Azithromycin Therapy Research Articles

Risk of relapse in patients receiving azithromycin after allogeneic HSCT.

Following publication of the ALLOZITHRO trial, the FDA released a safety announcement warning that azithromycin should not be given long-term to prevent BOS in patients with a blood or lymph cancer who have undergone allogeneic HSCT. Our site typically initiated azithromycin when patients were diagnosed with BOS post-transplant rather than empirically as prevention. The purpose of our study was to discern whether the use of azithromycin at the time of diagnosis of BOS increased risk of disease relapse in patients who received an allogeneic HSCT for malignant disease. We retrospectively reviewed 432 patients in 3 cohorts: Cohort (1) patients who received greater than or equal to 2 weeks of azithromycin therapy (n = 98); Cohort (2) patients who received azithromycin therapy for less than 2 weeks (n = 63); and Cohort (3) patients who never received azithromycin therapy (n = 271). Neither patients in Cohort 1 (HR 0.44; 95% CI, 0.12-1.53, P = 0.19) nor Cohort 2 (HR 0.66; 95% CI, 0.2-2.19, P = 0.49) were associated with an increased risk of relapse when compared to those who had never received azithromycin. Our data indicate that the prolonged use of azithromycin after allogeneic HSCT is not associated with an increased rate of hematologic relapse.

Safety and Effectiveness of Hydroxychloroquine and Azithromycin Combination Therapy for Treatment of Hospitalized Patients with COVID-19: A Propensity-Matched Study.

IntroductionWe sought to determine the effectiveness and safety of hydroxychloroquine–azithromycin (HCQ-AZM) therapy in hospitalized patients with COVID-19.MethodsThis was a retrospective cohort study of 613 patients hospitalized (integrated health system involving three hospitals) for RT-PCR-confirmed COVID-19 infection between March 1, 2020 and April 25, 2020. Intervention was treatment with HCQ-AZM in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Outcomes of interest were in-hospital all-cause mortality, cardiovascular mortality, pulseless electrical activity (PEA) arrest, non-lethal arrhythmias, and length of hospital stay. Secondary measures included in-hospital corrected QT (QTc) interval parameters and serum biomarkers levels.ResultsPropensity-matched groups were composed of 173 patients given HCQ-AZM and 173 matched patients who did not receive treatment. There was no significant difference in in-hospital mortality (odds ratio [OR] 1.52; 95% confidence interval [CI] 0.80–2.89; p = 0.2), PEA arrest (OR 1.68, CI 0.68–4.15; p = 0.27), or incidence of non-lethal arrhythmias (10.4% vs. 6.8%; p = 0.28). Length of hospital stay (10.5 ± 7.4 vs. 5.8 ± 6.1; p < 0.001), peak CRP levels (252 ± 136 vs. 166 ± 124; p < 0.0001), and degree of QTc interval prolongation was higher for the HCQ-AZM group (28 ± 32 vs. 9 ± 32; p < 0.0001), but there was no significant difference in incidence of sustained ventricular arrhythmias (2.8% vs. 1.7%; p = 0.52). HCQ-AZM was stopped in 10 patients because of QT interval prolongation and 1 patient because of drug-related polymorphic ventricular tachycardia.ConclusionIn this propensity-matched study, there was no difference in in-hospital mortality, life-threatening arrhythmias, or incidence of PEA arrest between the HCQ-AZM and untreated control groups. QTc intervals were longer in patients receiving HCQ-AZM, but only one patient developed drug-related ventricular tachycardia.Electronic supplementary materialThe online version of this article (10.1007/s40119-020-00201-7) contains supplementary material, which is available to authorized users.

Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients With COVID-19.

Conflicting evidence regarding the use of hydroxychloroquine (HCQ) and azithromycin for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection do exist. We performed a retrospective single‐center cohort study including 377 consecutive patients admitted for pneumonia related to coronavirus disease 2019 (COVID‐19). Of these, 297 were in combination treatment, 17 were on HCQ alone, and 63 did not receive either of these 2 drugs because of contraindications. The primary end point was in‐hospital death. Mean age was 71.8 ± 13.4 years and 34.2% were women. We recorded 146 deaths: 35 in no treatment, 7 in HCQ treatment group, and 102 in HCQ + azithromycin treatment group (log rank test for Kaplan–Meier curve P < 0.001). At multivariable Cox proportional hazard regression analysis, age (hazard ratio (HR) 1.057, 95% confidence interval (CI) 1.035–1.079, P < 0.001), mechanical ventilation/continuous positive airway pressure (HR 2.726, 95% CI 1.823–4.074, P < 0.001), and C reactive protein above the median (HR 2.191, 95% CI 1.479–3.246, P < 0.001) were directly associated with death, whereas use of HCQ + azithromycin (vs. no treatment; HR 0.265, 95% CI 0.171–0.412, P < 0.001) was inversely associated. In this study, we found a reduced in‐hospital mortality in patients treated with a combination of HCQ and azithromycin after adjustment for comorbidities. A large randomized trial is necessary to confirm these findings.

QTc interval prolongation associated with inpatient azithromycin therapy for pneumonia.

In 2013, the US Food and Drug Administration issued a warning regarding the use of azithromycin and the risk of fatal dysrhythmias after a 14-year retrospective analysis showed increased risk of cardiovascular-related death in patients who had taken a 5-day course of azithromycin compared with those who took amoxicillin, ciprofloxacin, or no antibiotics. At the authors' institution, pneumonia is the most common diagnosis for which azithromycin is used as a treatment for patients who are hospitalized. To compare corrected QT (QTc) interval measurements on electrocardiogram (ECG) before and after inpatient azithromycin treatment for pneumonia. The authors retrospectively reviewed the medical records of 642 patients age 18 years and older who were diagnosed with pneumonia and treated with azithromycin at an academic teaching hospital between January 1, 2017 and December 31, 2017. Patients who had an ECG performed both before and after azithromycin treatment were included and divided into 2 groups: those who had 1 dose of azithromycin (Group 1) and those who had 2 doses (Group 2). Patients were excluded if they had a baseline QTc interval on initial ECG greater than or equal to 500ms, any signs of ischemia or myocardial infarction, any initial dysrhythmia or underlying ECG abnormalities, or absence of pre- and post-ECG results. Outcomes measures included a comparison of QTc intervals on ECG before and after azithromycin, and an analysis of the percentage of patients with a QTc interval measurement greater than 500ms on ECG after azithromycin treatment. Our primary outcome measurement was the QTc interval measurement on ECG before and after azithromycin in patients treated with azithromycin for community acquired pneumonia. Our secondary outcome measurement was the percentage of patients with a QTc interval measurement of greater than 500ms on ECG after azithromycin treatment. A Wilcoxon signed-rank test was used to evaluate repeated QTc measures of our primary outcome in Group 1 and Group 2. Our secondary outcome was reported as a percentage of total patients with a QTc interval of greater than 500ms after azithromycin doses on ECG. Of 642 patients, 142 had available pre- and post-EGC results available; 100 were included in Group 1 (1 dose) and 42 in Group 2 (2 doses). Mean QTc interval differences after 1 dose of azithromycin exhibited an increase compared to baseline values (424 vs 477ms). A Wilcoxon signed-rank test indicated a significant QTc prolongation after 1 dose of azithromycin (mean rank, 43.76; Z=-4.921; P<.001). QTc interval differences after 2 doses of azithromycin did not reach statistical significance when compared to baseline values (422 vs 444ms). A total of 10 patients (10%) in Group 1 and 4 patients (9.5%) in Group 2 had a QTc interval >500ms after azithromycin. There were no documented dysrhythmias during hospitalization in this study period. QTc interval increases were observed during inpatient azithromycin therapy for pneumonia, but were not found to be associated with cardiac dysrhythmias during hospitalization.

Safely Administering Potential QTc Prolonging Therapy Across a Large Health Care System in the COVID-19 Era.

The severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) has resulted in a global pandemic. Hydroxychloroquine±azithromycin have been widely used to treat coronavirus disease 2019 (COVID-19) despite a paucity of evidence regarding efficacy. The incidence of torsade de pointes remains unknown. Widespread use of these medications forced overwhelmed health care systems to search for ways to effectively monitor these patients while simultaneously trying to minimize health care provider exposure and use of personal protective equipment. Patients with COVID-19 positive who received hydroxychloroquine±azithromycin across 13 hospitals between March 1 and April 15 were included in this study. A comprehensive search of the electronic medical records was performed using a proprietary python script to identify any mention of QT prolongation, ventricular tachy-arrhythmias and cardiac arrest. The primary outcome of torsade de pointes was observed in 1 (0.015%) out of 6476 hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin. Sixty-seven (1.03%) had hydroxychloroquine±azithromycin held or discontinued due to an average QT prolongation of 60.5±40.5 ms from a baseline QTc of 473.7±35.9 ms to a peak QTc of 532.6±31.6 ms. Of these patients, hydroxychloroquine±azithromycin were discontinued in 58 patients (86.6%), while one or more doses of therapy were held in the remaining nine (13.4%). A simplified approach to monitoring for QT prolongation and arrythmia was implemented on April 5. There were no deaths related to the medications with the simplified monitoring approach and health care provider exposure was reduced. The risk of torsade de pointes is low in hospitalized patients with COVID-19 receiving hydroxychloroquine±azithromycin therapy.

Study protocol: azithromycin therapy for chronic lung disease of prematurity (AZTEC) - a randomised, placebo-controlled trial of azithromycin for the prevention of chronic lung disease of prematurity in preterm infants

IntroductionChronic lung disease of prematurity (CLD), also known as bronchopulmonary dysplasia (BPD), is a cause of significant respiratory morbidity in childhood and beyond. Coupled with lung immaturity, infections (especially by...

Safety assessment of drug combinations used in COVID-19 treatment: in silico toxicogenomic data-mining approach

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are “old”, their pharmacological and toxicological profile in SARS-CoV-2 – infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders.

Influence of adjunctive azithromycin on microbiological and clinical outcomes in periodontitis patients: 6-month results of randomized controlled clinical trial

BackgroundOur aim was to determine if azithromycin therapy, as an adjunct to scaling and root planing (SRP), decreases the number of pathobiontic subgingival plaque species and sites demonstrating pocket depth (PD) ≥ 5 mm and bleeding on probing (BOP) 6 months post-treatment.MethodsIn a double-blind randomized parallel-arm placebo-controlled trial, 40 patients received nonsurgical periodontal treatment in two sessions within 7 days. Patients then received systemic antibiotic therapy (n = 20, azithromycin 500 mg/day for 3 days) or placebo (n = 20). Pooled microbiologic samples were taken before and 6 months after therapy and analysed by established culture methods. The primary outcome variable was the number of sites with PD ≥ 5 mm and BOP at the 6-month re-evaluation. Using multivariate multilevel logistic regression, the effects of gender, age, antibiotic therapy, presence of P. gingivalis or A. actinomycetemcomitans, smoking, tooth being a molar and interdental location were evaluated.ResultsThe number of sites with PD ≥ 5 mm and BOP after 6 months was similar in the test (Me = 4, IQR = 0–11) and control (Me = 5, IQR = 1–22) group. Adjunctive azithromycin treatment, compared to SRP alone, resulted in more frequent eradication of A. actinomycetemcomitans (p = 0.013) and C. rectus (p = 0.029), decreased proportion (p = 0.006) and total counts (p = 0.003) of P. gingivalis, and decreased proportion of C. rectus (p = 0.012). Both groups showed substantial but equivalent improvements in periodontal parameters, with no intergroups differences at initially shallow or deep sites. The logistic regression showed a lower odds ratio for healing of diseased sites on molars (OR = 0.51; p < 0,001).ConclusionDespite significant changes in numbers of A. actinomycetemcomitans, P. gingivalis and C. rectus, patients with periodontitis do not benefit from adjunctive systemic azithromycin in terms of number of persisting sites with PD ≥ 5 mm and BOP.Trial registrationEUDRA-CT: 2015–004306-42; https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-004306-42/SI, registered 17. 12. 2015.

High rates of persistent and recurrent chlamydia in pregnant women after treatment with azithromycin

BACKGROUND:Chlamydia trachomatis is a common bacterial sexually transmitted infection that can persist or recur after antibiotic treatment. Universal screening for chlamydia in pregnancy is recommended to prevent adverse birth outcomes. Single-dose oral azithromycin has been the first-line therapy for chlamydia in pregnancy since 2006.OBJECTIVE:In the setting of limited data and rising sexually transmitted infection rates in the United States, our goal was to document rates and risk factors for persistent or recurrent chlamydia after azithromycin treatment in pregnancy.STUDY DESIGN:This retrospective cohort study included pregnancies with urogenital chlamydia and follow-up testing in women who delivered at an Alabama facility between November 2012 and December 2017. Pregnancies with prescribed azithromycin therapy and repeat chlamydia testing ≥21 days later were included. Chlamydia trachomatis nucleic acid amplification testing was performed on genital swab or urine samples. Descriptive characteristics and birth outcomes were compared for categories stratified by repeat test results: persistence (+ +), recurrence (+ − +), or clearance (+ −). Logistic regression models were used to identify demographic and clinical risk factors for persistent or recurrent chlamydia in pregnancy.RESULTS:Among 810 women with 840 pregnancies with repeat chlamydia testing after azithromycin treatment, 114 (14%) had persistence and an additional 72 (9%) had recurrence later in pregnancy. The median time to repeat testing was 30 days (interquartile range, 24–49 days). Concomitant gonorrhea or syphilis in pregnancy was independently associated with persistent or recurrent chlamydia (adjusted odds ratio, 1.6; 95% confidence interval, 1.1–2.4).CONCLUSION:Persistent or recurrent chlamydia after azithromycin treatment was detected in nearly 1 in 4 pregnancies with repeat testing in our urban center, highlighting the importance of performing a test of cure and ensuring partner therapy to reduce recurrent chlamydia risk.

Effects on QT interval of hydroxychloroquine associated with ritonavir/darunavir or azithromycin in patients with SARS-CoV-2 infection.

IntroductionMost of the drugs associations that have been used to treat patients with SARS-CoV-2 infection increase the risk of prolongation of the corrected QT interval (QTc).ObjectiveTo evaluate the effects of an association therapy of hydroxychloroquine (HY) plus ritonavir/darunavir (RD) or azithromycin (AZ) on QTc intervals.MethodsAt the beginning of COVID-19 pandemic patients admitted to our hospital were treated with the empiric association of HY/RD; one week later the therapeutic protocol was modified with the combination of HY/AZ. Patients underwent an ECG at baseline, then 3 and 7 days after starting therapy. We prospectively enrolled 113 patients (61 in the HY/RD group-52 in the HY/AZ group).ResultsA significant increase in median QTc was reported after seven days of therapy in both groups: from 438 to 452 ms in HY/RD patients; from 433 to 440 ms in HY/AZ patients (p = 0.001 for both). 23 patients (21.2%) had a QTc > 500 ms at 7 days. The risk of developing a QTc > 500 ms was greater in patients with prolonged baseline QTc values (≥ 440 ms for female and ≥ 460 ms for male patients) (OR 7.10 (95% IC 1.88–26.81); p = 0.004) and in patients with an increase in the QTc > 40 ms 3 days after onset of treatment (OR 30.15 (95% IC 6.96–130.55); p = 0.001). One patient per group suffered a malignant ventricular arrhythmia.ConclusionHydroxychloroquine with both ritonavir/darunavir or azithromycin therapy significantly increased the QTc-interval at 7 days. The risk of developing malignant arrhythmias remained relatively low when these drugs were administered for a limited period of time.

Drug Interactions and Side Effects of Co-Administration of Chloroquine/Hydroxychloroquine and Azithromycin: on the Issue of Rational Pharmacotherapy of Patients with COVID-19 with Antimalarial Drugs

This review analyzes existing approaches to the treatment of COVID-19 patients with antimalarial drugs from the standpoint of rational pharmacotherapy. Particular attention is paid to drug interactions and side effects of co-administration of chloroquine/hydroxychloroquine and azithromycin, considering the problem of cardiotoxicity and the high likelihood of cardiovascular disease in middle-aged and elderly people with COVID-19. The article discusses the prospects of using another representative from the group of antimalarial drugs - mefloquine in the treatment of COVID-19. Special attention is paid to the “proarrhythmogenic” side effects of azithromycin therapy, as well as to the problem of resistance of microorganisms to macrolides during antibiotic therapy of pneumonia, in particular to azithromycin. In conclusion, the article discusses the possibilities of alternative methods in the treatment of this disease.

Coronavirus Disease 2019 (COVID-19) in Children: Prevalence, Diagnosis, Clinical Symptoms, and Treatment.

In this article, we have reviewed the prevalence, diagnosis, symptoms, and treatment of COVID-19 in children. The incidence of COVID-19 among children under 18 years was 2.1% based on the reported studies, where the mortality rate in the same age group was 0.2%. No death has been reported in children under 9-years old. There are some articles that report children with COVID-19 having symptoms similar to Kawasaki’s disease. In these cases, heart complications were observed. The best markers for diagnosing the severity of the disease in children are the levels of bilirubin and hepatic enzymes. Large number of angiotensin converting enzyme 2 (ACE2) receptors on cell surfaces, effective innate immune system, and high level of blood lymphocyte have been reported to be the potent reasons for lower incidence of severe symptoms of COVID-19 among children. Children can very well be the carriers of this virus. Children with severe COVID-19 clinical symptoms, especially those suffering from pneumonia, must be hospitalized similar to adults, while quarantine is required for those having mild symptoms. Antiviral medication (lopinavir, darunavir, favipiravir, remdesivir, ribavirin, oseltamivir, tocilizumab, and umifenovir), ACE inhibitors, interferon-α2b, co-therapy with azithromycin, inhaling iNO, and oxygen therapy can be used for treatment. For the treatment of children without any clinical and infection symptoms, home isolation protocol has been recommended.

COVID-19 in Liver Transplant Recipients: An Initial Experience From the US Epicenter

COVID-19 in Liver Transplant Recipients: An Initial Experience From the US Epicenter

Azithromycin and Diminazene Aceturate Combination Therapy in Experimental Multidrug-resistant Trypanosoma brucei brucei Infection in Albino Rats

Azithromycin and diminazene aceturate combination therapy in experimental multidrug-resistant Trypanosoma brucei brucei infection in albino rats was evaluated. A total of forty-five female albino rats were used. These rats were randomly assigned to nine groups of five rats each. Group 1 was the uninfected-untreated group while groups 2 - 6 were infected with 1 × 106 trypanosomes suspended in 0.3 ml of normal saline intraperitoneally. Following infection and parasitaemia, group 2 was untreated while group 3 was treated once with 7 mg/kg diminazene aceturate. Groups 4 - 6 were treated with 10, 20 and 30 mg/kg azithromycin respectively for 7 days. Groups 7 - 9 were treated with combination of 7 mg/kg diminazene aceturate (DA) once and 10, 20 and 30 mg/kg azithromycin (AZT) respectively for 7 days. Level of parasitaemia, haematological indices (packed cell volume, total erythrocyte count, total leukocyte count, haemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration), survivability, body weight and rectal temperature were used to assess the effectiveness of the combination therapy. A significant reduction in parasitaemia levels was observed in the DA-treated group and AZT-treated group 6 while clearance of parasitaemia was observed in the DA-AZT treated groups 7 – 9 for periods between 1 and 5 days post treatment. The haematological indices and survivability of the DA-AZT treated groups were better than the DA-treated group despite the relapse recorded in those groups. One rat each in the DA-AZT combination groups survived till the end of the experiment. In conclusion, the DA-AZT combination treatment can be used as a possible adjunct to DA in the treatment of multidrug-resistant T. brucei brucei. The combination also enhanced survivability and decreased the effect of the disease in rats.

Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19.

Azithromycin (AZ) is a broad‐spectrum macrolide antibiotic with a long half‐life and a large volume of distribution. It is primarily used for the treatment of respiratory, enteric, and genitourinary bacterial infections. AZ is not approved for the treatment of viral infections, and there is no well‐controlled, prospective, randomized clinical evidence to support AZ therapy in coronavirus disease 2019 (COVID‐19). Nevertheless, there are anecdotal reports that some hospitals have begun to include AZ in combination with hydroxychloroquine or chloroquine (CQ) for treatment of COVID‐19. It is essential that the clinical pharmacology (CP) characteristics of AZ be considered in planning and conducting clinical trials of AZ alone or in combination with other agents, to ensure safe study conduct and to increase the probability of achieving definitive answers regarding efficacy of AZ in the treatment of COVID‐19. The safety profile of AZ used as an antibacterial agent is well established.1 This work assesses published in vitro and clinical evidence for AZ as an agent with antiviral properties. It also provides basic CP information relevant for planning and initiating COVID‐19 clinical studies with AZ, summarizes safety data from healthy volunteer studies, and safety and efficacy data from phase II and phase II/III studies in patients with uncomplicated malaria, including a phase II/III study in pediatric patients following administration of AZ and CQ in combination. This paper may also serve to facilitate the consideration and use of a priori–defined control groups for future research.

Azithromycin Treatment vs Placebo in Children With Respiratory Syncytial Virus–Induced Respiratory Failure

Despite a high disease burden, there is no effective treatment for respiratory syncytial virus (RSV) infection. To determine whether administration of azithromycin (AZM) to children with RSV-induced respiratory failure is safe and to define the effect of AZM therapy on nasal matrix metalloproteinase 9 (MMP-9) levels. This randomized, double-blind, placebo-controlled phase 2 trial was conducted at a single tertiary pediatric intensive care unit from February 2016 to February 2019. The study included children with RSV infection who were admitted to the pediatric intensive care unit and required respiratory support via positive pressure ventilation (invasive and noninvasive). A total of 147 children were screened; 90 were excluded for not meeting inclusion criteria, having an absent legal guardian, lacking pharmacy support, or having a language barrier and 9 declined participation, resulting in 48 patients enrolled in the study. Receipt of standard dose AZM (10 mg/kg/d), high-dose AZM (20 mg/kg/d), or a matching placebo of normal saline intravenously for 3 days. Nasal and endotracheal samples were collected at baseline as well as at 24 hours and 48 hours after start of treatment. The secondary outcome was to determine treatment effect on clinical outcome measures, including days of positive pressure ventilation and length of hospital stay. A total of 48 patients were enrolled in the trial, with a median (range) age at randomization of 12 (1 to 125) months; 36 participants (75.0%) were younger than 2 years. Overall, 26 participants (54.2%) were boys, and 29 (60.4%) had a comorbidity. A total of 16 patients were randomized into each trial group (ie, placebo, standard-dose AZM, and high-dose AZM). Baseline demographic characteristics were comparable among the 3 groups. Both doses of AZM were safe, with no adverse events observed. No difference in nasal MMP-9 levels were observed between treatment groups. Among those who required mechanical ventilation and received high-dose AZM, endotracheal active and total MMP-9 levels were lower on day 3. Compared with baseline, active and total MMP-9 levels in endotracheal aspirates were 1.0 log lower in the high-dose AZM group (active MMP-9: 99.8% CI, -1.28 to -0.64; P < .001; total MMP-9: 99.8% CI, -1.37 to -0.57; P < .001). Patients who received high-dose AZM had fewer median (interquartile range) hospital days compared with those receiving the placebo (8 [6-14] days vs 11 [8-20] days; mean ratio estimate, 0.57; 95% CI, 0.38-0.87; P = .01). In this phase 2 randomized clinical trial, both doses of AZM were safe. While nasal MMP-9 levels were unchanged among treatment groups, endotracheal MMP-9 levels were lower among those who received high-dose AZM. The positive secondary clinical outcome, while exploratory, provides insight for end points in a multicenter randomized trial. ClinicalTrials.gov Identifier: NCT02707523.

Structures of glyceraldehyde 3-phosphate dehydrogenase in Neisseria gonorrhoeae and Chlamydia trachomatis.

Neisseria gonorrhoeae (Ng) and Chlamydia trachomatis (Ct) are the most commonly reported sexually transmitted bacteria worldwide and usually present as co-infections. Increasing resistance of Ng to currently recommended dual therapy of azithromycin and ceftriaxone presents therapeutic challenges for syndromic management of Ng-Ct co-infections. Development of a safe, effective, and inexpensive dual therapy for Ng-Ct co-infections is an effective strategy for the global control and prevention of these two most prevalent bacterial sexually transmitted infections. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a validated drug target with two approved drugs for indications other than antibacterials. Nonetheless, any new drugs targeting GAPDH in Ng and Ct must be specific inhibitors of bacterial GAPDH that do not inhibit human GAPDH, and structural information of Ng and Ct GAPDH will aid in finding such selective inhibitors. Here, we report the X-ray crystal structures of Ng and Ct GAPDH. Analysis of the structures demonstrates significant differences in amino acid residues in the active sites of human GAPDH from those of the two bacterial enzymes suggesting design of compounds to selectively inhibit Ng and Ct is possible. We also describe an efficient in vitro assay of recombinant GAPDH enzyme activity amenable to high-throughput drug screening to aid in identifying inhibitory compounds and begin to address selectivity.

Drug Interactions Between COVID-19 and Psychiatric Medications: A Mini Review

Coronavirus disease 2019 (COVID-19) has become a pandemic with 8,708,000 confirmed cases and 461,715 death in the world until June 21, 2020. The Severe Acute Respiratory Syndrome Coronavirus 2 virus, which is an enveloped and single-stranded RNA virus belonging to Coronaviridea family, causes multiple organ systems diseases such as respiratory, gastrointestinal, hepatic, and neurological tracts in humans and animals. With the rapid and global spread of COVID-19, the scientific authorities have developed treatment algorithms for COVID-19. Besides the supportive care, chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, tocilizumab, azithromycin, Vitamin C, and convalescent plasma therapy are frequently used off-label to treat COVID-19. For severe COVID-19 cases, the US Food and Drug Administration has issued an Emergency Use Authorization Remdesivir, which is the first drug to earn the title. COVID-19 treatment may cause many side effects and drug interactions. Psychiatric diseases are also chronic diseases, and psychiatric drugs may have severe interactions with COVID-19 medications. Drug interactions with psychiatric medication and neuropsychiatric side effects should be considered within the action mechanism of COVID-19 treatments. Thus, in this review, we aimed to elucidate the interactions of COVID-19 medications with the antidepressants, antipsychotics, and the other psychotropic drugs that have been frequently used in psychiatric diseases. Chloroquine, hydroxychloroquine, azithromycin, ribavirin, and lopinavir/ritonavir have interactions with psychiatric medications such as antidepressants, antipsychotics, anticonvulsants, and anxiolytics in terms of QTc interval prolongation, hepatotoxicity, myelosuppression, increased or decreased concentration of medications. Remdesivir has lower interactions with most of the psychiatric drugs except St John's Wort and some anticonvulsants. However, favipiravir is considered as the COVID-19 medication, which has lower interaction and side effects in combination with psychiatric medication. The use of tocilizumab is also safe with most of the psychiatric drugs and has a positive effect on depressive symptoms, although there is a risk of hepatotoxicity.

Effects of Prolonged Azithromycin Therapy on Bacterial Resistance to Functionally Analogous Antibiotics

Bacteria may be innately resistant to antibiotics or acquire antimicrobial resistance through a variety of mediums. Under certain conditions, bacteria develop cross-resistance, a reduction in susceptibility to many antibiotics they have never been exposed to before. Most frequently, chemical similarities between antibiotics cause cross-resistance since bacterial defenses are counteractive to a specific molecule. However, cross-resistance to many chemically different antibiotics can occur when bacteria mutate to develop non-specific defenses. This study investigated a subject who had received prolonged azithromycin therapy for a neuropsychiatric condition related to chronic Group A Streptococcus infection. Given the possibility of cross-resistance, we hypothesized that, after prolonged azithromycin therapy, any bacteria collected from the subject would be resistant to structurally analogous antibiotics. We also hypothesized that, if bacteria from the subject had developed metabolic mutations, resistance to functionally analogous antibiotics would be present. From a series of antibiotic susceptibility tests, we concluded that the subject bacteria were resistant to erythromycin, a structural analog of azithromycin, but exhibited standard sensitivity to functional antibiotic analogs. The results of our study will help identify the risks associated with prolonged antibiotic therapy for a variety of conditions.

Intermittent Treatment with Azithromycin and Ethambutol for Noncavitary Mycobacterium avium Complex Pulmonary Disease.

We evaluated the efficacy of intermittent azithromycin and ethambutol therapy for noncavitary Mycobacterium avium complex pulmonary disease (MAC-PD). Twenty-nine (76%) of 38 patients achieved sputum culture conversion after 12 months of treatment, and sputum smear positivity was an independent factor for failure to achieve culture conversion (adjusted odds ratio, 26.7; 95% confidence interval, 2.1 to 339.9; P = 0.011). Intermittent azithromycin and ethambutol may be an optional treatment regimen for noncavitary MAC-PD.