Efficacy of prophylactic antibiotics for preterm premature rupture of membranes: a systematic review and network meta-analysis.

OBJECTIVE: Various prophylactic antibiotic regimens are used in the management of preterm premature rupture of membranes. We investigated the efficacy and safety of these regimens in terms of maternal and neonatal outcomes. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception to July 20, 2021. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials involving pregnant women with preterm premature rupture of membranes before 37 weeks of gestation and a comparison of ≥2 of the following 10 antibiotic regimens: control/placebo, erythromycin, clindamycin, clindamycin plus gentamicin, penicillins, cephalosporins, co-amoxiclav, co-amoxiclav plus erythromycin, aminopenicillins plus macrolides, and cephalosporins plus macrolides. METHODS: Two investigators independently extracted published data and assessed the risk of bias with a standard procedure following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Network meta-analysis was conducted using the random-effects model. RESULTS: A total of 23 studies that recruited a total of 7671 pregnant women were included. Only penicillins (odds ratio, 0.46; 95% confidence interval, 0.27-0.77) had significantly superior effectiveness for maternal chorioamnionitis. Clindamycin plus gentamicin reduced the risk of clinical chorioamnionitis, with borderline significance (odds ratio, 0.16; 95% confidence interval, 0.03-1.00). By contrast, clindamycin alone increased the risk of maternal infection. For cesarean delivery, no significant differences were noted among these regimens. CONCLUSION: Penicillins remain the recommended antibiotic regimen for reducing maternal clinical chorioamnionitis. The alternative regimen includes clindamycin plus gentamicin. Clindamycin should not be used alone.

Erythromycin prior to endoscopy for acute upper gastrointestinal haemorrhage.

BACKGROUND: Upper endoscopy is the definitive treatment for upper gastrointestinal haemorrhage (UGIH). However, up to 13% of people who undergo upper endoscopy will have incomplete visualisation of the gastric mucosa at presentation. Erythromycin acts as a motilin receptor agonist in the upper gastrointestinal (GI) tract and increases gastric emptying, which may lead to better quality of visualisation and improved treatment effectiveness. However, there is uncertainty about the benefits and harms of erythromycin in UGIH. OBJECTIVES: To evaluate the benefits and harms of erythromycin before endoscopy in adults with acute upper gastrointestinal haemorrhage, compared with any other treatment or no treatment/placebo. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 October 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that investigated erythromycin before endoscopy compared to any other treatment or no treatment/placebo before endoscopy in adults with acute UGIH. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. UGIH-related mortality and 2. serious adverse events. Our secondary outcomes were 1. all-cause mortality, 2. visualisation of gastric mucosa, 3. non-serious adverse events, 4. rebleeding, 5. blood transfusion, and 5. rescue invasive intervention. We used GRADE criteria to assess the certainty of the evidence for each outcome.  MAIN RESULTS: We included 11 RCTs with 878 participants. The mean age ranged from 53.13 years to 64.5 years, and most participants were men (72.3%). One RCT included only non-variceal haemorrhage, one included only variceal haemorrhage, and eight included both aetiologies. We defined short-term outcomes as those occurring within one week of initial endoscopy. Erythromycin versus placebo Three RCTs (255 participants) compared erythromycin with placebo. There were no UGIH-related deaths. The evidence is very uncertain about the short-term effects of erythromycin compared with placebo on serious adverse events (risk difference (RD) -0.01, 95% confidence interval (CI) -0.04 to 0.02; 3 studies, 255 participants; very low certainty), all-cause mortality (RD 0.00, 95% CI -0.03 to 0.03; 3 studies, 255 participants; very low certainty), non-serious adverse events (RD 0.01, 95% CI -0.03 to 0.05; 3 studies, 255 participants; very low certainty), and rebleeding (risk ratio (RR) 0.63, 95% CI 0.13 to 2.90; 2 studies, 195 participants; very low certainty). Erythromycin may improve gastric mucosa visualisation (mean difference (MD) 3.63 points on 16-point ordinal scale, 95% CI 2.20 to 5.05; higher MD means better visualisation; 2 studies, 195 participants; low certainty). Erythromycin may also result in a slight reduction in blood transfusion (MD -0.44 standard units of blood, 95% CI -0.86 to -0.01; 3 studies, 255 participants; low certainty). Erythromycin plus nasogastric tube lavage versus no intervention/placebo plus nasogastric tube lavage Six RCTs (408 participants) compared erythromycin plus nasogastric tube lavage with no intervention/placebo plus nasogastric tube lavage. There were no UGIH-related deaths and no serious adverse events. The evidence is very uncertain about the short-term effects of erythromycin plus nasogastric tube lavage compared with no intervention/placebo plus nasogastric tube lavage on all-cause mortality (RD -0.02, 95% CI -0.08 to 0.03; 3 studies, 238 participants; very low certainty), visualisation of the gastric mucosa (standardised mean difference (SMD) 0.48 points on 10-point ordinal scale, 95% CI 0.10 to 0.85; higher SMD means better visualisation; 3 studies, 170 participants; very low certainty), non-serious adverse events (RD 0.00, 95% CI -0.05 to 0.05; 6 studies, 408 participants; very low certainty), rebleeding (RR 1.13, 95% CI 0.63 to 2.02; 1 study, 169 participants; very low certainty), and blood transfusion (MD -1.85 standard units of blood, 95% CI -4.34 to 0.64; 3 studies, 180 participants; very low certainty). Erythromycin versus nasogastric tube lavage Four RCTs (287 participants) compared erythromycin with nasogastric tube lavage. There were no UGIH-related deaths and no serious adverse events. The evidence is very uncertain about the short-term effects of erythromycin compared with nasogastric tube lavage on all-cause mortality (RD 0.02, 95% CI -0.05 to 0.08; 3 studies, 213 participants; very low certainty), visualisation of the gastric mucosa (RR 1.19, 95% CI 0.79 to 1.79; 2 studies, 198 participants; very low certainty), non-serious adverse events (RD -0.10, 95% CI -0.34 to 0.13; 3 studies, 213 participants; very low certainty), rebleeding (RR 0.77, 95% CI 0.40 to 1.49; 1 study, 169 participants; very low certainty), and blood transfusion (median 2 standard units of blood, interquartile range 0 to 4 in both groups; 1 study, 169 participants; very low certainty). Erythromycin plus nasogastric tube lavage versus metoclopramide plus nasogastric tube lavage One RCT (30 participants) compared erythromycin plus nasogastric tube lavage with metoclopramide plus nasogastric tube lavage. The evidence is very uncertain about the effects of erythromycin plus nasogastric tube lavage on all the reported outcomes (serious adverse events, visualisation of gastric mucosa, non-serious adverse events, and blood transfusion). AUTHORS' CONCLUSIONS: We are unsure if erythromycin before endoscopy in people with UGIH has any clinical benefits or harms. However, erythromycin compared with placebo may improve gastric mucosa visualisation and result in a slight reduction in blood transfusion.

Pregnancy outcomes following maternal macrolide use: A systematic review and meta-analysis.

To determine whether gestational use of all or specific macrolides (azithromycin, clarithromycin, roxithromycin or erythromycin) lead to an increase in rates of overall major congenital malformations, organ-specific malformations, and other adverse pregnancy outcomes in infants. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox® databases were searched. Dichotomous outcomes or calculated log odds ratios and standard errors from observational studies are combined using the random-effects method in Review Manager 5.3. No significant increased risks for major congenital malformation (OR 1.06 [95% CI 0.99, 1.13]) and congenital heart defect (OR 1.05 [95% CI 0.92, 1.19]) following all macrolides use during the first trimester were detected. Prenatal azithromycin use was associated with a significantly increased risk of major congenital malformations in the analysis of cohort studies (OR 1.21 [95% CI 1.08-1.36]). This significance was also present in the sensitivity analysis. There were no statistically significant associations between the risk of organ specific malformations and all or specific macrolide exposures except for the decreased risk in hypospadias following erythromycin use in the meta-analysis of case-control studies (OR 0.38 [95% CI 0.18, 0.81]. Also, a significant 1.5-fold increased risk for spontaneous abortion following macrolide use was detected. A slight yet significantly increased rate of major congenital malformation with azithromycin exposure during pregnancy may be associated with maternal confounders. Nevertheless, level II ultrasound can be suggested following maternal azithromycin use during the first trimester. Future studies should take into account the inclusion of a disease-matched control group and accurate classification of the malformations.

Efficacy of erythromycin compared to clarithromycin and azithromycin in adults or adolescents with community-acquired pneumonia: A Systematic Review and meta-analysis of randomized controlled trials.

BACKGROUND: It is debatable whether erythromycin has similar efficacy to other macrolides in treating community-acquired pneumonia (CAP). The aim of this meta-analysis is to compare the efficacy of erythromycin with clarithromycin and azithromycin. METHODS: We performed this meta-analysis of randomized controlled trials (RCTs) of adults or adolescents with CAP which compared the efficacy of erythromycin monotherapy to either azithromycin or clarithromycin. We searched PubMed and EMBASE and Cochrane Library databases and three clinical trial registries up to November 02, 2021. We evaluated heterogeneity and used random-effects models to perform risk ratios with 95% confidence intervals. RESULTS: We included four RCTs (total of 472 patients), which compared the clinical efficacy of erythromycin versus clarithromycin. No studies comparing monotherapy of erythromycin versus azithromycin were found. Erythromycin use was associated with significantly lower rates of clinical success (RR, 0.79; 95% CI, 0.64 to 0.98; P-value = 0.033; I2 = 20.27%), clinical cure (RR,0.67; 95% CI, 0.48 to 0.92; P-value = 0.014; I2 = 8.75%), and radiological success (RR, 0.84; 95% CI, 0.71 to 0.996; P-value = 0.045; I2 = 20.12%) than clarithromycin. CONCLUSION: Erythromycin is less effective than clarithromycin as empiric treatment of CAP in adults and adolescents. Because of this and the higher rate of adverse reactions, erythromycin should not be used in the majority of CAP patients when azithromycin and clarithromycin are available.

Effects of the Moderate CYP3A4 Inhibitor Erythromycin on the Pharmacokinetics of Palbociclib: A Randomized Crossover Trial in Patients With Breast Cancer.

Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-24h ), maximum plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) were 1.46 × 103  ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103  ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0-24h , Cmax , and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24-1.66), 1.43 (1.20-1.69), and 1.46 (1.30-1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0-24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.

Torsade de pointe due to QT prolongation following erythromycin administration in a preterm infant.

BACKGROUND: Neonatal sepsis is a major cause of morbidity and mortality in preterm infants. Chorioamnionitis is an important risk factor for the development of sepsis, therefore neonates born to mothers developing signs of amnionitis need to be treated with antibiotics immediately after birth. Ureaplasma spp can be a causative agent of vaginal or intra amniotic infection needing antibiotic treatment. Macrolides are frequently used to treat maternal intrauterine infection, but antibiotic treatment of the neonate should be consciously chosen with consideration of potential side effects. Indeed, macrolides are great purveyors of heart rhythm disorders. CASE PRESENTATION: We describe the case of a 29 weeks preterm infant born to a mother with Ureaplasma spp infection. The baby was treated with erythromycin immediately after birth. During the second day of life, the baby presented some episodes of tachyarrhythmia with premature ventricular beats (PVBs) that were followed by a non-sustained ventricular tachycardia as high as 270 bpm leading to a cardiac arrest. After resuscitation, tachycardia resolved but the rhythm was characterised by numerous PVBs and an electrocardiogram (ECG) diagnosed a Long QT Syndrome (LQTS). Erythromycin was discontinued, and the rhythm normalised a few days after withdrawal. CONCLUSIONS: Erythromycin should be administered in neonates only if no other choice is available, as although generally well tolerated, its administration can be associated with QTc interval prolongation. When no other option is available, paediatricians should be aware to perform cardiac monitoring or at least serial ECGs before and during erythromycin administration.

Delirium associated with the use of macrolide antibiotics: a review.

OBJECTIVE: This review aimed to explore and summarise available cases of delirium suspected to be associated with the use of macrolide antibiotics reported in the literature and the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. METHODS: Electronic searches of the literature were conducted in four online databases: PubMed/MEDLINE, Scopus, Web of Science and Serbian Citation Index (SCIndeks). A search of FAERS database was also conducted to supplement the findings of the literature search. Descriptive statistics, narrative summation and tabulation of the extracted data were made. RESULTS: Cases of delirium which satisfied inclusion criteria were found for clarithromycin, azithromycin, erythromycin and telithromycin. Delirium was described in patients of various age groups, including children. Drug-drug interactions may have contributed to its occurrence in some of the cases. Average time to onset of delirium was 2.5 days for azithromycin and 3.3 days for clarithromycin. CONCLUSIONS: Considering that these drugs may be a possible cause of delirium, clinicians should be aware that timely recognition of this possible side effect can lead to earlier discontinuation of the culprit drug, reduce time spent in a delirious state and improve patients' outcomes.KEY POINTSCases of delirium which satisfied inclusion criteria were found for clarithromycin, azithromycin, erythromycin and telithromycin.Cases of delirium were described in patients of various age groups, including children.Drug-drug interactions may have contributed to the occurrence of delirium in some of the cases.Time to onset of delirium ranged from 2 to 3.5 days (mean: 2.5 days) for azithromycin and from 1 to 7 days (mean: 3.3 days) for clarithromycin.Cessation of the macrolide antibiotic seems to be the best management strategy, although some of the patients may, in addition, require antipsychotics.

Safe Use of Erythromycin For Refractory Gastroparesis After Small Bowel Transplantation.

Current therapeutic options with prokinetic agents for posttransplant gastroparesis are limited. Erythromycin is associated with adverse reactions, including corrected QT interval prolongation and cytochrome P450 3A4 isoenzyme inhibition. The use of erythromycin has been avoided in patients undergoing treatment with cyclosporine or tacrolimus because of significant fluctuations in therapeutic immunosuppression levels. We report herein the successful use of erythromycin after visceral transplant to treat delayed gastric emptying. Two patients were managed with oral erythromycin (initial dose of 750 mg/d divided into 3 doses) for gastroparesis after visceral transplant. Patient 1 was a woman aged 42 years with a history of chronic intestinal pseudo-obstruction syndrome who underwent isolated small bowel transplant with dual (gastric and duodenal) proximal allograft anastomosis. Posttransplant gastroparesis was initially managed with oral metoclopramide. The patient also required high doses of tacrolimus (36 mg/d) to maintain adequate immunosuppression levels. The decision was made to change metoclopramide to erythromycin, which significantly decreased the daily tacrolimus dose requirement (from 36 to 9 mg/d), with resolution of nausea and intermittent bloating symptoms. Patient 2 was a woman aged 35 years with ultra-short gut syndrome after extensive enterectomy due to intestinal volvulus who underwent uneventful combined intestinal and colon transplant. Conventional pharmacologic therapy for gastroparesis was initiated after surgery without success. Erythromycin was started 15 days posttransplant, with significant improvement in her symptoms, and discontinued 47 days post-transplant. To maintain therapeutic levels (8-10 mg/dL), daily tacrolimus dose was decreased 75.8% and 36.5% for patients 1 and 2, respectively. No significant side effects associated with erythromycin use were observed in either patient. Our findings here suggest that erythromycin may be safely used for gastroparesis after small bowel transplant. Close monitoring of immunosuppressive drug levels and dose adjustments of other medications affected by inhibition of cytochrome P450 3A4 are advised.

Dynamics of the QTc interval over a 24-h dose interval after start of intravenous ciprofloxacin or low-dose erythromycin administration in ICU patients.

QTc interval prolongation is an adverse effect associated with the use of fluoroquinolones and macrolides. Ciprofloxacin and erythromycin are both frequently prescribed QTc-prolonging drugs in critically ill patients. Critically ill patients may be more vulnerable to developing QTc prolongation, as several risk factors can be present at the same time. Therefore, it is important to know the QTc-prolonging potential of these drugs in the intensive care unit (ICU) population. The aim of this study was to assess the dynamics of the QTc interval over a 24-hour dose interval during intravenous ciprofloxacin and low-dose erythromycin treatment. Therefore, an observational study was performed in ICU patients (≥18 years) receiving ciprofloxacin 400 mg t.i.d. or erythromycin 100 mg b.i.d. intravenously. Continuous ECG data were collected from 2 h before to 24 h after the first administration. QT-analyses were performed using high-end holter software. The effect was determined with a two-sample t-test for clustered data on all QTc values. A linear mixed model by maximum likelihood was applied, for which QTc values were assessed for the available time intervals and therapy. No evident effect over time on therapy with ciprofloxacin and erythromycin was observed on QTc time. There was no significant difference (p = 0.22) in QTc values between the ciprofloxacin group (mean 393 ms) and ciprofloxacin control group (mean 386 ms). The erythromycin group (mean 405 ms) and erythromycin control group (mean 404 ms) neither showed a significant difference (p = 0.80). In 0.6% of the registrations (1.138 out of 198.270 samples) the duration of the QTc interval was longer than 500 ms. The index groups showed slightly more recorded QTc intervals over 500 ms. To conclude, this study could not identify differences in the QTc interval between the treatments analyzed.

Risk of corneal epithelial defects with and without postoperative erythromycin ointment after laser photocoagulation for retinopathy of prematurity.

Purpose: We aim to compare the incidence of corneal epithelial defects after laser for retinopathy of prematurity (ROP) with and without the use of postoperative erythromycin ointment. Methods: In this retrospective observational cohort study, a total of 100 infants (200 eyes) consecutively treated with laser for ROP between 2012 and 2018. The primary outcome was presence or absence of corneal epithelial defect using fluorescein on bedside examination within the first week following laser for ROP. Additional data assessed included: the use of postoperative prophylactic erythromycin ointment for 1 week, postoperative day on which examination using fluorescein occurred, presence of corneal opacity, gender, birth weight, and gestation age. The presence or absence of postoperative corneal epithelial defects was compared between eyes receiving postoperative erythromycin ointment or not using a Fisher's exact test. Results: Postoperative corneal epithelial defects were more common in eyes which did not receive postoperative erythromycin (7 of 40 eyes; 17.5%), compared to eyes which did receive erythromycin (1 of 160 eyes; 0.6%; P < 0.0001). Postoperative bedside examinations with fluorescein were performed within 2 days of surgery on 136 of 200 of eyes (68%). Corneal opacities were noted in 3 of 200 eyes (1.5%). Conclusion: We observed less corneal epithelial defects in eyes which received postoperative erythromycin ointment for 1 week after laser for ROP than in those which did not. While multiple variables may influence the presence or absence of postoperative corneal epithelial defects following laser for ROP, consideration for postoperative lubricating ointment following laser for ROP seems reasonable.

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.

Real-World Fetal Exposure to Acne Treatments in the United States: A Retrospective Analysis from 2006 to 2015.

INTRODUCTION: Several studies have evaluated the effects of changes in isotretinoin risk mitigation programs, but little is known about actual fetal exposure rates in the context of other acne treatments. OBJECTIVE: Our objective was to quantify fetal exposure rates during the use of common acne treatments. METHODS: Employing the insurance claims data of > 100,000 acne treatment users between 2006 and 2015, we created three user cohorts: (1) isotretinoin (strong teratogen/mandatory risk mitigation program), (2) doxycycline/minocycline (mild teratogen, label warning), and (3) topical clindamycin/erythromycin (no fetal risk). Fetal exposure rates overall and stratified by age were compared after adjusting for potential confounders. RESULTS: Contraceptive use during acne treatment was < 50% in isotretinoin users and < 30% in the other study groups. Long-acting contraceptives contributed to 1% of all contraceptives used, with 90% being oral contraceptives. Isotretinoin users had 19.2 (95% confidence interval [CI] 20.3 to 17.9) fewer fetal exposures per 1000 person-years of use compared with doxycycline/minocycline users, which in turn had 28.8 (95% CI 31.2 to 26.3) fewer pregnancies compared with clindamycin/erythromycin users. Stratification by age showed attenuated differences in fetal exposure among acne treatment groups for teenagers. CONCLUSION: Fetal exposure to acne treatments varied according to levels of teratogenicity, with reduced rates among users of isotretinoin and to a lesser extent doxycycline/minocycline. Teenagers had low pregnancy rates but less pronounced differences in fetal exposure across acne treatments.

The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2.

A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.

Effects of a combination of erythromycin sequential therapy and azithromycin on lung function and inflammatory factors in children with severe mycoplasma pneumonia.

This study aimed to investigate the effect of erythromycin sequential therapy plus azithromycin on lung function and inflammatory factors in children with severe mycoplasma pneumonia (MP). Ninety-three severe MP children were selected and randomized into azithromycin group, erythromycin group, and combination group, 31 cases in each. The disappearance time of cough, fever, lung rale and X-ray shadow in the combination group were shorter than those in the azithromycin group and erythromycin group. The clinical treatment efficiency of the combination group was higher than that of the azithromycin group. After treatment, FVC, FEV1/FVC and PEF in combination group were higher than before treatment; IL-8, IL-6, CRP in combination group were lower than erythromycin group and azithromycin group. IL-8, IL-6, CRP are negatively correlated with disappearance time of cough, fever, pulmonary rale, X-ray shadow and clinical treatment efficiency; FEV1/FVC is positively correlated with disappearance time of cough and fever, pulmonary rales and X-ray shadow, and clinical treatment efficiency. Sequential erythromycin therapy combined with azithromycin in the treatment of MP can effectively inhibit high inflammatory reactions, control the disease in a timely manner, improve lung function and produce fewer adverse reactions.

Stevens-Johnson syndrome and toxic epidermal necrolysis associated with the use of macrolide antibiotics: a review of published cases.

Macrolides are one of the most commonly prescribed antibiotics. In several studies, their use was associated with the occurrence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review aimed to explore and summarize available cases of SJS/TEN suspected to be associated with the use of macrolide antibiotics reported in the literature. Electronic searches were conducted in PubMed/MEDLINE, Web of Science, Scopus, and Serbian Citation Index (SCIndeks). Twenty-five publications describing a total of 27 patients were included. Cases of SJS/TEN which satisfied inclusion criteria were found for azithromycin (n = 11), clarithromycin (n = 7), erythromycin (n = 5), roxithromycin (n = 2), and telithromycin (n = 2). The age of the patients ranged from 2 to 77 years (median: 29 years). There were 14 female (51.9%) and 13 male (48.1%) patients. SJS was diagnosed in 16 patients (59.3%), TEN in 10 patients (37.0%), and SJS/TEN overlap in one patient (3.7%). Time to onset of the first symptoms ranged from 1 to 14 days (median: 3 days). All patients received some form of supportive and symptomatic care. Systemic corticosteroids were reported to be administered in 12 patients (44.4%) and intravenous immunoglobulin in five patients (18.5%). Three patients (11.1%) died. Considering that SJS/TEN is a severe and potentially life-threatening reaction, physicians should be aware that they could be adverse effects of macrolide antibiotics and keep in mind that prompt recognition of SJS/TEN and discontinuation of the culprit drug in combination with supportive care is essential.

Vaginal Microbiome in Preterm Rupture of Membranes.

There is an association between vaginal microbiota dysbiosis and preterm premature rupture of membranes (PPROM). In PPROM, reduced Lactobacillus spp abundance is linked to the emergence of high-risk vaginal microbiota, close to the time of membrane rupture. Although PPROM itself can change vaginal microbial composition, antibiotic therapy profoundly effects community structure. Erythromycin may have a beneficial effect in women deplete in Lactobacillus spp but damages a healthy microbiome by targeting Lactobacillus spp. Increased rates of chorioamnionitis and early-onset neonatal sepsis are associated with vaginal microbiota dysbiosis close to the time of delivery.

A retrospective assessment and comparison of the effectiveness of benzoyl peroxide; the combination of topical niacinamide, gallic acid, and lauric acid; and the combination of benzoyl peroxide and erythromycin in acne vulgaris.

Acne vulgaris is a chronic inflammatory skin disease that mostly develops during adolescence and continues throughout adulthood. It affects the face, the main location of cosmetic appearance. Despite many developments in acne treatment, various combination therapies are needed to create the best option. Ninety patients were included in this study. We used the global acne grading system (GAGS) and the lesion counting and photographic standards that were used by Hayashi et al., to assess acne severity. The patients were randomly divided into three groups as group 1 (using only 5% BPO, twice a day), group 2 (using only the combination of 5% BPO + 3% erythromycin, twice a day), and group 3 (using only the combination of 4% niacinamide + 1% gallic acid + 1% lauric acid, twice a day). Thirty patients were included in each group. The scores were evaluated at weeks 0, 2, 4 and 8, and compared with each other. As a result of the study, all three treatment types were found to be effective. The combination of 4% niacinamide + 1% gallic acid + 1% lauric acid can be used as an alternative topical treatment for acne vulgaris to prevent resistance against topical antibiotics and the side effects of some other treatments.

Topical azelaic acid, salicylic acid, nicotinamide, sulphur, zinc and fruit acid (alpha-hydroxy acid) for acne.

BACKGROUND: Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha-hydroxy acid is unclear. OBJECTIVES: To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for acne. SEARCH METHODS: We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers. SELECTION CRITERIA: Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life. MAIN RESULTS: We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA. The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years. We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias. We grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor adverse events. Azelaic acid In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate-quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low-quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). Low-quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low-quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low-quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling. Salicylic acid For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low-quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide. There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low-quality evidence). For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low-quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness. Nicotinamide Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low-quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison. Alpha-hydroxy (fruit) acid There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low-quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low-quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low. Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head-to-head trials against commonly used active drugs.

A genome-wide analysis of targets of macrolide antibiotics in mammalian cells.

Macrolide antibiotics, such as erythromycin and josamycin, are natural polyketide products harboring 14- to 16-membered macrocyclic lactone rings to which various sugars are attached. These antibiotics are used extensively in the clinic because of their ability to inhibit bacterial protein synthesis. More recently, some macrolides have been shown to also possess anti-inflammatory and other therapeutic activities in mammalian cells. To better understand the targets and effects of this drug class in mammalian cells, we used a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate cellular sensitivity to josamycin. Among the most sensitizing hits were proteins involved in mitochondrial translation and the mitochondrial unfolded protein response, glycolysis, and the mitogen-activated protein kinase signaling cascade. Further analysis revealed that cells treated with josamycin or other antibacterial agents exhibited impaired oxidative phosphorylation and metabolic shifts to glycolysis. Interestingly, we observed that knockdown of the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) gene, which contributes to p38 mitogen-activated protein kinase signaling, sensitized cells only to josamycin but not to other antibacterial agents. There is a growing interest in better characterizing the therapeutic effects and toxicities of antibiotics in mammalian cells to guide new applications in both cellular and clinical studies. To our knowledge, this is the first report of an unbiased genome-wide screen to investigate the effects of a clinically used antibiotic on human cells.