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Clinical Infectious Diseases : An... May 2020Scrub typhus, a neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi, is a major cause of fever across the Asia Pacific... (Review)
Review
Scrub typhus, a neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi, is a major cause of fever across the Asia Pacific region with more than a billion people at risk. Treatment with antibiotics such as doxycycline or chloramphenicol is effective for the majority of patients. In the 1990s, reports from northern Thailand raised a troubling observation; some scrub typhus patients responded poorly to doxycycline, which investigators attributed to doxycycline resistance. Despite the controversial nature of these reports, independent verification was neglected, with subsequent studies speculating on the role of doxycycline resistance in contributing to failure of treatment or prophylaxis. In this review, we have outlined the evidence for drug-resistant Orientia tsutsugamushi, assessed the evidence for doxycycline resistance, and highlight more recent findings unsupportive of doxycycline resistance. We conclude that doxycycline resistance is a misconception, with treatment outcome likely to be determined by other bacterial, host, and pharmacological factors.
Topics: Anti-Bacterial Agents; Doxycycline; Humans; Orientia tsutsugamushi; Scrub Typhus; Thailand
PubMed: 31570937
DOI: 10.1093/cid/ciz972 -
Hong Kong Medical Journal = Xianggang... Jun 2024
Topics: Humans; Doxycycline; Anti-Bacterial Agents; Male; Female; Middle Aged
PubMed: 38618912
DOI: 10.12809/hkmj2310708 -
JCI Insight Nov 2022Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggesting that...
Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggesting that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via a targeted metabolomics approach, we characterized significantly altered metabolic signatures in patients with rosacea, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid were highlighted and positively correlated with the disease severity in patients with rosacea. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulated the production of vasodilation-related neuropeptides from peripheral neurons and keratinocytes and induced the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of patients with rosacea possibly by targeting the amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.
Topics: Animals; Mice; Endothelial Cells; Aspartic Acid; Glutamic Acid; Rosacea; Doxycycline
PubMed: 36219476
DOI: 10.1172/jci.insight.161870 -
Topics in Antiviral Medicine Dec 2023Doxycycline postexposure prophylaxis (doxy-PEP) is a novel strategy now demonstrated in several clinical trials to dramatically reduce incidence rates of gonorrhea,... (Review)
Review
Doxycycline postexposure prophylaxis (doxy-PEP) is a novel strategy now demonstrated in several clinical trials to dramatically reduce incidence rates of gonorrhea, chlamydia, and syphilis in some key populations at high risk of sexually transmitted infections. Even so, much remains unknown about the long-term consequences of doxy-PEP, and several concerns, including the potential for the development of antibiotic resistance and disturbances to the microbiome, balance the benefits. This review highlights the history of antibiotic prophylaxis for sexually transmitted infections, and the rationale, current evidence, and future directions for doxy-PEP.
Topics: Humans; Doxycycline; Sexually Transmitted Diseases; Syphilis; Gonorrhea; Antibiotic Prophylaxis
PubMed: 38198668
DOI: No ID Found -
Genome Biology Jan 2023CRISPR-based toolkits have dramatically increased the ease of genome and epigenome editing. SpCas9 is the most widely used nuclease. However, the difficulty of...
BACKGROUND
CRISPR-based toolkits have dramatically increased the ease of genome and epigenome editing. SpCas9 is the most widely used nuclease. However, the difficulty of delivering SpCas9 and inability to modulate its expression in vivo hinder its widespread adoption in large animals.
RESULTS
Here, to circumvent these obstacles, a doxycycline-inducible SpCas9-expressing (DIC) pig model was generated by precise knock-in of the binary tetracycline-inducible expression elements into the Rosa26 and Hipp11 loci, respectively. With this pig model, in vivo and/or in vitro genome and epigenome editing could be easily realized. On the basis of the DIC system, a convenient Cas9-based conditional knockout strategy was devised through controlling the expression of rtTA component by tissue-specific promoter, which allows the one-step generation of germline-inherited pigs enabling in vivo spatiotemporal control of gene function under simple chemical induction. To validate the feasibility of in vivo gene mutation with DIC pigs, primary and metastatic pancreatic ductal adenocarcinoma was developed by delivering a single AAV6 vector containing TP53-sgRNA, LKB1-sgRNA, and mutant human KRAS gene into the adult pancreases.
CONCLUSIONS
Together, these results suggest that DIC pig resources will provide a powerful tool for conditional in vivo genome and epigenome modification for fundamental and applied research.
Topics: Animals; Humans; CRISPR-Cas Systems; Doxycycline; Gene Editing; Genome; Mutation; Swine; RNA, Guide, CRISPR-Cas Systems
PubMed: 36650523
DOI: 10.1186/s13059-023-02851-x -
Dental Materials : Official Publication... Jun 2023To evaluate the effect of doxycycline and dexamethasone doped nanoparticles covering titanium surfaces, on osteoblasts proliferation and differentiation.
OBJECTIVES
To evaluate the effect of doxycycline and dexamethasone doped nanoparticles covering titanium surfaces, on osteoblasts proliferation and differentiation.
METHODS
Doxycycline and dexamethasone doped polymeric nanoparticles were applied on titanium discs (Ti-DoxNPs and Ti-DexNPs). Undoped NPs and uncovered Ti discs were used as control. Human MG-63 osteoblast-like cells were cultured. Osteoblasts proliferation was tested by MTT assay. Alkaline phosphatase activity was analyzed. Differentiation gene expression was assessed by real-time quantitative polymerase chain reaction. Scanning Electron Microscopy was performed to assess osteoblasts morphology. Mean comparisons were conducted by ANOVA and Wilcoxon or Tukey tests (p < 0.05).
RESULTS
No differences in osteoblasts proliferation were found. Osteoblasts grown on Ti-DoxNPs significantly increased alkaline phosphatase activity. Doxycycline and dexamethasone nanoparticles produced an over-expression of the main osteogenic proliferative genes (TGF-β1, TGF-βR1 and TGF-βR2). The expression of Runx-2 was up-regulated. The osteogenic proteins (AP, OSX and OPG) were also overexpressed on osteoblasts cultured on Ti-DoxNPs and Ti-DexNPs. The OPG/RANKL ratio was the highest when DoxNPs were present (75-fold increase with respect to the control group). DexNPs also produced a significantly higher OPG/RANKL ratio with respect to the control (20 times higher). Osteoblasts grown on titanium discs were mainly flat and polygonal in shape, with inter-cellular connections. In contrast, osteoblasts cultured on Ti-DoxNPs or Ti-DexNPs were found to be spindle-shaped and had abundant secretions on their surfaces.
SIGNIFICANCE
DoxNPs and DexNPs were able to stimulate osteoblasts differentiation when applied on titanium surfaces, being considered potential inducers of osteogenic environment when performing regenerative procedures around titanium dental implants.
Topics: Humans; Titanium; Doxycycline; Alkaline Phosphatase; Cell Differentiation; Osteogenesis; Nanoparticles; Dexamethasone; Osteoblasts; Surface Properties; Cell Proliferation
PubMed: 37173196
DOI: 10.1016/j.dental.2023.05.004 -
Journal of Infection in Developing... Feb 2023Doxycycline is an antibiotic with known gastrointestinal (GI) adverse effects. Esophagitis is the most pronounced among these effects, and might be associated with a...
INTRODUCTION
Doxycycline is an antibiotic with known gastrointestinal (GI) adverse effects. Esophagitis is the most pronounced among these effects, and might be associated with a prolonged duration of therapy. The aim of this study is to evaluate the incidence of esophagitis and other GI side effects in adults who received doxycycline for at least a month.
METHODOLOGY
This retrospective descriptive study included adults who received oral doxycycline for at least one month between 2016 and 2018. The primary outcome was the frequency of esophagitis. The secondary outcomes were frequency of and discontinuation due to GI adverse effects.
RESULTS
A total of 189 subjects were included with a median age of 32 years. The median duration of doxycycline use was 44 days (interquartile range 30-60). Twelve patients (6.3%) reported having GI adverse effects resulting in doxycycline discontinuation in five of them (2.6%), and three patients (1.6%) had esophagitis. The incidence of GI adverse effects was significantly higher in patients who were ≥ 50 years than < 50 years old (8/50 vs. 4/139; p = 0.003) and in those who received a daily dose of 200 mg than 100 mg (12/93 vs. 0/96; p < 0.001).
CONCLUSIONS
GI adverse events, including esophagitis, are not rare with long-term use of oral doxycycline, particularly in older age and a higher dose of 200 mg/day. Future large and randomized studies are needed to compare the efficacy and safety of different doxycycline doses.
Topics: Adult; Humans; Doxycycline; Retrospective Studies; Anti-Bacterial Agents; Esophagitis
PubMed: 36897904
DOI: 10.3855/jidc.16677 -
Scientific Reports Mar 2022The main objective of this study was to determine the cellular and molecular effects of doxycycline on the blood-brain barrier (BBB) and protection against secondary...
The main objective of this study was to determine the cellular and molecular effects of doxycycline on the blood-brain barrier (BBB) and protection against secondary injuries following traumatic brain injury (TBI). Microvascular hyperpermeability and cerebral edema resulting from BBB dysfunction after TBI leads to elevation of intracranial pressure, secondary brain ischemia, herniation, and brain death. There are currently no effective therapies to modulate the underlying pathophysiology responsible for TBI-induced BBB dysfunction and hyperpermeability. The loss of BBB integrity by the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) is critical to TBI-induced BBB hyperpermeability, and doxycycline possesses anti-MMP-9 effect. In this study, the effect of doxycycline on BBB hyperpermeability was studied utilizing molecular modeling (using Glide) in silico, cell culture-based models in vitro, and a mouse model of TBI in vivo. Brain microvascular endothelial cell assays of tight junction protein immunofluorescence and barrier permeability were performed. Adult C57BL/6 mice were subjected to sham versus TBI with or without doxycycline treatment and immediate intravital microscopic analysis for evaluating BBB integrity. Postmortem mouse brain tissue was collected to measure MMP-9 enzyme activity. It was found that doxycycline binding to the MMP-9 active sites have binding affinity of -7.07 kcal/mol. Doxycycline treated cell monolayers were protected from microvascular hyperpermeability and retained tight junction integrity (p < 0.05). Doxycycline treatment decreased BBB hyperpermeability following TBI in mice by 25% (p < 0.05). MMP-9 enzyme activity in brain tissue decreased with doxycycline treatment following TBI (p < 0.05). Doxycycline preserves BBB tight junction integrity following TBI via inhibiting MMP-9 activity. When established in human subjects, doxycycline, may provide readily accessible medical treatment after TBI to attenuate secondary injury.
Topics: Animals; Blood-Brain Barrier; Brain; Brain Injuries, Traumatic; Doxycycline; Humans; Mice; Mice, Inbred C57BL
PubMed: 35354869
DOI: 10.1038/s41598-022-09394-4 -
Drug Discoveries & Therapeutics Mar 2021An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which began in Wuhan, China in December 2019, has rapidly spread all over the...
An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which began in Wuhan, China in December 2019, has rapidly spread all over the world. The World Health Organization characterized the disease caused by SARS-CoV-2 (COVID-19) as a pandemic in March 2020. In the absence of specific treatments for the virus, treatment options are being examined. Drug repurposing is a process of identifying new therapeutic uses for approved drugs. It is an effective strategy to discover drug molecules with new therapeutic indications. This strategy is time-saving, low-cost, and has a minimal risk of failure. Several existing approved drugs such as chloroquine, hydroxychloroquine, doxycycline, azithromycin, and ivermectin are currently in use because of their efficacy in inhibiting COVID-19. Multidrug therapy, such as a combination of hydroxychloroquine and azithromycin, a combination of doxycycline and ivermectin, or a combination of ivermectin, doxycycline, and azithromycin, has been successfully administered. Multidrug therapy is efficacious because the mechanisms of action of these drugs differ. Moreover, multidrug therapy may prevent the emergence of drug-resistant SARS-CoV-2.
Topics: Azithromycin; Doxycycline; Drug Repositioning; Drug Therapy, Combination; Humans; Hydroxychloroquine; Ivermectin; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33612572
DOI: 10.5582/ddt.2021.01005 -
Travel Medicine and Infectious Disease 2022Antibiotics predispose travellers to acquire multidrug-resistant bacteria, such as extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE). Although widely... (Review)
Review
BACKGROUND
Antibiotics predispose travellers to acquire multidrug-resistant bacteria, such as extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-PE). Although widely used in antimalarial prophylaxis, doxycycline has scarcely been studied in this respect.
METHODS
We explored the impact of doxycycline on rates of traveller's diarrhoea (TD), ESBL-PE acquisition and, particularly, doxycycline co-resistance among travel-acquired ESBL-PE in a sample of 412 visitors to low- and middle-income countries. We reviewed the literature on traveller studies of doxycycline/tetracycline resistance among stool pathogens and the impact of doxycycline on TD rates, ESBL-PE acquisition, and doxycycline/tetracycline resistance.
RESULTS
The TD rates were similar for doxycycline users (32/46; 69.6%) and non-users (256/366; 69.9%). Of the 90 travel-acquired ESBL-PE isolates, 84.4% were co-resistant to doxycycline: 100% (11/11) among users and 82.3% (65/79) among non-users. The literature on doxycycline's effect on TD was not conclusive nor did it support a recent decline in doxycycline resistance. Although doxycycline did not increase ESBL-PE acquisition, doxycycline-resistance among stool pathogens proved more frequent for users than non-users.
CONCLUSIONS
Our prospective data and the literature review together suggest the following: 1) doxycycline does not prevent TD; 2) doxycycline use favours acquisition of doxy/tetracycline-co-resistant intestinal bacteria; 3) although doxycycline does not predispose to travel-related ESBL-PE acquisition per se, it selects ESBL-PE strains co-resistant to doxycycline; 4) doxycycline resistance rates are high among stool bacteria in general with no evidence of any tendency to decrease.
Topics: Anti-Bacterial Agents; Antimalarials; Bacteria; Diarrhea; Doxycycline; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Prospective Studies; Travel; Travel-Related Illness; beta-Lactamases
PubMed: 35872253
DOI: 10.1016/j.tmaid.2022.102403