Potential Crown Discoloration Induced by the Combination of Various Intracanal Medicaments and Scaffolds Applied in Regenerative Endodontic Therapy.

BACKGROUND: Regenerative endodontics involves the use of various root canal medicaments and scaffolds, which may cause crown discoloration. AIM: This study aimed to investigate the combined crown discoloration of scaffolds [platelet-rich fibrin (PRF) and blood clot] applied after administration of different medicaments [modified triple antibiotic paste including doxycycline (mTAPd), modified double antibiotic paste (mDAP), calcium hydroxide (CH), and propolis]. METHODS: In total, 100 human mandibular premolar teeth were selected and prepared. The teeth were apically resected to simulate immature teeth. The positive and negative control groups (n = 10) consisted solely of blood-only and serum-only samples. The remaining 80 teeth were used for the experimental groups with four different medicaments. Three weeks later, either blood or PRF was applied as a scaffold after removing the medicaments (n = 10). Color changes were assessed before medication placement and at the end of the first, second, and third weeks, as well as on days 0, 1, 30, 60, and 90 after scaffold application. Analysis was carried out using repeated measures of variance, Friedman, one-way ANOVA, Kruskal-Wallis, the dependent paired t-test, and Wilcoxon test. RESULTS: Statistical significance was determined at P = 0.05. All groups including blood and the group including propolis and PRF combination, resulted in a significant increase in discoloration (P < 0.05) and discoloration exceeding clinically acceptable thresholds. CONCLUSIONS: CH and the modified versions of TAP (mTAPd) and DAP (mDAP) demonstrated an acceptable level of discoloration when used with a combination of PRF at day 90.

Drug-induced lupus erythematosus in childhood: Case-based review.

BACKGROUND: Drug-induced lupus erythematosus (DILE) is the development of lupus-like syndrome following a drug exposure. DILE has been reported less frequently among children than adults. METHODS: In this study, we present four children with DILE and similar published cases through a systematic literature review. RESULTS: We report four children (three girls and one boy) who developed DILE associated with the use of topiramate, doxycycline, etanercept, and ethosuximide. Three of them were positive for anti-histone antibodies. In all patients, the drug was discontinued and symptoms resolved completely. The literature review revealed 48 articles describing 61 children with DILE. In the evaluation of 65 patients (our 4 patients and 61 patients from the literature), the most frequently reported drugs associated with DILE were ethosuximide (n = 13) and minocycline (n = 12). Fever (n = 33), arthralgia (n = 31), rash (n = 30), and arthritis (n = 29) were the most common clinical manifestations. Antinuclear antibody (ANA) was positive in 93.5% of patients and anti-histone antibodies were detected in 72.2% of the patients. As for treatment, the responsible drug was discontinued in all patients, and corticosteroids were initiated in 53.3%. Improvement was achieved in 92.0% of patients. CONCLUSION: For children presenting with SLE features, proper drug history is crucial since DILE may be more frequent than anticipated. An association of the relevant drug with the symptoms, and resolution of symptoms on drug withdrawal provides evidence for the diagnosis of DILE.

A case report of acute renal failure caused by anti-brucellosis treatment.

RATIONALE: Rifampicin, as a main chemotherapy drug treating brucellosis, is widely used in clinical practice. Rifampicin-associated ARF is not rare, especially in those rifampicin re-exposure patients. However, this was rare complication of severe renal involvement due to multiple factors including rifampicin, nephrotoxic gentamicin, and contrast medium, and few studies have reported it. PATIENT CONCERNS: A 59-year-old male presented to our hospital with acute renal failure (ARF) caused by anti-brucellosis treatment with rifampicin (675 mg/day), gentamicin (320 mg/day), and doxycycline (200 mg/day). He had a contrast-enhanced CT of the upper abdomen before the onset of. After stopping rifampicin and undergoing integrated therapy, the patient's renal function gradually recovered. DIAGNOSES: Considering that the patient had a history of using rifampicin for pulmonary tuberculosis in the past, based on the examination results, the patient was diagnosed with rifampicin-associated ARF. INTERVENTIONS: Symptomatic treatment such as hemodialysis, and anti-brucella treatment with doxycycline and moxifloxacin were given. OUTCOMES: The patient had significant anuric and polyuric periods and acute tubular necrosis is considered. After treatment, his renal function and urine volume returned to normal, and Brucella melitensis was not isolated from blood cultures. LESSONS: The case reveals that severe renal involvement due to multiple factors including rifampicin, nephrotoxic gentamicin, and contrast medium. Misdiagnosis and mistreatment can deteriorate the patient's condition. Renal function should be closely monitored in the susceptible patients. Early recognition can provide appropriate therapy to patients. If unexplained renal failure during the use of rifampicin, especially in those rifampicin re-exposure patients, rifampicin-associated ARF should be considered.

Pharmacokinetics of single dose doxycycline in the rectum, vagina, and urethra: implications for prevention of bacterial sexually transmitted infections.

BACKGROUND: Clinical trials showed a single oral dose of doxycycline taken after sex protects against STIs among men who have sex with men (MSM) but not women. Pharmacokinetic data at vaginal, rectal and penile sites of STI exposure are lacking. We examined vaginal, rectal and urethral doxycycline concentrations in men and women to better inform STI prevention. METHODS: Doxycycline pharmacokinetics in male and female participants 18-59 years of age were evaluated in blood and urine and on rectal and vaginal swabs collected at 1, 2, 4, 8, 24, 48, 72, 96 and 168 h after receiving a 200 mg oral doxycycline dose in a non-randomised single dose open label single centre study in Atlanta, Georgia. Rectal, vaginal, and cervical biopsies and male urethral swabs were collected 24 h after dosing (Trial registration: NCT04860505). Doxycycline was measured by liquid chromatography-mass spectrometry. FINDINGS: Eleven male and nine female participants participated in the study. Doxycycline concentrations on rectal and vaginal swabs collected up to 96 h after dosing were approximately twice those of plasma and remained above minimum inhibitory concentrations (MICs) for at least four, three, and two days for Chlamydia trachomatis, Treponema pallidum, and tetracycline-sensitive Neisseria gonorrhoeae, respectively. Geometric mean doxycycline concentrations in male urethral secretions (1.166 µg/mL; 95% CI 0.568-2.394 µg/mL), male rectal (0.596 µg/g; 0.442-0.803 µg/g), vaginal (0.261 µg/g; 0.098-0.696 µg/g) and cervical tissue (0.410 µg/g; 0.193-0.870 µg/g) in biopsies collected 24 h after dosing exceeded MICs. Plasma and urine doxycycline levels defined adherence markers up to four and seven days postdosing, respectively. No adverse events were reported in this study. INTERPRETATION: Doxycycline efficiently distributes to the rectum, vagina and urethra. Findings can help explain efficacy of STI prevention by doxycycline. FUNDING: Funded by CDC intramural funds, CDC contract HCVJCG-2020-45044 (to CFK).

A Case of Doxycycline-Induced Pancreatitis.

INTRODUCTION: Acute pancreatitis is a common cause of hospitalizations in the United States, causing approximately 230 000 to 275 000 annual admissions We present the case of a patient with acute pancreatitis likely due to doxycycline. CASE PRESENTATION: A 64-year-old male was admitted after developing acute epigastric pain radiating to his back, a lipase of 6611 (units/L), and a computed tomography scan showing moderate peripancreatic inflammation. He had no recent alcohol use, his gallbladder was surgically absent, and he had no gallbladder pathology on evaluation; however, he had been started on doxycycline 10 days prior. While hospitalized, he was treated with pain medications, fluids, and antibiotics for aspiration pneumonia. His acute symptoms resolved, except for minor intermittent abdominal pain 2 months after discharge. DISCUSSION: Doxycycline-induced pancreatitis has been reported within 3 to 17 days of medication initiation. Given the temporal correlation and lack of other inciting etiologies, we determined the most likely etiology was doxycycline. CONCLUSIONS: Further study is needed to understand the pathophysiology and incidence of doxycycline-induced pancreatitis.

Efficacy of Spironolactone Compared with Doxycycline in Moderate Acne in Adult Females: Results of the Multicentre, Controlled, Randomized, Double-blind Prospective and Parallel Female Acne Spironolactone vs doxyCycline Efficacy (FASCE) Study.

Acne in adult females is triggered mainly by hormones. Doxycycline is a reference treatment in acne. Spironolactone targets the androgen receptor of sebaceous glands and is prescribed off-label for female adult acne. This multicentre, controlled, randomized, double-blind prospective and parallel study assessed the efficacy of spironolactone compared with doxycycline in adult female acne. A total of 133 women with moderate acne were randomized to receive treatment with: (i) doxycycline and benzoyl peroxide for 3 months followed by a 3-month treatment with its placebo and benzoyl peroxide, or (ii) spironolactone and benzoyl peroxide for 6 months. Successfully treated patients continued with benzoyl peroxide or spironolactone alone for a further 6 months. Primary endpoints were treatment success at month 4 and month 6 with the AFAST score. At all visits, the ECLA score, lesion counts, local and systemic safety and quality of life were assessed. Spironolactone performed better at month 4 and showed a statistically significant better treatment success after 6 months than doxycycline (p = 0.007). Spironolactone was 1.37-times and 2.87-times more successful compared with doxycycline at respective time-points. AFAST and ECLA scores, as well as lesion counts always improved more with spironolactone. Patients' quality of life was better with spironolactone at month 4 and month 6. Spironolactone was very well tolerated. This is the first study to show that, in female adults with moderate acne, treatment with spironolactone is significantly more successful than doxycycline and very well tolerated.

Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells.

The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.

Long-Term Safety Profiles of Macrolides and Tetracyclines: A Systematic Review and Meta-Analysis.

Macrolides and tetracyclines are antibiotics that have a range of anti-inflammatory properties beyond their microbial capabilities. Although these antibiotics have been in widespread use, the long-term safety profiles are limited. We performed a systematic review and meta-analysis of randomized clinical trials that compared macrolides or tetracyclines with placeboes to provide long-term safety information. We searched Medline and EMBASE from inception to October 2022 and identified studies that reported study drug-related death, serious adverse events (SAEs), or withdrawal rates, and common adverse effects of each drug. Relative risk (RR) and number needed to harm were calculated. Of the 52 randomized clinical trials included, there are 3151 participants on doxycycline, 2519 participants on minocycline, 3049 participants on azithromycin, 763 participants on clarithromycin, 262 participants on erythromycin, and 100 participants on roxithromycin. There was no death related to any study drugs and rates of SAE were not significantly different from placebo in any drug. Overall withdrawal rates were slightly higher than placebo in doxycycline (RR, 1.30; 95% CI, 1.12-1.52) and minocycline (RR, 1.29; 95% CI, 1.15-1.46). Withdrawal rates due to adverse events were higher in doxycycline (RR, 2.82; 95% CI, 1.88-4.22), minocycline (RR, 1.48; 95% CI, 1.09-1.98), and azithromycin (RR, 1.53; 95% CI, 1.13-2.08). Gastrointestinal disturbances are the most common tolerable adverse effects for every drug. Photosensitivity and rash are the second most common adverse effects for doxycycline and minocycline. We found no evidence that long-term use up to 2 years of macrolides or tetracyclines was associated with increased risk of SAEs.

Preclinical In-Vivo Safety and Toxicokinetics of D-PLEX100 in an Abdominal Surgery Incision Model in Juvenile Miniature Swine.

D-PLEX100 (D-PLEX) is a novel product candidate made of a polymer-lipid-based matrix (PLEX platform) which contains doxycycline that is being released at a constant rate for 30 days. D-PLEX was developed to prevent surgical site infections, which are a major global health challenge. Previous studies have shown its safety in adult humans, adult swine, and adult rabbits. The aim of this study was to assess the toxicity and safety of D-PLEX also in juvenile animals to support future clinical trials in pediatric patients. Yucatan miniature swine were selected as a model, primarily due to their relatively larger mass. D-PLEX or placebo (formulation without doxycycline) was administered locally to abdominal incisions, and the animal's safety parameters were followed for 9 months and compared to sham-control swine. There was no evidence of any systemic safety concern or local toxicity at the incision site in D-PLEX-treated animals. D-PLEX was detected after 1 month and was fully resorbed at the 3-month time point. The surgical incision sites were fully healed at the 6-month time point in all D-PLEX-treated animals. Toxicokinetic (TK) assessments revealed that doxycycline exhibited low Cmax and therefore minimal systemic exposure following a single dose of local administration. This study provides evidence for the safety of D-PLEX and PLEX-based formulation in juvenile miniature swine and supports its further testing in clinical pediatric population. In addition, it can be used as a reference for future preclinical studies aiming to evaluate the safety of other PLEX-based product candidates for the pediatric population.

Systemic antibiotic treatment for meibomian gland dysfunction-A systematic review and meta-analysis.

PURPOSE: To review the efficacy and safety of oral doxycycline antibiotics versus macrolides in the treatment of meibomian gland dysfunction (MGD). DESIGN: Systematic review and meta-analysis. METHODS: We performed a systematic search of electronic databases for all peer-reviewed published studies which included clinical outcomes of oral antibiotic MGD treatment. Individual study data were extracted and evaluated in a weighted pooled analysis, including total sign and symptom scores, meibomian gland secretion score, tear break-up time (TBUT), fluorescein staining score and rate of complications. RESULTS: Two thousand nine hundred and thirty-three studies were found, of which 54 were eligible for the systematic review, and six prospective studies were ultimately included for analysis, reporting on 563 cases from three countries. Age of affected patients ranged between 12 and 90 years. Overall, both treatment methods induced improvement in MGD signs and symptoms. In pooled analysis, macrolides were significantly superior in the total signs score (pooled standardized mean difference (SMD) -0.51, 95% confidence interval (CI): -0.99 to -0.03), meibomian gland secretion score (pooled SMD -0.25, 95%CI: [-0.48, -0.03]), TBUT (SMD -0.31, 95%CI: [-0.50, -0.13]) and fluorescein staining score (SMD -1.01, 95%CI: [-1.72, -0.29]). Moreover, while no severe complications were reported for both treatments, the macrolide group exhibited significantly less adverse events (pooled odds ratio 0.24 with a 95% CI of 0.16 to 0.34). CONCLUSIONS: Both macrolides and tetracyclines are effective treatments for MGD. In this study, macrolides exhibited better efficacy and safety profile compared to tetracyclines.

Doxycycline Prophylaxis to Prevent Sexually Transmitted Infections in Women.

BACKGROUND: Doxycycline postexposure prophylaxis (PEP) has been shown to prevent sexually transmitted infections (STIs) among cisgender men and transgender women, but data from trials involving cisgender women are lacking. METHODS: We conducted a randomized, open-label trial comparing doxycycline PEP (doxycycline hyclate, 200 mg taken within 72 hours after condomless sex) with standard care among Kenyan women 18 to 30 years of age who were receiving preexposure prophylaxis against human immunodeficiency virus (HIV). The primary end point was any incident infection with Chlamydia trachomatis, Neisseria gonorrhoeae, or Treponema pallidum. Hair samples were collected quarterly for objective assessment of doxycycline use. RESULTS: A total of 449 participants underwent randomization; 224 were assigned to the doxycycline-PEP group and 225 to the standard-care group. Participants were followed quarterly over 12 months. A total of 109 incident STIs occurred (50 in the doxycycline-PEP group [25.1 per 100 person-years] and 59 in the standard-care group [29.0 per 100 person-years]), with no significant between-group difference in incidence (relative risk, 0.88; 95% confidence interval [CI], 0.60 to 1.29; P = 0.51). Among the 109 incident STIs, chlamydia accounted for 85 (78.0%) (35 in the doxycycline-PEP group and 50 in the standard-care group; relative risk, 0.73; 95% CI, 0.47 to 1.13). No serious adverse events were considered by the trial investigators to be related to doxycycline, and there were no incident HIV infections. Among 50 randomly selected participants in the doxycycline-PEP group, doxycycline was detected in 58 of 200 hair samples (29.0%). All N. gonorrhoeae-positive isolates were resistant to doxycycline. CONCLUSIONS: Among cisgender women, the incidence of STIs was not significantly lower with doxycycline PEP than with standard care. According to hair-sample analysis, the use of doxycycline PEP among those assigned to receive it was low. (Funded by the National Institutes of Health; dPEP ClinicalTrials.gov number, NCT04050540.).

Seasonal Patterns in Tetracycline-Associated Hyperpigmentation Among Patients With Acne Vulgaris.

BACKGROUND: Oral tetracyclines (TCNs) are commonly prescribed for acne, but they have been shown to increase the risk of hyperpigmentation, particularly in the setting of sun exposure. OBJECTIVE: We evaluated seasonal trends in TCN-associated hyperpigmentation incidence in addition to Google search trends for hyperpigmentation-related terms. METHODS: We performed a retrospective review of acne patients seen at Massachusetts General Brigham and Women’s Hospital between 1992 and 2022. We calculated the incidence of new hyperpigmentation diagnoses for each drug cohort. We also analyzed search volume of hyperpigmentation-related terms extracted from Google Trends. RESULTS: Seasonal differences in new hyperpigmentation diagnoses were identified among acne patients prescribed doxycycline (P=0.016), with peak incidence in April. In the control group of patients who had never received a TCN, diagnoses peaked in May. There were no significant seasonal differences among patients prescribed minocycline (P=0.885). There was greater search volume for hyperpigmentation-related terms in spring and summer compared to fall and winter (P<0.001). Limitations of this study include its retrospective nature and reliance on prescription and diagnosis coding data. CONCLUSIONS: Our findings support the seasonal periodicity of acne-related hyperpigmentation, underscoring the importance of photoprotection counseling for patients with acne. Additionally, doxycycline may be associated with an earlier onset of hyperpigmentation, suggesting a potential benefit of considering minocycline or other alternatives to doxycycline. J Drugs Dermatol. 2023;22(11):e9-e11    doi:10.36849/JDD.7409e.

ß-Lactams plus doxycycline versus azithromycin for treatment of severe community-acquired pneumonia in critically ill patients.

OBJECTIVES: Community-acquired pneumonia (CAP) is a significant source of hospital admissions and mortality. Atypical organisms are implicated in up to 40% of cases of CAP diagnoses. We studied the difference in outcomes of severe CAP patients treated with doxycycline versus azithromycin in addition to ß-lactam therapy. PATIENTS AND METHODS: This was a prospective observational cohort study from March 2020 to July 2022 in a medical ICU (MICU) of an academic quaternary medical center. Adults ≥18 years admitted to the MICU receiving doxycycline or azithromycin in addition to ß-lactam therapy for the treatment of CAP were included for analysis. The primary outcomes were in-hospital and 30 day mortality. Secondary outcomes were ICU and hospital length-of-stay, 30 day readmission, days of mechanical ventilation, escalation and duration of antibiotics, adverse effects such as Clostridioides difficile infection and QTc prolongation. RESULTS: Sixty-three patients were in the azithromycin group and eighty-six patients in the doxycycline group. Both groups had similar APACHE IV and CURB-65 scores. The mean Charlson Comorbidity Index score was higher for the doxycycline group compared with the azithromycin group (P = 0.04). There was no statistically significant difference in in-hospital and 30 day mortality between the groups (P = 0.53, P = 0.57). There were no significant differences in any of the secondary outcomes. CONCLUSIONS: MICU patients with severe CAP who received doxycycline versus azithromycin in addition to ß-lactam treatment showed no significant differences in outcomes. These data offer support for inclusion of doxycycline as an alternative regimen in current IDSA recommendations.

Doxycycline for the Treatment of Lyme Disease in Young Children.

BACKGROUND: Doxycycline is considered the first-line treatment of Lyme disease in adolescents and adults, but largely disproven concerns of permanent tooth staining prevented its use and evaluation in children <8 years old. We sought to describe short-term adverse effects and treatment failures among young children receiving oral doxycycline for Lyme disease. METHODS: We completed a 2-pronged evaluation of children with Lyme disease treated with doxycycline. We performed a retrospective case series of patients <8 years old who were diagnosed with Lyme disease and treated with doxycycline. We then performed a telephone follow-up survey study of the patients' parents to gather additional details regarding clinical outcomes and adverse reactions to doxycycline. Descriptive statistics were calculated. RESULTS: A total of 32 patients were identified through the retrospective case series and 18 participated in the follow-up survey. The most common clinical diagnosis (22/32; 69%) was single erythema migrans. Seven (22%) had neurological Lyme disease. Three patients (9%) stopped doxycycline treatment prematurely due to adverse effects. During telephone follow-up, 2 children were reported to have dental staining. No patients were identified with treatment failure during the retrospective case series. On telephone follow-up, 3 patients had residual symptoms after treatment, though none were convincing of treatment failure. CONCLUSIONS: Our study suggests that doxycycline is generally well-tolerated and an effective treatment of Lyme disease in young children. Prospective, observational studies with long-term assessment of dental staining and clinical outcomes are needed. Alternative antibiotics, principally amoxicillin, remain the preferred treatment of non-neurological Lyme disease manifestations in young children, but doxycycline is likely a safe and effective alternative when needed.

Severe Ureaplasma urealyticum infection in a patient with ocrelizumab-induced hypogammaglobulinaemia.

Infections caused by Ureaplasma urealyticum in immune-competent people are typically simple and uncomplicated. However, in cases of immunosuppression, severe disseminated infections can occur.This case report describes the case of a severe, disseminated infection caused by U. urealyticum in a young female with unacknowledged humoral immunosuppression due to treatment with ocrelizumab for multiple sclerosis.The patient was admitted due to a recurrent episode of a tubo-ovarian abscess. Throughout the following 2 months of hospitalisation, treatment with several types of antibiotics and the placement of various drains led to no improvement. As extensive investigations indicated hypogammaglobulinaemia, U. urealyticum was suspected, and tests came back positive. Treatment with doxycycline and moxifloxacin led to a full recovery.This demonstrates how humoral immunosuppression is a risk factor for severe disseminated infections and how these may be avoided through monitoring of immunoglobulin levels in patients treated with ocrelizumab.

Efficacy of supramolecular salicylic acid in combination with doxycycline in the treatment of acne.

To determine the efficacy of supramolecular salicylic acid combined with doxycycline on acne, totally 70 patients with acne treated in our dermatology department from May 2020 to May 2021 were enrolled and randomized (1:1) into control or experimental groups using the random number table method. The control group was given doxycycline for oral administration while the experimental group was given oral doxycycline combined with supramolecular salicylic acid for topical administration. The overall effective rate of treatment was significantly higher in the experimental group versus control group (97.14% vs. 82.86%, P<0.05). Patients in the control group had significantly longer mean acne regression time after treatment versus experimental group (P<0.05). After treatment, patients in the experimental group had significantly lower self-rating depression scale (SDS) scores and self-perceived burden (SPB) scores than the control group, while Short Form 36-item health survey (SF-36) scores were significantly higher than the control group (P<0.05). The overall incidence of adverse reactions was significantly lower in the experimental group versus control group (5.71% vs. 17.14%, P<0.05). Supramolecular salicylic acid in combination with doxycycline in the treatment of patients with acne is an optimal option, as it could better promote acne regression, reduce the level of depression and reduce the patient's self-perceived burden.