Use Of Macrolides Research Articles

Regional and National Trends in Consumption of Antimicrobials in Pakistan; Pre and Post-COVID (2019-2021).

Efforts to combat antimicrobial resistance, a growing public health problem in Pakistan, have been hampered by the lack of high-quality national and provincial-level antimicrobial consumption data. The singular objective of this retrospective study was to measure antimicrobial consumption over 3 years between 2019 and 2021. The study was designed to estimate antimicrobial consumption at National and Regional levels. Antimicrobial consumption data was collected by IQVIA covering 110 districts of Pakistan in which 88% of sales are census (accurate sales collected directly from distributors), whereas 12% of sales (sales of 300 pharmacies) are projected on the national level. To determine the usage for 3 consecutive years, the consumption of antibiotics was calculated as defined daily doses (DDD) of antibiotics per 1000 inhabitants per day (DID). The results of our study demonstrated a steep increase in the consumption of antimicrobials from 2019 to 2021. An increase in consumption of most classes of antibiotics was observed both nationally and Regionally. Quinolones, penicillins (co-amoxiclav), macrolides, and third-generation cephalosporins remained the most frequently used antibiotics nationally. A 40% increase in intravenous use of antimicrobials was observed between 2019 and 2021 at the national level. Moxifloxacin, Levofloxacin, Ciprofloxacin, and linezolid were the most commonly used intravenous antibiotics. Region 7 (Peshawar) demonstrated the highest consumption, followed by Region 1 (Karachi) and Region 6 (Faisalabad). Among the most commonly used antibiotics, the use of third-generation cephalosporin (cefixime), quinolones, penicillins (amoxicillin + clavulanic acid), and macrolides (azithromycin) was most noticeable in all regions, particularly in those with the higher consumption of antibiotics. Although the increase in consumption of all antibiotics is concerning, the steep increase in the use of watch and reserve category antibiotics during the study period calls for immediate actions to limit and regulate their usage.

Antibiotic Potentiation as a Promising Strategy to Combat Macrolide Resistance in Bacterial Pathogens.

Antibiotics, which hit the market with astounding impact, were once called miracle drugs, as these were considered the ultimate cure for infectious diseases in the mid-20th century. However, today, nearly all bacteria that afflict humankind have become resistant to these wonder drugs once developed to stop them, imperiling the foundation of modern medicine. During the COVID-19 pandemic, there was a surge in macrolide use to treat secondary infections and this persistent use of macrolide antibiotics has provoked the emergence of macrolide resistance. In view of the current dearth of new antibiotics in the pipeline, it is essential to find an alternative way to combat drug resistance. Antibiotic potentiators or adjuvants are non-antibacterial active molecules that, when combined with antibiotics, increase their activity. Thus, potentiating the existing antibiotics is one of the promising approaches to tackle and minimize the impact of antimicrobial resistance (AMR). Several natural and synthetic compounds have demonstrated effectiveness in potentiating macrolide antibiotics against multidrug-resistant (MDR) pathogens. The present review summarizes the different resistance mechanisms adapted by bacteria to resist macrolides and further emphasizes the major macrolide potentiators identified which could serve to revive the antibiotic and can be used for the reversal of macrolide resistance.

Current status and trends in antimicrobial use in food animals in China, 2018–2020

Antimicrobial resistance poses a significant threat to global public health, and excessive antimicrobial use (AMU) in animals is a major contributing factor. We used national AMU data for food animals to examine the current status and trends for AMU in food animals in China from 2018–2020. In 2020, China used 32,776.30 tons of antimicrobials in food animals, amounting to 165 g of antimicrobials per ton of animal products. AMU in China increased throughout the 2018–2020 study period; however, the data still showed a consistent and notable reduction from those of 2017, coinciding with the implementation of the China National Action Plan for Combating Animal Antimicrobial Resistance. Among the antimicrobials used, tetracyclines, macrolides and β-lactams (including β-lactam inhibitors) were the most commonly used in food animals. Analysis by antimicrobial class revealed shifts in usage patterns, such as decreased tetracycline use and increased macrolide and β-lactam use. Furthermore, the use of antimicrobial growth promoters decreased sharply, from 51.78% in 2018 to 28.7% in 2020. Compared with AMU data from other countries, China used more antimicrobials, but the values were relatively lower when adjusted for population correction units. These findings highlight China's remarkable efforts in combating antimicrobial resistance and promoting antimicrobial stewardship, thus contributing significantly to global initiatives.

Risk of major cardiovascular events and bleeding in atrial fibrillation patients with chronic obstructive pulmonary disease treated with low dose azithromycin prophylaxis

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events in patients with atrial fibrillation (AF). Low Dose Azithromycin Prophylaxis (LDAP) is associated with improved outcomes in people suffering frequent exacerbations of COPD, but the widespread use of macrolides in patients with underlying cardiovascular disease has been debated due to safety concerns. Aims and Objectives To investigate the safety and efficacy of LDAP in AF patients with COPD in a large global federated dataset. Methods We conducted a retrospective cohort study within the global TriNetX Platform, including AF patients with COPD exacerbations. Risks for all-cause death, major adverse cardiovascular events (MACE: acute coronary syndrome, thromboembolic events, severe ventricular arrhythmias, and heart failure), intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding were recorded up to 30 days post-COPD exacerbations and compared between LDAP users (at least 3 months use and using LDAP at index) and an active control group (non-Azithromycin users receiving inhaled corticosteroids (ICS)). Cox regression analyses compared outcomes between groups after propensity-score-matching (PSM) for cardiovascular risk factors. Results We identified 2791 LDAP users with COPD and AF (mean age 71.5±10.6 years, 48.9% female), and 61054 controls. Before PSM, LDAP users showed a lower prevalence of cardiovascular risk factors and were less likely to be prescribed oral anticoagulation (68.1% vs 76.1%, p<0.001). After PSM no significant baseline differences were found between two groups. After COPD exacerbation, LDAP users were associated with a lower 30-day risk of all-cause death (HR: 0.72, 95%CI 0.60-0.97), MACE (HR 0.72, 95%CI 0.57-0.90), ICH (0.48, 95%CI 0.27-0.88) and GI bleeding (HR 0.69,95%CI 0.46-0.89) compared to the conventional treatment with ICS. Analysing the different time frames, the lower risk of thrombotic events was observed during the second week after COPD exacerbation while the magnitude of the bleeding risk reduction was more evident in the first 7 days (Figure 1). Conclusion LDAP use is associated with a lower risk of all-cause death, MACE and bleeding in AF patients with COPD. Further studies are needed to investigate the possible role of LDAP as part of the integrated care management of AF patients with COPD.

The Effectiveness and Safety of Long-Term Macrolide Therapy for COPD in Stable Status: A Systematic Review and Meta-Analysis.

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition with fewer treatments available as the severity increases. Previous systematic reviews have demonstrated the benefits of long-term macrolide use. However, the therapeutic differences between different macrolides and the optimal duration of use remain unclear. Methods: A systematic review and meta-analysis were conducted to assess the effectiveness of long-term macrolide use in reducing COPD exacerbations, compare the therapeutic differences among macrolides, and determine the appropriate treatment duration. Four databases (PubMed, Cochrane Library, Web of Science, and ICHU-SHI) were searched until 20 March 2023, and a random-effects model was used to calculate the pooled effect. Results: The meta-analysis included nine randomized controlled trials involving 1965 patients. The analysis revealed an odds ratio (OR) of 0.34 (95% confidence interval [CI] 0.19, 0.59, p < 0.001) for the reduction in exacerbation frequency. Notably, only azithromycin or erythromycin showed suppression of COPD exacerbations. The ORs for reducing exacerbation frequency per year and preventing hospitalizations were -0.50 (95% CI: -0.81, -0.19; p = 0.001) and 0.60 (95% CI: 0.3, 0.97; p = 0.04), respectively. Statistical analyses showed no significant differences between three- and six-month macrolide prescriptions. However, studies involving a twelve-month prescription showed an OR of 0.27 (95% CI: 0.11, 0.68; p = 0.005; I2 = 81%). Although a significant improvement in St George's Respiratory Questionnaire (SGRQ) total scores was observed with a mean difference of -4.42 (95% CI: -9.0, 0.16; p = 0.06; I2 = 94%), the minimal clinically important difference was not reached. While no adverse effects were observed between the two groups, several studies have reported an increase in bacterial resistance. Conclusions: Long-term use of azithromycin or erythromycin suppresses COPD exacerbations, and previous studies have supported the advantages of a 12-month macrolide prescription over a placebo.

Infantile Hypertrophic Pyloric Stenosis: Review of Pathophysiology, Clinical Presentation, Treatment and Outcomes

Infantile hypertrophic pyloric stenosis (IHPS) is considered one of the most common pediatric surgical conditions. Presentation is most common between the ages of 2 to 12 weeks with a mean and median age of 5 weeks. IHPS has been reported to be more common in males than females (5:1) and in first-born children (30-40%). Throughout history, the etiology of this condition has been studied, discovering multiple genetic and environmental factors, such as newborns with increased acid secretion, nitric oxide synthase deficiency, poor innervation of the pyloric muscle, smoking during pregnancy, neonatal use of macrolides and cesarean section; however, the exact cause remains uncertain. The classic clinical presentation begins with a recent history of severe, nonbilious projectile vomiting immediately after feeding and a strong, persistent appetite. During abdominal examination, palpation of the "pyloric olive" in the epigastrium by an experienced doctor is considered a pathognomonic sign. Laboratory tests may show low chloride, potassium, and hydrogen ion levels, leading to metabolic alkalosis due to persistent vomiting. Ultrasound is the gold standard imaging study if history and physical examination are insufficient to diagnose IHPS with a reported sensitivity and specificity of up to 98% and 100% by allowing evaluation of pyloric morphology and behavior. Pyloromyotomy is considered the definitive treatment for infantile hypertrophic pyloric stenosis, but should not be performed until the baby is adequately resuscitated. Patients typically experience positive outcomes after pyloromyotomy, with low morbidity and mortality rates. Most cases recover quickly and without complications.

The effect of complex therapy of cows with genital mycoplasmosis on indicators of nonspecific resistance

Animal husbandry on an industrial basis involves the maximum use of the reproductive capabilities of females and obtaining healthy offspring. A significant obstacle to achieving this goal are diseases that negatively affect the reproductive function of females, one of which is genital mycoplasmosis of cattle. The basis of etiotropic therapy of mycoplasmosis is the use of macrolide and fluoroquinolone antibiotics, but at the same time the animals remain immunodeficient. The aim of our research was to assess the dynamics of indicators of nonspecific resistance of the organism of patients with genital mycoplasmosis of cows when the immunomodulator thymalin was included in the treatment regimen. Studies were carried out on three groups of pregnant cows, the first group of animals with mycoplasmosis was treated with tulatromycin, the second group was treated with tulatromycin in combination with thymalin, the third group was clinically healthy cows. The results of the experiment showed that the combined use of tulatromycin and thymalin in genital mycoplasmosis of cattle, compared with monotherapy with tulatromycin, increases therapeutic efficacy by 25%, and also contributes to a significant increase in bactericidal and lysozyme activity of blood serum, phagocytic index, which even slightly exceed similar indicators in clinically healthy animals.

Utilización de antibióticos en faringoamigdalitis aguda en la provincia de Albacete

Introduction: acute tonsillitis is one of the most prevalent pathologies among the pediatric population and one of the leading causes of antibiotic prescribing in this group. Materials and methods: observational and descriptive study of the use of antibiotics in acute tonsillitis. We have included all the children from our health area who have been prescribed antibiotics as treatment of an acute tonsillitis during the three years of the study. Results: a total of 53,995 acute tonsillitis were diagnosed during the three years of the project, some of which, 33,426 (61.9%), were treated with antibiotics. In children under the age of 3 years, 10,901 cases of acute tonsillitis were diagnosed (20.2% of the tonsillitis), being treated with antibiotics 6,494 (59.6%). We have observed that the most prescribed antibiotics were beta-lactamase sensitive penicillins (phenoxymethylpenicillin, benzathine phenoxymethylpenicillin) and amoxicillin: 60.3% in the first year, 60.9% in the second one and 66.8% in the third year, meanwhile other groups of antibiotics were less commonly used: amoxicillin/clavulanic acid in 2,475 cases (18.2%) in the first year of the study, 1,754 (17.7%) in the second and 1,644 (16.6%) in the third one. Furthermore, a decreased use of macrolides has been observed: 2,825 (20.7%) in the first year, 1,933 (19.6%) in the second and 1,419 (14.3%) in the last one. Conclusions: the use of amoxicillin/clavulanic acid and macrolides is significantly above from what could be expected considering the low prevalence of carriers of Streptococcus pyogenes in the pharynx or of children allergic to penicillin.

Seasonality of antimicrobial use in Dutch food-producing animals.

Due to globally increasing antimicrobial resistance (AMR), it is pivotal to understand factors contributing to antimicrobial use (AMU) to enable development and implementation of AMR-reducing interventions. Therefore, we explored seasonal variations of systemic AMU in food-producing animals in the Netherlands. Dutch surveillance data from January 2013 to December 2018 from cattle, pig, and broiler farms were used. AMU was expressed as the number of Defined Daily Dosages Animal per month (DDDA/animal-month) per farm by animal sector, antimicrobial line (first, second, and third), antimicrobial class, and farm type. Seasonality of AMU was analyzed using Generalized Additive Models (GAMs) with DDDA/animal-month as outcome variable, and year and month as independent variables. Year and month were modelled as smooth terms represented with penalized regression splines.Significant seasonality of AMU was found in the cattle and pig sectors, but not in broilers. Significant seasonality of AMU was found mainly for first-line antimicrobials. In the cattle sector, a significant increase during winter was found for the use of amphenicols (an increase of 23.8%) and long-acting macrolides (an increase of 3.4%). In the pig sector, seasonality of AMU was found for pleuromutilins (p<0.001) with an increase of 20% in October-November. The seasonality of pleuromutilins was stronger in sows/piglets (an increase of 47%) than in fattening pigs (16% increase). Only in fattening pigs, the use of amphenicols showed a significant seasonality with an increase of 11% during winter (P<0.001). AMU in cattle and pig sectors shows seasonal variations likely caused by seasonality of diseases. In broilers, no AMU seasonality was observed, possibly due to the controlled environment in Dutch farms. In the context of the one health concept, future studies are necessary to explore whether this seasonality is present in other populations and whether it has implications for antimicrobial resistance in humans through the food chain.

The Burden of Self-Reported Antibiotic Allergies in Health Care and How to Address It: A Systematic Review of the Evidence.

Antibiotics are the first-line treatment for bacterial infections; however, overuse and inappropriate prescribing have made antibiotics less effective with increased antimicrobial resistance. Unconfirmed reported antibiotic allergy labels create a significant barrier to optimal antimicrobial stewardship in health care, with clinical and economic implications. A systematic review was conducted to summarize the impact of patient-reported antibiotic allergy on clinical outcomes and various strategies that have been employed to effectively assess and remove these allergy labels, improving patient care. The review was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A critical appraisal was conducted on all studies and a narrative synthesis was performed to identify themes. Four themes emerged: the prevalence of antibiotic allergy, impact of antibiotic allergy on antimicrobial prescribing, impact of antibiotic allergy on clinical outcomes, and delabeling strategies to improve clinical outcomes. Of the 32 studies, including 1,089,675 participants, the prevalence of reported antibiotic allergy was between 5% and 35%. Patients with a reported antibiotic allergy had poorer concordance with prescribing guidelines in 30% to 60% of cases, with a higher use of alternatives such as quinolone, tetracycline, macrolide, lincosamide, and carbapenem and lower use of beta-lactam antibiotics. Antibiotic allergy delabeling was identified as an intervention and recommendation to advance the state of the science. There is substantial evidence within the literature that antibiotic allergy labels significantly impact patient clinical outcomes and a consensus that systematic assessment of reported antibiotic allergies, commonly referred to as delabeling, improves the clinical management of patients.

Assessing the utilization of antimicrobial agents in pediatric pneumonia during the era of the 13-valent pneumococcal conjugate vaccine: A retrospective, single-center study

Background and purposePneumonia and bronchopneumonia are the most common infectious diseases in children. This study aimed to analyze changes in causative pathogens and antibiotic use for bronchopneumonia or pneumonia after the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in children. MethodsThis retrospective study was conducted from 2009 to 2019. Hospitalized children aged 6 months–3 years with a discharge diagnosis of bronchopneumonia or pneumonia were included to analyze changes in the potential mismatch between the diagnosed pathogen and antibiotic use. ResultsThe cohort comprised 1100 patients, including 648 (59%) and 452 (41%) with a discharge diagnosis of bronchopneumonia and pneumonia, respectively. The trend of viral pneumonia increased every year (rs = 0.101, p < 0.05) Antibiotics were administered in 97% patients, with an increasing annual trend in macrolide use (rs = 0.031, p = 0.009). Regarding antibiotic utilization, no significant variations were observed in the days of therapy (DOT) (rs = 0.076, p = 0.208) or length of therapy (LOT) (rs = −0.027, p = 0.534) per patient-year throughout the study duration. Interestingly, the LOT for combined therapy with macrolides and first-line beta-lactams was high (rs = 0.333, p = 0.028). In viral pneumonia treatment, neither the DOT nor LOT exhibited significant variations (rs = −0.006, p = 0.787 and rs = −0.156, p = 0.398). ConclusionAfter the introduction of PCV13 in Taiwan, no decrease in antibiotic use has been observed among children aged 6 months–3 years with a discharge diagnosis of bronchopneumonia and pneumonia.

Systematic Review and Meta-analysis: Macrolide in the Treatment of Chronic Rhinosinusitis After Endoscopic Sinus Surgery.

To evaluate the efficacy and safety of macrolide antibiotics therapy in patients with chronic rhinosinusitis (CRS) receiving endoscopic sinus surgery. PubMed, Web of Science, Embase, and Cochrane Library. The electronic databases were comprehensively searched on June 2, 2022, for randomized controlled trials on macrolide antibiotics in the treatment of patients undergoing CRS endoscopic surgery. The primary outcome measures were the sinonasal outcome test (SNOT) score and the visual analog scale (VAS) score. The secondary outcome measures were the nasal endoscopy score (NES), the sinus computed tomography score, and adverse events. A total of 8 studies were included, involving 606 patients who used macrolide for a long time. Meta-analysis showed that no significant difference was observed in SNOT (standardized mean difference [SMD] = -0.13; 95% confidence interval [CI]: -0.38 to 0.13, I2 = 0%) and VAS (SMD = -0.10; 95% CI, -0.88 to 0.68, I2 = 81%) between the macrolide and placebo groups. However, macrolide outperformed the placebo in improving NES (SMD = -0.32; 95% CI, -0.62 to -0.03, I2 = 21%). The use of macrolide did not increase the incidence of adverse events. Long-term use of macrolide after CRS surgery may not significantly improve the quality of life and disease severity of the patients but may play a role in improving postoperative NES in patients with CRS. There is still no sufficient evidence to determine whether the disease phenotype of CRS or the patient's race will affect the efficacy of long-term use of macrolide after CRS.

Baseline azithromycin resistance in the gut microbiota of preterm born infants

BackgroundMacrolides, including azithromycin, are increasingly used in preterm-born infants to treat Ureaplasma infections. The baseline carriage of macrolide resistance genes in the preterm stool microbiota is unknown.ObjectivesIdentify carriage of azithromycin resistant bacteria and the incidence of macrolide resistant genes.MethodsAzithromycin resistant bacteria were isolated from serial stool samples obtained from preterm infants (≤32 weeks’ gestation) by culturing aerobically/anaerobically, in the presence/absence of azithromycin. Using quantitative PCR, we targeted 6 common macrolide resistance genes (erm(A), erm(B), erm(C), erm(F), mef(A/E), msr(A)) in DNA extracted from selected bacteria resistant to azithromycin.ResultsFrom 89 stool samples from 37 preterm-born infants, 93.3% showed bacterial growth in aerobic or anaerobic conditions. From the 280 azithromycin resistant isolates that were identified, Staphylococcus (75%) and Enterococcus (15%) species dominated. Macrolide resistance genes were identified in 91% of resistant isolates: commonest were erm(C) (46% of isolates) and msr(A) (40%). Multiple macrolide resistance genes were identified in 18% of isolates.ConclusionMacrolide resistance is common in the gut microbiota of preterm-born infants early in life, most likely acquired from exposure to the maternal microbiota. It will be important to assess modulation of macrolide resistance, if macrolide treatment becomes routine in the management of preterm infants.Impact StatementAzithromycin resistance is present in the stool microbiota in the first month of life in preterm infants91% of azithromycin resistant bacteria carried at least one of 6 common macrolide resistant genesIncreasing use of macrolides in the preterm population makes this an important area of study

Factors Associated with Extended-spectrum β-lactamase-producing Enterobacteria Isolated from Respiratory Samples.

Objective Although extended-spectrum β-lactamase (ESBL)-producing bacteria are a global threat, as they may cause respiratory infection, the factors associated with the isolation of these bacteria from sputum remain unclear. We therefore explored the factors related to ESBL-producing Klebsiella pneumoniae and Escherichia coli isolated from sputum samples. Patients and Methods This study included consecutive patients admitted to our department from 2010 to 2021 with K. pneumoniae or E. coli isolated from their sputum. The patients were categorized into ESBL-producing and non-ESBL-producing groups, and the factors associated with ESBL-producing bacteria isolation were assessed using a binomial logistic regression analysis. Results We included 82 patients, and ESBL-producing pathogens were isolated from 23 (28%). The usage rates of cephem [odds ratio (OR) 4.000, 95% confidence interval (CI) 1.402-11.409, p=0.010], quinolone (OR 2.961, 95% CI 1.097-7.996, p=0.032), and macrolide (OR 4.273, 95% CI 1.518-12.028, p=0.006) in the past year were significantly higher in the ESBL-producing group than in the non-ESBL-producing group. The multivariate analysis revealed that the applications of cephem (adjusted OR: 4.130, 95% CI: 1.233-13.830, p=0.021) and macrolide (adjusted OR: 6.365, 95% CI: 1.922-21.077, p=0.002) was independently associated with the isolation of ESBL-producing bacteria. Conclusions A history of cephem and macrolide use can be considered a risk factor for ESBL-producing bacteria isolation from sputum samples. Physicians need to consider these risk factors when determining antibiotics for the treatment of patients with respiratory infections.

Oral fluoroquinolones and risk of aortic aneurysm or dissection: A nationwide population-based propensity score-matched cohort study.

To investigate risk of aortic aneurysm or dissection in patients using oral fluoroquinolones compared to those using macrolides in real-world clinical practice among a large US general population. Retrospective cohort study design. MarketScan commercial and Medicare supplemental databases. Adults patients with at least one prescription fill for fluoroquinolone or macrolide antibiotics. Fluoroquinolone or macrolide antibiotics. The primary outcome was estimated incidence of aortic aneurysm or dissection associated with the use of fluoroquinolones compared with macrolides during a 60-day follow-up period in a 1:1 propensity score-matched cohort. We identified 3,174,620 patients (1,587,310 in each group) after 1:1 propensity score matching. Crude incidence of aortic aneurysm or dissection was 1.9 cases per 1000 person-years among fluoroquinolone users and 1.2 cases per 1000 person-years among macrolide users. In multivariable Cox regression, compared with macrolides, the use of fluoroquinolones was associated with an increased risk of aortic aneurysm or dissection (aHR: 1.34; 95% CI: 1.17-1.54). The association was primarily driven by a high incidence of aortic aneurysm cases (95.8%). Results of sensitivity (e.g., fluoroquinolone exposure ranging from 7 to 14 days (aHR: 1.47; 95% CI: 1.26-1.71)) and subgroup analyses (e.g., ciprofloxacin (aHR: 1.26; 95% CI: 1.07-1.49) and levofloxacin (aHR: 1.44; 95% CI: 1.19-1.52)) remained consistent with main findings. Fluoroquinolone use was associated with a 34% increased risk of aortic aneurysm or dissection compared with macrolide use among a general US population.

Impact of the COVID-19 Pandemic on Community Consumption of Antibiotics for Systemic Use and Resistance of Invasive Streptococcus pneumoniae in Slovenia.

The present study aims to investigate the impact of the COVID-19 pandemic on community antibiotic consumption and the resistance of invasive Streptococcus pneumoniae (2015-2022) to penicillin in Slovenia. During the pandemic in 2020 and 2021, the total use of antibiotics for systemic use decreased by 23.5% and 24.3%, expressed in defined daily doses per 1000 inhabitants per day (DID), while the use of penicillins, macrolides and broad-spectrum penicillins decreased by 30%, 20% and by 17.5%, respectively, and that of broad-spectrum macrolides fell by 17.1%. The incidence of invasive pneumococcal diseases (IPD) in Slovenia had a large decline during the pandemic. Decreased resistance to macrolides was significantly associated with decreased use of macrolides, while for penicillins the correlation could not be statistically confirmed. The proportion of PCV13 serotypes in IPD in Slovenia decreased after the introduction of the vaccine in the national programme, falling from 81.6% in 2015 to 45.5% in 2022. We noticed a decrease in the serotypes 1, 14, 9V, 7F, 4, 6A and an increase in the serotypes 3, 8, 22F, 11A, 23A and 15A. National interventions during the COVID-19 pandemic substantially decreased outpatients' antibiotic consumption, as well as incidence and resistance of invasive S. pneumoniae.

Application of new indicators to assess the quality of antimicrobial use in intensive care units

This study explored the feasibility of a bundle of indicators aimed at assessing the quality of antimicrobial use in intensive care units (ICUs) through an observational prospective study spanning 12 quarters (January 2019-December 2021) in a 1290-bed teaching hospital in Spain. Members of the antimicrobial stewardship programme team selected the indicators to analyse the quality of antimicrobial use based on consumption data from a list proposed in a previous study. Antimicrobial use in the ICU was measured as defined daily dose (DDD) per 100 occupied bed-days. Trends and points of change were analysed with segmented regression. The intravenous macrolides/intravenous respiratory fluoroquinolones ratio in the ICU increased progressively, although not significantly, by 11.14% per quarter, likely related to prioritization of the use of macrolides in serious community-acquired pneumonia and the coronavirus disease 2019 pandemic. A remarkable upward trend of 2.5% per quarter was detected in the anti-methicillin-susceptible Staphylococcus aureus/anti-methicillin-resistant S. aureus agents ratio in the ICU, which could be explained by the low prevalence of methicillin-resistant S. aureus at the study centre. Patterns of amoxicillin-clavulanic acid/piperacillin-tazobactam ratio and diversification of anti-pseudomonal beta-lactams showed an increment in use over the study. The use of these novel indicators provides additional information for the current analysis of DDD. Implementation is feasible, and led to the detection of patterns that agree with local guidelines and cumulative antibiogram reports, and foster targeted improvement actions within antimicrobial stewardship programmes.

Antimicrobial resistance monitoring in the Danish swine production by phenotypic methods and metagenomics from 1999 to 2018.

BackgroundIn Denmark, antimicrobial resistance (AMR) in pigs has been monitored since 1995 by phenotypic approaches using the same indicator bacteria. Emerging methodologies, such as metagenomics, may allow novel surveillance ways.AimThis study aimed to assess the relevance of indicator bacteria (Escherichia coli and Enterococcus faecalis) for AMR surveillance in pigs, and the utility of metagenomics.MethodsWe collated existing data on AMR and antimicrobial use (AMU) from the Danish surveillance programme and performed metagenomics sequencing on caecal samples that had been collected/stored through the programme during 1999-2004 and 2015-2018. We compared phenotypic and metagenomics results regarding AMR, and the correlation of both with AMU.ResultsVia the relative abundance of AMR genes, metagenomics allowed to rank these genes as well as the AMRs they contributed to, by their level of occurrence. Across the two study periods, resistance to aminoglycosides, macrolides, tetracycline, and beta-lactams appeared prominent, while resistance to fosfomycin and quinolones appeared low. In 2015-2018 sulfonamide resistance shifted from a low occurrence category to an intermediate one. Resistance to glycopeptides consistently decreased during the entire study period. Outcomes of both phenotypic and metagenomics approaches appeared to positively correlate with AMU. Metagenomics further allowed to identify multiple time-lagged correlations between AMU and AMR, the most evident being that increased macrolide use in sow/piglets or fatteners led to increased macrolide resistance with a lag of 3-6 months.ConclusionWe validated the long-term usefulness of indicator bacteria and showed that metagenomics is a promising approach for AMR surveillance.

Pulmonary exacerbations in insured patients with bronchiectasis over 2 years.

Patients with bronchiectasis experience persistent symptoms and frequent pulmonary exacerbations; this study investigated the frequency of exacerbations and all-cause hospitalisation. This longitudinal, retrospective, claims database study (IBM® MarketScan®) identified patients aged ≥18 years from 1 July 2015 through 30 September 2018. Exacerbations were identified by bronchiectasis inpatient claim or a healthcare interaction, followed by antibiotic prescription within 7 days. Patients with ≥36 months of continuous health plan enrolment (12 months preceding the first bronchiectasis claim, i.e., baseline period and ≥24 months of follow-up) were included. Patients with cystic fibrosis at baseline were excluded. A multivariable logistic regression model identified baseline factors associated with having ≥2 exacerbations over the 2-year follow-up period. In total, 14 798 patients with bronchiectasis were identified; 64.5% were female, 82.7% were aged ≥55 years and 42.7% had ≥2 exacerbations at baseline. Having ≥2 exacerbations after 2 years was positively associated with chronic macrolide use, long-acting β2 agonist use, gastro-oesophageal reflux disease, heart failure and Pseudomonas aeruginosa. Frequent exacerbations (≥2) at baseline were significantly associated with greater likelihood of experiencing ≥2 exacerbations during the first and second year's follow-up (unadjusted odds ratios 3.35 (95% CI 3.1-3.6) and 2.96 (95% CI 2.8-3.2), respectively). The proportion of patients experiencing ≥1 all-cause hospitalisation cumulatively increased from 41.0% in the first year of follow-up to 51.1% over 2 years' follow-up. Frequent exacerbations in patients with bronchiectasis may increase the likelihood of future exacerbations over 2 years of follow-up, with increased hospitalisation rates over time.

Macrolides Decrease the Proinflammatory Activity of Macrolide-Resistant Streptococcus pneumoniae.

Over the past 2 decades, the prevalence of macrolide-resistant Streptococcus pneumoniae (MRSP) has increased considerably, due to widespread macrolide use. Although macrolide usage has been proposed to be associated with treatment failure in patients with pneumococcal diseases, macrolides may be clinically effective for treating these diseases, regardless of the susceptibility of the causative pneumococci to macrolides. As we previously demonstrated that macrolides downregulate the transcription of various genes in MRSP, including the gene encoding the pore-forming toxin pneumolysin, we hypothesized that macrolides affect the proinflammatory activity of MRSP. Using HEK-Blue cell lines, we found that the supernatants from macrolide-treated MRSP cultures induced decreased NF-κB activation in cells expressing Toll-like receptor 2 and nucleotide-binding oligomerization domain 2 compared to the supernatants from untreated MRSP cells, suggesting that macrolides inhibit the release of these ligands from MRSP. Real-time PCR analysis revealed that macrolides significantly downregulated the transcription of various genes encoding peptidoglycan synthesis-, lipoteichoic acid synthesis-, and lipoprotein synthesis-related molecules in MRSP cells. The silkworm larva plasma assay demonstrated that the peptidoglycan concentrations in the supernatants from macrolide-treated MRSP cultures were significantly lower than those from untreated MRSP cultures. Triton X-114 phase separation revealed that lipoprotein expression decreased in macrolide-treated MRSP cells compared to the lipoprotein expression in untreated MRSP cells. Consequently, macrolides may decrease the expression of bacterial ligands of innate immune receptors, resulting in the decreased proinflammatory activity of MRSP. IMPORTANCE To date, the clinical efficacy of macrolides in pneumococcal disease is assumed to be linked to their ability to inhibit the release of pneumolysin. However, our previous study demonstrated that oral administration of macrolides to mice intratracheally infected with macrolide-resistant Streptococcus pneumoniae resulted in decreased levels of pneumolysin and proinflammatory cytokines in bronchoalveolar lavage fluid samples compared to the levels in samples from untreated infected control mice, without affecting the bacterial load in the fluid. This finding suggests that additional mechanisms by which macrolides negatively regulate proinflammatory cytokine production may be involved in their efficacy in vivo. Furthermore, in this study, we demonstrated that macrolides downregulated the transcription of various proinflammatory-component-related genes in S. pneumoniae, which provides an additional explanation for the clinical benefits of macrolides.