Effect of periodontal debridement plus systemic azithromycin in subjects with stage III periodontitis: a randomized controlled clinical trial / Efecto del desbridamiento periodontal más azitromicina sistémica en sujetos con periodontitis estadio III: un ensayo clínico controlado aleatorio

Aim: To evaluate the effect of the systemic administration of azi-thromycin (AZM) as an adjunct to non-surgical periodontal therapy (NSPT) on the clinical and microbiological variables of patients with periodontitis. Material and Methods: Eighteen volunteers received NSPT combined with placebo or AZM (500 mg/day) for 3 days (n=9/group). They were monitored clinically for probing pocket depth (PPD), clinical attachment level (CAL), O'Leary index (OI), bleeding on probing (BoP) at baseline and during the first, third and sixth month and microbiologically, at baseline and at 3 and 6 months after therapy, by conventional polymerase chain reaction tests. Results: Fourteen patients completed the study (n=7/group). Differences statistically significant were observed among both groups. The experimental group presented: A PPD mean (p=0.04) significantly lower and PPD reduction (p=0.02), at 6-months post NSPT. Regarding changes (∆), at the third month post NSPT, there was a significant increase in the number of shallow sites (p<0.001) and a decrease in the intermediate sites (p<0.001). In addition, a significant decrease in the mean number of deep sites (p=0.04) was detected at 6 months post treatment. There was also a significant decrease in periodontal index BoP at 1 (p=0.01), 3 (p<0.001) and 6 (p=0.01) months and OI at 3- and 6-months (p<0.001), post treatment. Regarding the presence of periodontal pathogens, no significant differences were observed, intra and inter groups. Conclusion: AZM as an adjuvant to NSPT provides additional beneficial effects for PPD and BoP compared to NSPT alone.

Objetivo: Evaluar el efecto de la administración sistémica de azitromicina (AZM) como coadyuvante de la terapia periodontal no quirúrgica (TPNQ) en las variables clínicas y microbiológicas de pacientes con periodontitis. Material y Métodos: Dieciocho voluntarios recibieron TPNQ combinado con placebo o AZM (500 mg/día) durante 3 días (n=9/grupo). Fueron monitoreados clínicamente para determinar Profundidad de Sondaje del Saco (PSS), Nivel de Inserción Clínica (NIC), Índice de O'Leary (IO), Sangrado al sondaje (SS) al inicio y durante el primer, tercer y sexto mes y microbiológicamente, al inicio y a los 3 y 6 meses después de la terapia, mediante la reacción en cadena de la polimerasa convencional. Resultados: Catorce pacientes completaron el estudio (n=7/grupo). Se observaron diferencias estadísticamente significativas entre ambos grupos. El grupo experimental presentó una media de PSS significativamente menor (p=0,04) y una reducción de PSS (p=0,02), a los 6 meses post TPNQ. En cuanto al delta (∆) pre y post tratamiento, al tercer mes post TPNQ, hubo un aumento significativo en el número de sitios poco profundos (p<0.001) y una disminución en los sitios intermedios (p<0.001). Además, se detectó una disminución significativa en la media de los sitios profundos (p=0.04) a los 6 meses post tratamiento. También hubo una disminución significativa en el índice SS al primer (p=0.01), tercer (p<0. 0 01) y sexto mes (p=0.01) post TPNQ y del IO al tercer y sexto mes (p<0.001), post tratamiento. En cuanto a la presencia de patógenos periodontales, no se observaron diferencias significativas tanto intra como ínter grupos. Conclusión: AZM como adyuvante a TPNQ proporciona efectos benéficos adicionales en la PSS y SS en comparación a TPNQ solo.

Uso de macrólidos en niños hospitalizados en unidades de cuidados moderados e intensivos durante 2018 / Use of macrolides in children hospitalized in Intensive and moderate care units in 2018 / Uso de macrólidos em crianças hospitalizadas em unidades de cuidados intermediários e intensivos no 2018

Introducción: se describe a nivel mundial un aumento en la prescripción de macrólidos en niños y adolescentes, generando el riesgo de emergencia de cepas resistentes. Objetivo: caracterizar el uso de macrólidos en niños de 1 mes a 14 años hospitalizados en cuidados moderados e intensivos del Hospital Pediátrico del Centro Hospitalario Pereira Rossell (HP-CHPR). Metodología: estudio descriptivo transversal de niños hospitalizados tratados con macrólidos en el HP-CHPR en 2018. Variables: tipo de macrólido, duración del tratamiento, estudios y hallazgos microbiológicos y diagnóstico al egreso. Resultados: recibieron macrólidos 334 niños, mediana de edad 13 meses, 58,4% varones. 71,0% en Unidad de Terapia Intensiva (UTI). Predominó la prescripción de claritromicina (72,8%), durante los dos últimos cuatrimestres del año (77,5%) y por patología respiratoria (94%): bronquiolitis (23,3%), infección aguda no especificada de las vías respiratorias inferiores (21,9%) y crisis asmática (19,1%). Mediana de tratamiento con azitromicina y claritromicina 5 y 8 días respectivamente. Se realizaron estudios microbiológicos en 96,1% sin determinarse microorganismo en 58,3%. Conclusiones: se destaca el uso de macrólidos principalmente en la UTI y por patología respiratoria. La prescripción por fuera de las recomendaciones nacionales vigentes y la baja confirmación microbiológica que apoye el uso fueron los mayores problemas detectados, por lo que parece fundamental establecer estrategias tendientes a promover un uso racional de estos antibióticos.

Introduction: literature has described a global increase in the prescription of macrolides to children and adolescents , which has increased the risk of emergence of resistant strains. Objective: to characterize the use of macrolides in children from 1 month to 14 years of age hospitalized at the moderate and intensive care units of the Pereira Rossell Pediatric Hospital Center (HP-CHPR). Methodology: descriptive cross-sectional study of hospitalized children treated with macrolides at the HP-CHPR in 2018. Variables: macrolide type, treatment duration, microbiological studies and findings, and diagnosis at discharge. Results: 334 children received macrolides, median age 13 months, 58.4% males. 71.0% hospitalized atnan Intensive Care Unit (ICU). Clarithromycin was mainly prescribed in 72.8% of the cases, during the last two quarters of the year (77.5%), due to respiratory disease (94%): bronchiolitis (23.3%), lower respiratory tract unspecified acute infection (21.9%) and asthma crisis (19.1%). Median treatment included Azithromycin and Clarithromycin for 5 and 8 days respectively. Microbiological studies were carried out in 96.1% of the cases and 58.3% did not show the presence of microorganisms. Conclusions: the use of macrolides stands out, mainly at ICUs and due to respiratory pathologies. The main problems identified were prescriptions made outside the framework of the present national recommendations and the low microbiological confirmation for their use, which suggests it is essential to set strategies to promote a more rational use of these antibiotics.

Introdução: a literatura descreve um aumento a nível global na prescrição de macrolídeos para crianças e adolescentes, o que tem aumentado o risco de surgimento de cepas resistentes. Objetivo: caracterizar o uso de macrolídeos em crianças de 1 mês a 14 anos de idade internadas nas unidades de terapia moderada e intensiva do Centro Hospitalar Pediátrico Pereira Rossell (HP-CHPR). Metodologia: estudo transversal descritivo de crianças hospitalizadas tratadas com macrolídeos no HP-CHPR em 2018. Variáveis: tipo de macrolídeo, duração do tratamento, estudos e achados microbiológicos e diagnóstico no momento da alta. Resultados: 334 crianças receberam macrolídeos, idade mediana de 13 meses, 58,4% do sexo masculino. 71,0% internados em Unidade de Terapia Intensiva (UTI). A Claritromicina foi prescrita principalmente em 72,8% dos casos, nos últimos dois trimestres do ano (77,5%), devido a doença respiratória (94%): bronquiolite (23,3%), infecção aguda não especificada do trato respiratório inferior (21,9%) e crise de asma (19,1%). O tratamento médio incluiu Azitromicina e Claritromicina por 5 e 8 dias, respectivamente. Estudos microbiológicos foram realizados em 96,1% dos casos e 58,3% não evidenciaram a presença de microrganismos. Conclusões: destaca-se o uso de macrolídeos, principalmente em UTIs, e devido a patologias respiratórias. Os principais problemas identificados foram as prescrições feitas fora das atuais recomendações nacionais e a baixa confirmação microbiológica para sua utilização, o que sugere que é essencial definir estratégias para promover uma utilização mais racional destes antibióticos.

Clinical Characteristics and Outcomes of COVID-19 in Turkish Patients with Hematological Malignancies

Objective: Patients with solid malignancies are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection than the healthy population. The outcome of SARS-CoV-2 infection in highly immunosuppressed populations, such as in patients with hematological malignancies, is a point of interest. We aimed to analyze the symptoms, complications, intensive care unit admissions, and mortality rates of patients with hematological malignancies infected with SARS-CoV-2 in Turkey. Materials and Methods: In this multicenter study, we included 340 adult and pediatric patients diagnosed with SARS-CoV-2 from March to November 2020. Diagnosis and status of primary disease, treatment schedules for hematological malignancies, time from last treatment, life expectancy related to the hematological disease, and comorbidities were recorded, together with data regarding symptoms, treatment, and outcome of SARS-CoV-2 infection. Results: Forty four patients were asymptomatic at diagnosis of SARS-CoV- 2 infection. Among symptomatic patients, fever, cough, and dyspnea were observed in 62.6%, 48.8%, and 41.8%, respectively. Sixty-nine (20%) patients had mild SARS-CoV-2 disease, whereas moderate, severe, and critical disease was reported in 101 (29%), 71 (20%), and 55 (16%) patients, respectively. Of the entire cohort, 251 (73.8%) patients were hospitalized for SARS-CoV-2. Mortality related to SARS-CoV-2 infection was 26.5% in the entire cohort; this comprised 4.4% of those patients with mild disease, 12.4% of those with moderate disease, and 83% of those with severe or critical disease. Active hematological disease, lower life expectancy related to primary hematological disease, neutropenia at diagnosis of SARS-CoV-2, ICU admission, and first-line therapy used for coronavirus disease-2019 treatment were found to be related to higher mortality rates. Treatments with hydroxychloroquine alone or in combination with azithromycin were associated with a higher rate of mortality in comparison to favipiravir use. Conclusion: Patients with hematological malignancy infected with SARS-CoV-2 have an increased risk of severe disease and mortality.

Proxy Responses for Mass Drug Administration Coverage Surveys: The Trends and Biases When Others are Allowed to Respond.

Coverage surveys for mass drug administration (MDA) rely on respondent recall and often permit proxy responses, whereby another household member is allowed to respond on behalf of an absent individual. In this secondary analysis of coverage surveys in Malawi, Burkina Faso, and Uganda, we explore the characteristics of individuals who require proxy responses and quantify the association between proxy responses and reported drug coverage. The adjusted logistic regression model found that men 11-39 years and women 11-18 years who were eligible for MDA had greater odds of requiring a proxy response compared with ineligible men and women in the same age groups. A hierarchical multivariable analysis found that proxy responses had 1.70 times the odds of reporting ingestion of MDA drugs compared with first-person responses, controlling for age and sex (95% CI: 1.17, 2.46). This finding is surprising, given that individuals absent during a coverage survey may also have been absent during the MDA, and suggests that proxy responses may be leading to an inflation of survey estimates of drug coverage. This study highlights the possibility for recall bias in proxy responses to MDA coverage; however, excluding absent individuals from coverage surveys would introduce a new bias. Further research is necessary to determine the best method for obtaining information on drug coverage when individuals are absent.

Azithromycin concentrations during long-term regimen, a pilot study in patients with MALT lymphoma.

In view of the antineoplastic effects of the macrolide clarithromycin in mucosa associated lymphatic tissue (MALT)-lymphoma, we performed a pilot study assessing levels of azithromycin in plasma, peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMN) of MALT-lymphoma patients to determine the pharmacokinetics and potential influences of respective concentrations on the therapeutic outcome. In total 16 patients with MALT-lymphoma received 1.5 g of oral azithromycin once-weekly over 6 months. Blood was sampled directly prior to the following dose every 4 weeks during treatment. Drug levels were analysed by high performance liquid chromatography in plasma and intracellularly in PBMC and PMN. They were correlated with patients' age, weight and body-mass-index and compared between patients responsive or unresponsive to treatment. Mean azithromycin plasma levels of all patients were 58.97 ± 30.48 ng/ml, remaining stable throughout the treatment period. Correlation analysis of plasma azithromycin showed no significance. Intracellular PBMC concentrations were 6648 ± 8479 ng/ml, without any significant difference between responders and non-responders. Mean PMN levels were 39,274 ± 25,659 ng/ml and significantly higher in patients unresponsive to treatment (t = 2.858, p = 0.017). Our drug regime led to continuously high plasma and exceedingly high intracellular concentrations of azithromycin in PBMC and PMN. Age, weight or body-mass-index had no significant influence on plasma levels and thence should not be considered in dosage finding. High AZM levels in PBMC did not lead to a better treatment response, whereas enrichment in PMN suggested a poorer outcome. The threshold for immunomodulatory effects on lymphoma cells might not have been reached. Additionally, the finding of stable plasma and intracellular concentrations over months with high-dose azithromycin administered in intervals might also be important for the further design of azithromycin-based trials against MALT-lymphoma.Trial registration: EudraCT 2016-001521-13, 14/06/2016.

Effect of seasonal malaria chemoprevention plus azithromycin on Plasmodium falciparum transmission: gametocyte infectivity and mosquito fitness.

BACKGROUND: Seasonal malaria chemoprevention (SMC) consists of administration of sulfadoxine-pyrimethamine (SP) + amodiaquine (AQ) at monthly intervals to children during the malaria transmission period. Whether the addition of azithromycin (AZ) to SMC could potentiate the benefit of the intervention was tested through a double-blind, randomized, placebo-controlled trial. The effect of SMC and the addition of AZ, on malaria transmission and on the life history traits of Anopheles gambiae mosquitoes have been investigated. METHODS: The study included 438 children randomly selected from among participants in the SMC + AZ trial and 198 children from the same area who did not receive chemoprevention. For each participant in the SMC + AZ trial, blood was collected 14 to 21 days post treatment, examined for the presence of malaria sexual and asexual stages and provided as a blood meal to An. gambiae females using a direct membrane-feeding assay. RESULTS: The SMC treatment, with or without AZ, significantly reduced the prevalence of asexual Plasmodium falciparum (LRT X22 = 69, P < 0.0001) and the gametocyte prevalence (LRT X22 = 54, P < 0.0001). In addition, the proportion of infectious feeds (LRT X22 = 61, P < 0.0001) and the prevalence of oocysts among exposed mosquitoes (LRT X22 = 22.8, P < 0.001) was reduced when mosquitoes were fed on blood from treated children compared to untreated controls. The addition of AZ to SPAQ was associated with an increased proportion of infectious feeds (LRT X21 = 5.2, P = 0.02), suggesting a significant effect of AZ on gametocyte infectivity. There was a slight negative effect of SPAQ and SPAQ + AZ on mosquito survival compared to mosquitoes fed with blood from control children (LRTX22 = 330, P < 0.0001). CONCLUSION: This study demonstrates that SMC may contribute to a reduction in human to mosquito transmission of P. falciparum, and the reduced mosquito longevity observed for females fed on treated blood may increase the benefit of this intervention in control of malaria. The addition of AZ to SPAQ in SMC appeared to enhance the infectivity of gametocytes providing further evidence that this combination is not an appropriate intervention.

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs.

BACKGROUND: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib's growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility. DATA SOURCES: All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

Nutritional status in young children prior to the malaria transmission season in Burkina Faso and Mali, and its impact on the incidence of clinical malaria.

BACKGROUND: Malaria and malnutrition remain major problems in Sahel countries, especially in young children. The direct effect of malnutrition on malaria remains poorly understood, and may have important implications for malaria control. In this study, nutritional status and the association between malnutrition and subsequent incidence of symptomatic malaria were examined in children in Burkina Faso and Mali who received either azithromycin or placebo, alongside seasonal malaria chemoprevention. METHODS: Mid-upper arm circumference (MUAC) was measured in all 20,185 children who attended a screening visit prior to the malaria transmission season in 2015. Prior to the 2016 malaria season, weight, height and MUAC were measured among 4149 randomly selected children. Height-for-age, weight-for-age, weight-for-height, and MUAC-for-age were calculated as indicators of nutritional status. Malaria incidence was measured during the following rainy seasons. Multivariable random effects Poisson models were created for each nutritional indicator to study the effect of malnutrition on clinical malaria incidence for each country. RESULTS: In both 2015 and 2016, nutritional status prior to the malaria season was poor. The most prevalent form of malnutrition in Burkina Faso was being underweight (30.5%; 95% CI 28.6-32.6), whereas in Mali stunting was most prevalent (27.5%; 95% CI 25.6-29.5). In 2016, clinical malaria incidence was 675 per 1000 person-years (95% CI 613-744) in Burkina Faso, and 1245 per 1000 person-years (95% CI 1152-1347) in Mali. There was some evidence that severe stunting was associated with lower incidence of malaria in Mali (RR 0.81; 95% CI 0.64-1.02; p = 0.08), but this association was not seen in Burkina Faso. Being moderately underweight tended to be associated with higher incidence of clinical malaria in Burkina Faso (RR 1.27; 95% CI 0.98-1.64; p = 0.07), while this was the case in Mali for moderate wasting (RR 1.27; 95% CI 0.98-1.64; p = 0.07). However, these associations were not observed in severely affected children, nor consistent between countries. MUAC-for-age was not associated with malaria risk. CONCLUSIONS: Both malnutrition and malaria were common in the study areas, high despite high coverage of seasonal malaria chemoprevention and long-lasting insecticidal nets. However, no strong or consistent evidence was found for an association between any of the nutritional indicators and the subsequent incidence of clinical malaria.

Pharmacokinetic interactions between ivacaftor and cytochrome P450 3A4 inhibitors in people with cystic fibrosis and healthy controls.

BACKGROUND: Ivacaftor is currently the only CFTR potentiator approved and is increasingly used since the development of CFTR correctors. Ivacaftor is metabolized by CYP3A4 and therefore dose reduction is required when treating patients on ivacaftor with CYP3A4 inhibiting drugs. As this advice is based on studies in healthy volunteers and not in cystic fibrosis (CF) patients, we need to investigate this in both groups to be able to extrapolate these data to CF. METHODS: A cohort of CF patients and healthy subjects were exposed to a single dose of ivacaftor in combination with a strong (ritonavir), moderate (clarithromycin) and mild (azithromycin) CYP3A4 inhibitor. Ivacaftor concentrations were measured in all blood samples in order to calculate the pharmacokinetic parameters for ivacaftor. RESULTS: We found that exposure to ivacaftor was higher in healthy volunteers than in subjects with CF. However this difference was not statistically significant. No differences were observed in the interaction potential of CYP3A4 inhibitors between both study groups. The strong CYP3A4 inhibitor ritonavir, increased exposure to ivacaftor 7 times. CONCLUSION: Our data support current recommendations for dose adjustment of ivacaftor in case of co-treatment with CYP3A4 inhibitors in people with CF. However, exposure to ivacaftor was higher in healthy subjects than in CF patients. Further study is needed to investigate the cause and implication of this difference.

The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation.Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively.Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed.Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Pharmacokinetics of oral antimycobacterials and dosing guidance for Mycobacterium avium complex treatment in cystic fibrosis.

BACKGROUND: Treatment failure of Mycobacterium avium complex (MAC) pulmonary disease occurs in about 30% of people with cystic fibrosis (CF) and may be a result of abnormal drug concentrations. METHODS: Prospective, cross-over, single-dose PK study of 20 pancreatic insufficient individuals with CF and 10 healthy controls (HC). CF subjects received simultaneous doses of oral azithromycin, ethambutol, and rifampin in the fasting state and with food and pancreatic enzymes, separated by two weeks. HC received fasting doses only. A non-compartmental model was used to estimate PK parameters of drugs and metabolites. RESULTS: Azithromycin maximum concentration (Cmax ) was higher and rifampin Cmax was lower in fasting CF subjects compared to HC, while other PK measures, including those for ethambutol, were similar. Addition of food and enzymes did not improve the Cmax of the antimycobacterial drugs. Nineteen of 20 CF subjects had one or more abnormal Cmax z-scores in either the fasting or fed state (or both), when compared to HC. CONCLUSION: PK profiles of azithromycin and ethambutol were similar between CF and HC, except azithromycin Cmax was slightly higher in people with CF after a single dose. Rifampin PK parameters were altered in persons with CF. Addition of food and enzymes in CF subjects did not improve PK parameters. Standard dosing guidelines should be used as a starting point for people with CF initiating MAC therapy and therapeutic drug monitoring should be routinely performed to prevent the possibility of treatment failure due to abnormal drug concentrations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02372383 Prior abstract publication: 1. Martiniano S, Wagner B, Brennan L, Wempe M, Anderson P, Nick J, Sagel S. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. Am J Resp Crit Care Med A4842-A4842, 2017. 2. Martiniano SL, Wagner BD, Brennan L, Wempe MF, Anderson PL, Nick JA, Sagel SD. Pharmacokinetics of oral MAC antibiotics in cystic fibrosis. J Cyst Fibros 16: S52-53, 2017.

Successful use of azithromycin for Escherichia coli-associated renal allograft malakoplakia: a report of two cases.

Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.

Efficacy and Effect of Inhaled Adenosine Treatment in Hospitalized COVID-19 Patients.

Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO2/FiO2 was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression, reducing length of stay and inflammation parameters.

Clinical features and outcomes of hospitalized COVID-19 patients in a low burden region.

Data on the clinical features and outcomes of COVID-19 patients from countries with low disease burden are rare. Greece, however, presented a low burden of COVID-19 disease during the first pandemic outbreak. This is a retrospective study of COVID-19 hospitalized patients in Greece. Clinical data were extracted from medical records using univariable and multivariable logistic regression analyses to assess the factors associated with Intensive Care Unit (ICU) admission and in-hospital death. Eighty-five patients were included in this study, 49 (57.7%) male with median (25th-75th) age 60 (49-72) years old. Sixty-one (72%) of them had at least one comorbidity with hypertension being the most common (45,6%). More than half (56%) had severe or critical disease, 20% required ICU care (14% received invasive ventilation) and 10.7% died. Solid tumor (p = 0.021) and NEWS score (p = 0.048), thrombocytopenia (p = 0.036) or involvement of all lung fields in chest x-ray (p = 0.002) on admission were independent risk factors for ICU admission. Immunosuppression (p = 0.032) and thrombocytopenia (p = 0.049) were independent predictors of death. Hospitalized COVID-19 patients in a European country with a low burden of the disease, in which hospital capacities had not been overwhelmed, had lower mortality rate compared to those reported for patients hospitalized in regions with a high burden of the disease.

Neutrophil extracellular traps, disease severity, and antibiotic response in bronchiectasis: an international, observational, multicohort study.

BACKGROUND: Bronchiectasis is predominantly a neutrophilic inflammatory disease. There are no established therapies that directly target neutrophilic inflammation because little is understood of the underlying mechanisms leading to severe disease. Neutrophil extracellular trap (NET) formation is a method of host defence that has been implicated in multiple inflammatory diseases. We aimed to investigate the role of NETs in disease severity and treatment response in bronchiectasis. METHODS: In this observational study, we did a series of UK and international studies to investigate the role of NETs in disease severity and treatment response in bronchiectasis. First, we used liquid chromatography-tandem mass spectrometry to identify proteomic biomarkers associated with disease severity, defined using the bronchiectasis severity index, in patients with bronchiectasis (n=40) in Dundee, UK. Second, we validated these biomarkers in two cohorts of patients with bronchiectasis, the first comprising 175 patients from the TAYBRIDGE study in the UK and the second comprising 275 patients from the BRIDGE cohort study from centres in Italy, Spain, and UK, using an immunoassay to measure NETs. Third, we investigated whether pathogenic bacteria had a role in NET concentrations in patients with severe bronchiectasis. In a separate study, we enrolled patients with acute exacerbations of bronchiectasis (n=20) in Dundee, treated with intravenous antibiotics for 14 days and proteomics were used to identify proteins associated with treatment response. Findings from this cohort were validated in an independent cohort of patients who were admitted to the same hospital (n=20). Fourth, to assess the potential use of macrolides to reduce NETs in patients with bronchiectasis, we examined two studies of long-term macrolide treatment, one in patients with bronchiectasis (n=52 from the UK) in which patients were given 250 mg of azithromycin three times a week for a year, and a post-hoc analysis of the Australian AMAZES trial in patients with asthma (n=47) who were given 500 mg of azithromycin 3 times per week for a year. FINDINGS: Sputum proteomics identified that NET-associated proteins were the most abundant and were the proteins most strongly associated with disease severity. This finding was validated in two observational cohorts, in which sputum NETs were associated with bronchiectasis severity index, quality of life, future risk of hospital admission, and mortality. In a subgroup of 20 patients with acute exacerbations, clinical response to intravenous antibiotic treatment was associated with successfully reducing NETs in sputum. Patients with Pseudomonas aeruginosa infection had a lessened proteomic and clinical response to intravenous antibiotic treatment compared with those without Pseudomonas infections, but responded to macrolide therapy. Treatment with low dose azithromycin was associated with a significant reduction in NETs in sputum over 12 months in both bronchiectasis and asthma. INTERPRETATION: We identified NETs as a key marker of disease severity and treatment response in bronchiectasis. These data support the concept of targeting neutrophilic inflammation with existing and novel therapies. FUNDING: Scottish Government, British Lung Foundation, and European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC).

Protective effect of Rosuvastatin on Azithromycin induced cardiotoxicity in a rat model.

AIMS: Azithromycin is widely used broad spectrum antibiotic recently used in treatment protocol of COVID-19 for its antiviral and immunomodulatory effects combined with Hydroxychloroquine or alone. Rat models showed that Azithromycin produces oxidative stress, inflammation, and apoptosis of myocardial tissue. Rosuvastatin, a synthetic statin, can attenuate myocardial ischemia with antioxidant and antiapoptotic effects. This study aims to evaluate the probable protective effect of Rosuvastatin against Azithromycin induced cardiotoxicity. MAIN METHOD: Twenty adult male albino rats were divided randomly into four groups, five rats each control, Azithromycin, Rosuvastatin, and Azithromycin +Rosuvastatin groups. Azithromycin 30 mg/kg/day and Rosuvastatin 2 mg/kg/day were administrated for two weeks by an intragastric tube. Twenty-four hours after the last dose, rats were anesthetized and the following measures were carried out; Electrocardiogram, Blood samples for Biochemical analysis of lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The animals sacrificed, hearts excised, apical part processed for H&E, immunohistochemical staining, and examined by light microscope. The remaining parts of the heart were collected for assessment of Malondialdehyde (MDA) and Reduced Glutathione (GSH). KEY FINDINGS: The results revealed that Rosuvastatin significantly ameliorates ECG changes, biochemical, and Oxidative stress markers alterations of Azithromycin. Histological evaluation from Azithromycin group showed marked areas of degeneration, myofibers disorganization, inflammatory infiltrate, and hemorrhage. Immunohistochemical evaluation showed significant increase in both Caspase 3 and Tumor necrosis factor (TNF) immune stain. Rosuvastatin treated group showed restoration of the cardiac muscle fibers in H&E and Immunohistochemical results. SIGNIFICANCE: We concluded that Rosuvastatin significantly ameliorates the toxic changes of Azithromycin on the heart.

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.