetracyclines have previously shown efficacy in preclinical acute respiratory distress syndrome (ARDS) models and initial predictions and experimental reports suggest a direct antiviral activity against SARS-CoV2. Furthermore, a few clinical reports indicate their potential in COVID-19 patients. In addition to the scarcity and limitations of the scientific evidence, the effectiveness of tetracyclines in experimental ARDS has been proven extensively, counteracting the overt inflammatory reaction and fibrosis sequelae due to a synergic combination of pharmacological activities. AREAS COVERED: This paper discusses the scientific evidence behind the application of tetracyclines for ARDS/COVID-19. EXPERT OPINION: The benefits of their multi-target pharmacology and their safety profile overcome the limitations, such as antibiotic activity and low commercial interest. Immunomodulatory tetracyclines and novel chemically modified non-antibiotic tetracyclines have therapeutic potential. Further drug repurposing studies in ARDS and severe COVID-19 are necessary.

Road Less Traveled: Drug Hypersensitivity to Fluoroquinolones, Vancomycin, Tetracyclines, and Macrolides.

While fluoroquinolones, vancomycin, macrolides, and tetracyclines are generally safe antibiotics, they can induce both immediate and delayed hypersensitivity reactions (HSRs). Historically, less has been published on allergies to these antibiotics compared to beta lactams, but the prevalence of non-beta lactam HSRs is increasing. To fluoroquinolones, immediate HSRs are more common than delayed reactions. Both IgE and non-IgE mechanisms, such as the mast cell receptor Mas-related G protein-coupled receptor X2 (MRGPRX2), have been implicated in fluoroquinolone-induced anaphylaxis. Skin testing for fluoroquinolones is controversial, and the gold standard for diagnosis is a graded dose challenge. To vancomycin, the most common reaction is vancomycin infusion reaction (previously called "red man syndrome"), which is caused by infusion rate-dependent direct mast cell degranulation. Severity can range from flushing and pruritis to angioedema, bronchospasm, and hypotension that mimic type I HSRs. MRGPRX2 has been implicated in vancomycin infusion reactions. IgE-mediated HSRs to vancomycin are rare. Vancomycin skin testing yields high false positive rates. Thus, direct provocation challenge with slower infusion rate and/or antihistamine pre-treatment is preferred if symptoms are mild to moderate, and desensitization can be considered if symptoms are severe. To tetracyclines, non-IgE-mediated and delayed HSRs predominate with cutaneous reactions being the most common. There is no standardized skin testing for tetracyclines, and avoidance is generally recommended after a severe reaction because of the paucity of data for testing. Graded dose challenges and desensitizations can be considered for alternative or index tetracyclines if there are no alternatives. With macrolides, urticaria/angioedema is the most common immediate HSR, and rash is the most common delayed HSR. The predictive value for skin testing to macrolides is similarly poorly defined. In general, HSRs to fluroquinolones, vancomycin, macrolides, and tetracyclines are challenging to diagnose given the lack of validated skin testing and in vitro testing. Direct provocation challenge remains the gold standard for diagnosis, but the benefits of confirming an allergy may not outweigh the risk of a severe reaction. Skin testing, direct provocation challenge, and/or desensitization to the index non-beta lactam antibiotic or alternatives in its class may be reasonable approaches depending on the clinical context and patient preferences.

Efficacy and safety of tetracyclines for pemphigoid: a systematic review and meta-analysis.

The aim of this review was to evaluate the efficacy and safety of tetracyclines for treatment of pemphigoid. We searched PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library for studies involving pemphigoid patients treated with tetracyclines published in English before 29 February 2020. References of included studies were also screened to widen the scope of the literature search. Data regarding predefined clinical outcomes of 341 patients from 77 studies were extracted and analyzed. A meta-analysis was conducted on the basis of 4 studies including 2 randomized controlled trials and 2 comparative studies. The patients had a mean age of 74.60 ± 13.18 years, 45.4% were males, and 54.6% were females. There were 185 patients with mild-to-moderate and 143 patients with severe disease. The average initial doses were 1.62 ± 0.39 g/day for tetracycline, 0.20 ± 0.01 g/day for doxycycline, and 0.11 ± 0.05 g/day for minocycline. The average time on tetracyclines was 3.74 ± 5.99 months, and 261 (81.3%) patients reported partial or complete remission. Relapses occurred in 72 (28.3%) cases. Adverse effects were experienced by 130 (41.9%) patients. The pooled ORs for short-term effectiveness, relapse, adverse effects, and 1-year survival in patients treated with oral tetracyclines vs. systemic corticosteroids were 0.40 (95% CI, 0.22-0.76), 0.69 (95% CI, 0.44-1.10), 0.47 (95% CI, 0.27-0.82) and 2.02 (95% CI, 1.16-3.50), respectively. Compared to doxycycline and minocycline, tetracycline was significantly associated with better treatment outcomes and fewer adverse effects (p < 0.05). This review revealed tetracyclines' efficacy and safety in pemphigoid treatment and may offer support for clinical use of tetracyclines in pemphigoid.

Study of prescription-indication of tetracyclines in a population in Colombia.

The inappropriate use of antibiotics is associated with increased antimicrobial resistance, adverse reactions, medical care costs, and worse clinical outcomes. The objective of this study is to determine the prescription patterns and approved and unapproved indications for tetracyclines in a group of patients in Colombia. This was a cross-sectional study, based on a database of medication dispensing of approximately 8.5 million people affiliated with the Colombian Health System, of the indications for the use of tetracyclines in outpatients. Sociodemographic, pharmacological, and comorbidity variables were considered. A total of 20 699 patients with a prescription of tetracyclines were identified, with a median age of 26.1 years; 65.0% were women. The most prescribed tetracycline was doxycycline (95.1%), especially for the treatment of acne (55.3%). A total of 23.5% of the prescriptions was used for unapproved indications, for example, vaginitis-vulvitis-vulvovaginitis (8.1%). Increasing age, prescriptions of doxycycline made by general physician, and woman attended by general physician were associated with a greater probability that a tetracycline was used for unapproved indications. Residing in Bogota-Cundinamarca Region and woman that residing in Bogota-Cundinamarca reduced this risk. A high proportion of patients received tetracyclines for dermatological conditions, with a lower proportion of use for gynecological and respiratory infections. For approximately one quarter of the cases, tetracyclines were prescribed for indications not approved by regulatory agencies, especially in those over 18 years and when the prescriptions of doxycycline was made by a general practitioners.

A retrospective, multicentre evaluation of eravacycline utilisation in community and academic hospitals.

OBJECTIVES: Eravacycline is a novel, fully-synthetic tetracycline approved by the FDA for treatment of complicated intra-abdominal infections in August 2018. This study sought to characterise early clinical experience with this novel antibiotic. METHODS: Eravacycline utilisation for 66 patients was retrospectively evaluated. RESULTS: Eravacycline was used as monotherapy in 62.1% of cases. Mean duration of therapy was 13.1 ± 9.9 days. The majority (68.2%) of treatment was for off-label indications, including 34.8% for pulmonary and 28.8% for skin/soft tissue infections. A number of difficult-to-treat organisms were encountered: 50% of identified Gram-negative pathogens were resistant to carbapenems in vitro; and 48% of identified Gram-positive pathogens were resistant to vancomycin in vitro. The patient population had a high illness acuity, with 42.4% requiring ICU admission, 59.1% having ≥2 co-morbidities and 33.3% having ≥3 co-morbidities. Nevertheless, 95.5% experienced clinical improvement, with 86.4% achieving full infection resolution following eravacycline. Three patients who did not experience clinical improvement had an intra-abdominal source of infection without adequate source control. The remaining six who did not experience full infection resolution died from unrelated non-infectious causes during hospital admission. Adverse events were uncommon (4.5%), limited to nausea/vomiting, and not leading to eravacycline discontinuation. Although two patients had a history of Clostridioides difficile infection (CDI), no patients developed CDI while receiving eravacycline. CONCLUSION: These results illustrate the potential versatility of eravacycline with a broad activity spectrum, good safety and tolerability profile, flexibility for use in patients with renal injury or antibiotic allergies, and positive clinical outcomes in this real-world cohort.

Preparation of yellow-emitting carbon dots and their bifunctional detection of tetracyclines and Al3+ in food and living cells.

A novel bifunctional carbon dot (CD)-based sensing platform was constructed for detection of tetracyclines (TCs) and Al3+. The fluorescence CDs were fabricated by hydrothermal method using phenylenediamine (p-PD) and ethylenebis(oxyethylenenitrilo) tetraacetic acid (EGTA) as precursors. The obtained prepared CDs show bright yellow fluorescence (y-CDs, EX = 400 nm and Em = 556 nm), high fluorescence quantum yield (QY = 21.55 ± 0.06%), and preferable optical stability. TCs can directly quench the fluorescence of y-CDs based on static quenching characteristics and a small internal filtration effect (IEF). By adding Al3+ to the y-CDs + TCs system, the fluorescence is partly recovered because TCs escape from the surface of the y-CDs and form a more stable chelate with Al3+. The sensing platform displays good selectivity and high sensitivity to TCs and Al3+ with low detection limits of 0.057-0.23 µM and 0.091 µM, respectively. Importantly, this sensing platform has enabled the detection of TCs and Al3+ in milk samples with satisfactory recoveries and RSDs, confirming the reliability and feasibility of this method. Combining with low toxicity and preferable biocompatibility, the y-CDs are extended to cellular imaging and detection of CTC and Al3+ in A549 cells.

Treatment of rosacea during pregnancy.

BACKGROUND: Exacerbation of rosacea may occur during pregnancy and there are multiple associated cases of rosacea fulminans (RF). Treatment during pregnancy poses a significant challenge as many rosacea treatments are contraindicated or have limited evidence regarding potential adverse fetal effects. OBJECTIVE: Review the pregnancy categories of various treatments and develop algorithms for treating pregnant patients with rosacea and RF. METHODS: Rosacea treatments showing efficacy in randomized controlled trials were searched through DailyMed to review pregnancy labelling. Searching the PubMed/MEDLINE database for English articles using keywords "rosacea fulminans AND pregnancy" without publishing-time restrictions yielded 8 articles. We summarized treatments used in cases of RF during pregnancy. RESULTS: Topical ivermectin was more effective than metronidazole, but has a more concerning pregnancy category. Three pregnant women with RF were treated successfully with topical metronidazole in combination with other therapies. Azithromycin is the only oral rosacea therapy that is considered safe for pregnant patients and it has been used to treat RF. CONCLUSIONS: This review highlights the challenging aspects of treating pregnant patients with rosacea, as there is limited pregnancy-related treatment efficacy and safety data. The pregnancy categories of therapeutic options are summarized. Further studies are needed to learn which therapies are effective and safe for use during pregnancy.

Safety and efficacy of omadacycline by body mass index in patients with community-acquired bacterial pneumonia: Subanalysis from a randomized controlled trial.

OBJECTIVES: To examine the safety and efficacy of omadacycline by body mass index (BMI) in adults with community-acquired bacterial pneumonia (CABP) from a Phase III trial. METHODS: Patients hospitalized for suspected CABP were randomized 1:1 to receive intravenous omadacycline or moxifloxacin, with an optional transition to oral, for a total of 7-14 days. Early clinical response (ECR) was assessed 72-120 h after receipt of the first dose, and clinical success was assessed 5-10 days after the last dose (post-treatment evaluation [PTE]). ECR was defined as improvement in at least two CABP symptoms with no worsening of other symptoms or use of rescue antibacterial treatment; success at PTE was defined as resolution of signs and symptoms to the extent that further antibacterial therapy was unnecessary. Safety evaluations included treatment-emergent adverse events and laboratory measures. Between-treatment comparisons were made by World Health Organization BMI categories and by diabetes history. RESULTS: Distribution of patients in the normal weight, overweight, and obese subgroups was fairly even. Clinical success for omadacycline-treated patients at ECR were similar across ascending BMI groups (OMC: 82.9%, 80.5%, 76.9%; MOX: 88.6%, 80.7%, 76.9%). Outcomes by diabetes status were generally similar in omadacycline- and moxifloxacin-treated patients. Patients who had clinical success or clinical stability at ECR generally showed continued clinical success at PTE. Safety profiles for omadacycline and moxifloxacin were largely similar across BMI subgroups and by diabetes history. CONCLUSION: The omadacycline fixed-dosing strategy showed consistent safety and efficacy in patients with CABP of different body sizes.

Oral Sarecycline for Treatment of Papulopustular Rosacea: Results of a Pilot Study of Effectiveness and Safety.

BACKGROUND: Cutaneous rosacea is a common inflammatory skin disorder that often presents with facial papulopustular lesions that are frequently bothersome to patients. Studies have shown oral sarecycline to be effective and safe for acne, with a low risk of side effects that are historically associated with other tetracycline-class drugs such as doxycycline and minocycline, in addition to offering a reduced risk of emergence of resistant bacteria due to its narrow-spectrum of antibiotic activity. Oral sarecycline is FDA-approved for the treatment of acne (2018). OBJECTIVE: A pilot study to evaluate the efficacy and safety of oral sarecycline in papulopustular rosacea. METHODS: A 12-week, prospective, parallel-group, investigator-blinded, controlled pilot study was completed evaluating once-daily sarecycline, using weight-based oral dosing as recommended for acne vs control (multivitamin tablet), for the treatment of moderate-to-severe papulopustular rosacea in adult subjects (n=102), aged ≥18 years. The primary efficacy endpoint was Investigator's Global score (IGA; clear or almost clear) and percent reduction in inflammatory lesion count at week 12. Safety and tolerability assessments were performed as well. RESULTS: A total of 102 subjects were randomized; 97 completed the study. At week 12, IGA improvement was significantly greater for oral sarecycline when compared to the control (P<0.0001). Furthermore, absolute and percent reductions in inflammatory lesion counts were significantly greater in the sarecycline group for all weeks (4, 8, and 12) when compared to the control (P<0.001). Significant improvement in facial burning, erythema, and pruritus was reported in the sarecycline group, when compared to the control (P<0.05). No serious AEs were reported. CONCLUSION: Sarecycline was effective, safe, and well-tolerated for treating papulopustular rosacea in adults with marked superiority in efficacy compared to subjects in the control group. With its narrow-spectrum activity, oral sarecycline may be a good option for the treatment of papulopustular rosacea. Additional studies are warranted to confirm the positive results of this pilot study.

Louse-borne relapsing fever-A systematic review and analysis of the literature: Part 2-Mortality, Jarisch-Herxheimer reaction, impact on pregnancy.

Louse-borne relapsing fever (LBRF) is a classical epidemic disease, which in the past was associated with war, famine, poverty, forced migration, and crowding under poor hygienic conditions around the world. The disease's causative pathogen, the spirochete bacterium Borrelia recurrentis, is confined to humans and transmitted by a single vector, the human body louse Pediculus humanus corporis. Since the disease was at its peak before the days of modern medicine, many of its aspects have never been formally studied and to date remain incompletely understood. In order to shed light on some of these aspects, we have systematically reviewed the accessible literature on LBRF since the recognition of its mode of transmission in 1907, and summarized the existing data on mortality, Jarisch-Herxheimer reaction (JHR), and impact on pregnancy. Publications were identified by using a predefined search strategy of electronic databases and a subsequent review of the reference lists of the obtained publications. All publications reporting patients with a confirmed diagnosis of LBRF published in English, French, German, and Spanish since 1907 were included. Data extraction followed a predefined protocol and included a grading system to judge the certainty of the diagnosis of reported cases. The high mortality rates often found in literature are confined to extreme scenarios. The case fatality rate (CFR) of untreated cases is on average significantly lower than frequently assumed. In recent years, a rise in the overall CFRs is documented, for which reasons remain unknown. Lacking standardized criteria, a clear diagnostic threshold defining antibiotic treatment-induced JHR does not exist. This explains the wide range of occurrence rates found in literature. Pre-antibiotic era data suggest the existence of a JHR-like reaction also in cases treated with arsenicals and even in untreated cases. LBRF-related adverse outcomes are observed in 3 out of 4 pregnancies.