zithromax and Drug-Related-Side-Effects-and-Adverse-Reactions

Background Vibrio cholerae is a highly motile Gram-negative bacterium which is responsible for 3 million cases of diarrhoeal illness and up to 100,000 deaths per year, with an increasing burden documented over the past decade. Current WHO guidelines for the treatment of paediatric cholera infection (tetracycline 12.5 mg/kg four times daily for 3 days) are based on data which are over a decade old. In an era of increasing antimicrobial resistance, updated review of the appropriate empirical therapy for cholera infection in children (taking account of susceptibility patterns, cost and the risk of adverse events) is necessary. Methods A systematic review of the current published literature on the treatment of cholera infection in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was undertaken. International clinical guidelines and studies pertaining to adverse effects associated with treatments available for cholera infection were also reviewed. Results The initial search produced 256 results, of which eight studies met the inclusion criteria. Quality assessment of the studies was performed as per the Grading of Recommendations Assessment, Development and Evaluation guidelines. Conclusions In view of the changing non-susceptibility rates worldwide, empirical therapy for cholera infection in paediatric patients should be changed to single-dose azithromycin (20 mg/kg), a safe and effective medication with ease of administration. Erythromycin (12.5 mg/kg four times daily for 3 days) exhibits similar bacteriological and clinical success and should be listed as a second-line therapy. Fluid resuscitation remains the cornerstone of management of paediatric cholera infection, and prevention of infection by promoting access to clean water and sanitation is paramount.

Topics: Adolescent; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Cholera; Drug Resistance, Bacterial; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Guidelines as Topic; Humans; Infant; Infant, Newborn; Treatment Outcome; Vibrio cholerae; World Health Organization

Topics: Acne Vulgaris; Administration, Oral; Anti-Bacterial Agents; Azithromycin; Drug Costs; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Evidence-Based Medicine; Humans; Minocycline

Ceftriaxone is the foundation of currently recommended gonorrhea treatment. There is an urgent need for backup treatment options for patients with cephalosporin allergy or infections due to suspected cephalosporin-resistant Neisseria gonorrhoeae. We evaluated the efficacy and tolerability of 2 combinations of existing noncephalosporin antimicrobials for treatment of patients with urogenital gonorrhea.. We conducted a randomized, multisite, open-label, noncomparative trial in 5 outpatient sexually transmitted disease clinic sites in Alabama, California, Maryland, and Pennsylvania. Patients aged 15-60 years diagnosed with uncomplicated urogenital gonorrhea were randomly assigned to either gentamicin 240 mg intramuscularly plus azithromycin 2 g orally, or gemifloxacin 320 mg orally plus azithromycin 2 g orally. The primary outcome was microbiological cure of urogenital infections (negative follow-up culture) at 10-17 days after treatment among 401 participants in the per protocol population.. Microbiological cure was achieved by 100% (lower 1-sided exact 95% confidence interval [CI] bound, 98.5%) of 202 evaluable participants receiving gentamicin/azithromycin, and 99.5% (lower 1-sided exact 95% CI bound, 97.6%) of 199 evaluable participants receiving gemifloxacin/azithromycin. Gentamicin/azithromycin cured 10 of 10 pharyngeal infections and 1 of 1 rectal infection; gemifloxacin/azithromycin cured 15 of 15 pharyngeal and 5 of 5 rectal infections. Gastrointestinal adverse events were common in both arms.. Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed. Clinical Trials Registration. NCT00926796.

Topics: Administration, Oral; Adolescent; Adult; Anti-Bacterial Agents; Azithromycin; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Fluoroquinolones; Gastrointestinal Diseases; Gemifloxacin; Gentamicins; Gonorrhea; Humans; Injections, Intramuscular; Male; Middle Aged; Naphthyridines; Neisseria gonorrhoeae; Treatment Outcome; United States; Young Adult

Neglected tropical diseases are co-endemic in many areas of the world, including sub Saharan Africa. Currently lymphatic filariasis (albendazole/ivermectin) and trachoma (azithromycin) are treated separately. Consequently, financial and logistical benefit can be gained from integration of preventive chemotherapy programs in such areas.. 4 villages in two co-endemic districts (Kolondièba and Bougouni) of Sikasso, Mali, were randomly assigned to coadministered treatment (ivermectin/albendazole/azithromycin) or standard therapy (ivermectin/albendazole with azithromycin 1 week later). These villages had previously undergone 4 annual MDA campaigns with ivermectin/albendazole and 2 with azithromycin. One village was randomly assigned to each treatment arm in each district. There were 7515 eligible individuals in the 4 villages, 3011(40.1%) of whom participated in the study. No serious adverse events occurred, and the majority of adverse events were mild in intensity (mainly headache, abdominal pain, diarrhoea and "other signs/symptoms"). The median time to the onset of the first event, of any type, was later (8 days) in the two standard treatment villages than in the co-administration villages. Overall the number of subjects reporting any event was similar in the co-administration group compared to the standard treatment group [18.7% (281/1501) vs. 15.8% (239/1510)]. However, the event frequency was higher in the coadministration group (30.4%) than in the standard treatment group (11.0%) in Kolondièba, while the opposite was observed in Bougouni (7.1% and 20.9% respectively). Additionally, the overall frequency of adverse events in the co-administration group (18.7%) was comparable to or lower than published frequencies for ivermectin+albendazole alone.. These data suggest that co-administration of ivermectin+albendazole and azithromycin is safe; however the small number of villages studied and the large differences between them resulted in an inability to calculate a meaningful overall estimate of the difference in adverse event rates between the regimens. Further work is therefore needed before co-administration can be definitively recommended.. ClinicalTrials.gov; NCT01586169.

Topics: Adolescent; Adult; Aged; Albendazole; Anthelmintics; Anti-Bacterial Agents; Azithromycin; Chemoprevention; Child; Child, Preschool; Coinfection; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Elephantiasis, Filarial; Female; Humans; Ivermectin; Male; Mali; Middle Aged; Neglected Diseases; Trachoma; Young Adult

In Morocco, chloroquine/hydroxychloroquine + azithromycin have been used off-label for COVID-19 treatment. This study aimed to describe the distribution, nature and seriousness of the adverse drug reactions (ADRs) associated with the two drug combinations in COVID-19 in-patients. We conducted a prospective observational study based on intensive pharmacovigilance in national COVID-19 patients' management facilities from April 1 to June 12, 2020. Hospitalized patients treated with chloroquine/hydroxychloroquine + azithromycin and who experienced ADRs during their hospital stay were included in the study. The causality and seriousness of the ADRs were assessed using the World Health Organization-Uppsala Monitoring Centre method and the agreed criteria in the ICH guideline (E2A) respectively. A total of 237 (51.7%) and 221 (48.3%) COVID-19 in-patients treated respectively with chloroquine + azithromycin and hydroxychloroquine + azithromycin experienced 946 ADRs. Serious ADRs occurred in 54 patients (11.8%). Gastrointestinal system was most affected both in patients taking chloroquine + azithromycin (49.8%) or hydroxychloroquine + azithromycin (54.2%), followed by nervous system and psychiatric. Eye disorders were more frequent in patients receiving chloroquine + azithromycin (10.3%) than those receiving hydroxychloroquine + azithromycin (1.2%). Cardiac ADRs accounted for 6.4% and 5.1% respectively. Chloroquine + azithromycin caused more ADRs by patients than hydroxychloroquine + azithromycin (2.6 versus 1.5 ADRs/patient). Causality assessment was possible for 75.7% of the ADRs. Diabetes was identified as a risk factor for serious ADRs (ORa 3.56; IC: 95% 1.5-8.6). The off-label use of the two drug combinations in COVID-19 in-patients according to the national therapeutic protocol seems to be safe and tolerable. ADRs were mainly expected. However, precaution should be taken in using the drugs in diabetic patients to prevent the risk of serious ADRs.

Topics: Azithromycin; Chloroquine; COVID-19; COVID-19 Drug Treatment; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxychloroquine; Morocco; Pharmacovigilance

This study aimed to characterize adverse drug reactions (ADRs) to hydroxychloroquine in the setting of COVID-19, occurring in Italy in the period March to May 2020. The analysis of the combination therapy with azithromycin or/and lopinavir/ritonavir as well as a comparison with ADRs reported throughout 2019 was performed. ADRs collected by the Italian National Network of Pharmacovigilance were analyzed for their incidence, seriousness, outcome, coadministered drugs, and Medical Dictionary for Regulatory Activities classification. A total of 306 reports were gathered for the quarter of 2020: 54% nonserious and 46% serious, and half of the latter required either the hospitalization or its prolongation. However, most of them were either completely recovered (26%) or in the process of recovery (45%), except for 9 fatal cases. Throughout 2019, 38 reports were collected, 53% nonserious and 47% serious, but no deaths had been reported. Diarrhea, prolonged QT interval, and hypertransaminasemia were the most frequently ADRs reported in 2020, significantly higher than 2019 and specific for COVID-19 subjects treated with hydroxychloroquine. The logistic regression analyses demonstrated that the likelihood of serious ADRs, QT prolongation, and diarrhea significantly increased with hydroxychloroquine dosage. Coadministration of lopinavir/ritonavir and hydroxychloroquine showed a positive correlation with diarrhea and hypertransaminasemia and a negative relationship with the ADR seriousness. The combination therapy with azithromycin was another independent predictor of a serious ADR. Off-label use of hydroxychloroquine for COVID-19, alone or in combination regimens, was associated with increased incidence and/or seriousness of specific ADRs in patients with additional risk factors caused by the infection.

Topics: Azithromycin; COVID-19 Drug Treatment; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Off-Label Use; Pharmacovigilance; Ritonavir

We identified two reports of drug levels increased and acute kidney injury caused by the drug-drug interaction between azithromycin (AZM) and tacrolimus (TAC). However, it is unclear whether the combination of these two drugs causes additive or synergistic adverse drug reactions. Therefore, we evaluated the disproportionality in reporting drug level increased and acute kidney injury for these two drugs are used alone and in combination with each other.. Data from the US Food and Drug Administration's Adverse Event Reporting System from 1974 to Q3/2021 were used. Reports based on exposure to macrolide antibiotic alone, TAC alone, and each macrolide antibiotic + TAC were extracted. Proportional reporting ratios (PRRs) and 95% confidence intervals (CIs) were calculated, and a lower limit of the 95% CI (Lower95CI) value of 2.0 or higher was interpreted as a signal of safety.. Lower95CIs for macrolide antibiotic alone and TAC showed no potential signals of safety, including drug level increase, acute kidney injury, and control event. The PRRs and 95% CI for drug levels increased were 3.27 (2.69-3.97) for AZM + TAC, and 10.81 (9.59-12.17) for clarithromycin (CAM) + TAC. For CAM + TAC, the PRR and 95% CI were 8.42 (7.51-9.44) in acute kidney injury. However, AZM + TAC was not associated with a signal of safety in acute kidney injury.. This suggests that AZM + TAC has a low risk of causing acute kidney injury but may cause increased drug levels.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Azithromycin; Clarithromycin; Drug-Related Side Effects and Adverse Reactions; Humans; Tacrolimus

Azithromycin is commonly used to treat Neisseria gonorrhoeae. We compared its gastrointestinal side effects using 1 g single, 2 g single or 2 g split (i.e. 1 g plus 1 g 6-12 h later) dosing, representing our clinic's changing guidelines over the study period.. We recruited consecutive sexual health clinic patients who received azithromycin (and 500 mg ceftriaxone) for uncomplicated gonorrhoea. Each patient received a text message 48 h after their attendance to complete a questionnaire.. Patients received 1 g single (n = 271), 2 g single (218) or 2 g split (105) doses. Vomiting was less common for 1 g versus 2 g single dose [1.1% versus 3.7%; risk difference (RD): -2.6%; 95% CI: -0.2 to -5.4] and 2 g split versus 2 g single dose (0.9% versus 3.7%; RD: -2.8%; 95% CI: -0.3 to -5.8). Nausea was less common for 1 g versus 2 g single dose (13.7% versus 43.1%; RD: -29.5%; 95% CI: -21.7 to -37.2) and 2 g split versus 2 g single dose (16.4% versus 43.1%; RD: -26.8; 95% CI: -17.2 to -36.3). Diarrhoea was less common for 1 g versus 2 g single dose (25.5% versus 50.9%; RD: -25.5%; 95% CI: -17.0 to -33.9) and 2 g split versus 2 g single dose (30.9% versus 50.9%; RD: -20.0; 95% CI: -9.1 to -30.9). Almost all were willing to retake the same dosing for gonorrhoea in the future: 97% for 1 g single; 94% for 2 g single; and 97% for 2 g split dose.. Azithromycin 2 g split dose for gonorrhoea resulted in significantly less vomiting, nausea and diarrhoea than a 2 g single dose.

Topics: Anti-Bacterial Agents; Azithromycin; Ceftriaxone; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Gonorrhea; Humans; Nausea; Neisseria gonorrhoeae; Vomiting

Off-label use of azithromycin, hydroxychloroquine, and ivermectin (the "COVID kit") has been suggested for COVID-19 treatment in Brazil without clinical or scientific evidence of efficacy. These drugs have known adverse drug reactions (ADR). This study aimed to analyze if the sales of drugs in the "COVID kit" are correlated to the reported number of ADR after the COVID-19 pandemic began. Data was obtained from the Brazilian Health Regulatory Agency (Anvisa) website on reported sales and ADRs for azithromycin, hydroxychloroquine, and ivermectin for all Brazilian states. The period from March 2019 to February 2020 (before the pandemic) was compared to that from March 2020 to February 2021 (during the pandemic). Trend adjustment was performed for time series data and cross-correlation analysis to investigate correlation between sales and ADR within the same month (lag 0) and in the following months (lag 1 and lag 2). Spearman's correlation coefficient was used to assess the magnitude of the correlations. After the pandemic onset, sales of all investigated drugs increased significantly (69.75% for azithromycin, 10,856,481.39% for hydroxychloroquine, and 12,291,129.32% for ivermectin). ADR levels of all medications but azithromycin were zero before the pandemic, but increased after its onset. Cross-correlation analysis was significant in lag 1 for all drugs nationwide. Spearman's correlation was moderate for azithromycin and hydroxychloroquine but absent for ivermectin. Data must be interpreted cautiously since no active search for ADR was performed. Our results show that the increased and indiscriminate use of "COVID kit" during the pandemic correlates to an increased occurrence of ADRs.

Topics: Azithromycin; Brazil; Coronavirus Infections; COVID-19 Drug Treatment; Drug-Related Side Effects and Adverse Reactions; Humans; Hydroxychloroquine; Ivermectin; Pandemics; Pneumonia, Viral

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic as declared by World Health Organization (WHO). In the absence of an effective treatment, different drugs with unknown effectiveness, including antimalarial hydroxychloroquine (HCQ), with or without concurrent administration with azithromycin (AZM), have been tested for treating COVID-19 patients with developed pneumonia. However, the efficacy and safety of HCQ and/or AZM have been questioned by recent clinical reports. Direct effects of these drugs on the human heart remain very poorly defined. To better understand the mechanisms of action of HCQ +/- AZM, we employed bioengineered human ventricular cardiac tissue strip (hvCTS) and anisotropic sheet (hvCAS) assays, made with human pluripotent stem cell (hPSC)-derived ventricular cardiomyocytes (hvCMs), which have been designed for measuring cardiac contractility and electrophysiology, respectively. Our hvCTS experiments showed that AZM induced a dose-dependent negative inotropic effect which could be aggravated by HCQ; electrophysiologically, as revealed by the hvCAS platform, AZM prolonged action potentials and induced spiral wave formations. Collectively, our data were consistent with reported clinical risks of HCQ and AZM on QTc prolongation/ventricular arrhythmias and development of heart failure. In conclusion, our study exposed the risks of HCQ/AZM administration while providing mechanistic insights for their toxicity. Our bioengineered human cardiac tissue constructs therefore provide a useful platform for screening cardiac safety and efficacy when developing therapeutics against COVID-19.

Topics: Anti-Bacterial Agents; Antimalarials; Arrhythmias, Cardiac; Azithromycin; Chloroquine; COVID-19 Drug Treatment; Drug-Related Side Effects and Adverse Reactions; Humans; Myocardial Contraction; Myocytes, Cardiac; Pluripotent Stem Cells; Tissue Engineering; Ventricular Function

This is a review of the macrolide and ketolide field focusing on differentiating the pharmacodynamics and especially the toxicology of the macrolides and ketolides. We emphasize the diversity in pharmacodynamics and toxicity of the macrolides and ketolides, resulting from even small structural changes, which makes it important to consider the various different compounds separately, not necessarily as a class. The ketolide, telithromycin, was developed because of rising bacterial macrolide resistance but was withdrawn postapproval after visual disturbances, syncope, myasthenia gravis, and hepatotoxicity were noted. These diverse adverse effects could be attributed to inhibition of nicotinic acetylcholine receptors. Solithromycin, a later generation ketolide, was effective in treating bacterial pneumonia, but it was not approved by the U.S. Food and Drug Administration owing, in part, to its structural similarity to telithromycin. This Miniperspective describes that structurally similar macrolides/ketolides have clearly mechanistically distinct effects. Understanding these effects could help in developing and securing regulatory approval of a new macrolide/ketolide that is active against macrolide-resistant pathogenic bacteria.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Drug-Related Side Effects and Adverse Reactions; Humans; Ketolides; Macrolides

Topics: Anti-Infective Agents; Arrhythmias, Cardiac; Azithromycin; Betacoronavirus; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Drug-Related Side Effects and Adverse Reactions; Hospitalization; Humans; Hydroxychloroquine; Italy; Outcome Assessment, Health Care; Pandemics; Pneumonia, Viral; SARS-CoV-2; Time-to-Treatment

In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir).. Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences.. We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020.. In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs.. Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.

Topics: Abdominal Pain; Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; Antiviral Agents; Azithromycin; Chemical and Drug Induced Liver Injury; Chloroquine; COVID-19 Drug Treatment; Databases, Pharmaceutical; Diarrhea; Drug Combinations; Drug Eruptions; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Male; Nausea; Oseltamivir; Ritonavir; Sex Distribution; Sex Factors; Vomiting

Half of prescription drugs commonly given to children lack product labeling on pediatric safety, efficacy, and dosing. Two drugs most widely used off-label in pediatrics are azithromycin and fentanyl. We sought to determine the risk of serious adverse events (SAEs) when oral azithromycin or intravenous/intramuscular fentanyl are used off-label compared to on-label in pediatric intensive care units (ICUs).. Six pediatric hospitals participated in a retrospective chart review of patients administered oral azithromycin (n = 241) or intravenous/intramuscular fentanyl (n = 367) between January 5, 2013 and December 26, 2014. Outcomes were SAEs by drug and labeling status: off-label compared to on-label by Food and Drug Administration (FDA)-approved age and/or indication. Statistical analysis was performed using logistic regression to estimate odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs).. Twenty-one (9%) children receiving azithromycin experienced SAEs. Off-label use of azithromycin was not associated with a higher risk of SAE (OR 0.87, 95% CI 0.27-2.71, p = 0.81). Ninety-five (26%) children receiving fentanyl experienced SAEs. Fentanyl off-label use by both age and indication was not associated with a higher risk of overall SAEs compared to on-label use (OR 1.99, 95% CI 0.94-4.19, p = 0.07). However, the risk of the SAE respiratory depression was significantly greater when fentanyl was used off-label by both age and indication (OR 5.05, 95% CI 1.08-23.56, p = 0.044). Results based on HRs were similar.. Azithromycin off-label use in pediatric ICUs does not appear to be associated with an increased risk of SAEs. Off-label use of fentanyl appears to be more frequently associated with respiratory depression when used off-label by both age and indication in pediatric ICUs. Prospective studies should be undertaken to assess the safety and efficacy of fentanyl in the pediatric population so that data can be added to the FDA labeling.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Analgesics, Opioid; Anti-Bacterial Agents; Azithromycin; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Fentanyl; Hospitals, Pediatric; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Male; Off-Label Use; Prescription Drugs; Prospective Studies; Retrospective Studies; United States; Young Adult

Early target attainment is the key factor influencing the outcome of antimicrobial therapy. The objective of the present study was to evaluate the relationship between azithromycin concentrations during the first 24-48 h of therapy and the clinical outcome in order to optimize antimicrobial therapy.. All children with lower respiratory tract infections receiving intravenous azithromycin monotherapy were included. The relationship between azithromycin trough concentrations during the first 24-48 h and the effectiveness and safety was explored.. Data from 44 children [mean (SD) age = 5.25 (3.72) years] were available for final analysis. Children with trough concentrations >0.25 mg/L (n = 8) had a more significant improvement in antibacterial efficacy in terms of decreased C-reactive protein (P = 0.006) and the percentage of neutrophils (P = 0.043) compared with children with trough concentrations ≤0.25 mg/L (n = 36). No drug-related adverse events were shown to have a causal association with azithromycin therapy.. Our study showed the clinical benefits of early target attainment of azithromycin therapy. A target trough concentration of 0.25 mg/L in the first 24-48 h of hospitalization was required to ensure better antibacterial efficacy.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Azithromycin; C-Reactive Protein; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Humans; Leukocyte Count; Plasma; Respiratory Tract Infections; Time Factors; Treatment Outcome

Antibiotic dispensing without a prescription poses a threat to public health as it leads to excessive antibiotic consumption. Inappropriate antibiotic availability to the community has been documented to be amongst drivers of antimicrobial resistance emergence. Community pharmacies are a source of antibiotics in low and middle-income countries (LMICs). We aimed at assessing antibiotic dispensing practices by community pharmacy retailers in Moshi urban, Kilimanjaro, Tanzania and recommend interventions to improve practice. Using a Simulated Client (SC) Method, an observational cross-sectional survey of antibiotic dispensing practices was conducted from 10th June to 10th July 2017. Data analysis was done using Stata 13 (StataCorp, College Station, TX, USA). A total of 82 pharmacies were visited. Part I pharmacies were 26 (31.71%) and 56 (68.29%) were part II. Overall 92.3% (95% CI 77.8-97.6) of retailers dispensed antibiotics without prescriptions. The antibiotics most commonly dispensed without a prescription were ampiclox for cough (3 encounters) and azithromycin for painful urination (3 encounters). An oral third generation cephalosporin (cefixime) was dispensed once for painful urination without prescription by a part I pharmacy retailer. Out of 21, 15(71.43%) prescriptions with incomplete doses were accepted and had antibiotics dispensed. Out of 68, 4(5.9%) retailers gave instructions for medicine use voluntarily. None of the retailers voluntarily explained drug side-effects. In Moshi pharmacies, a high proportion of antibiotics are sold and dispensed without prescriptions. Instructions for medicine use are rarely given and none of the retailers explain side effects. These findings support the need for a legislative enforcement of prescription-only antibiotic dispensing rules and regulations. Initiation of clinician and community antibiotic stewardship and educational programs on proper antibiotic use to both pharmacists and public by the regulatory bodies are highly needed.

Topics: Anti-Bacterial Agents; Azithromycin; Cefixime; Community Pharmacy Services; Cross-Sectional Studies; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Pharmacists; Surveys and Questionnaires; Tanzania

Effectiveness of single-dose azithromycin (2 g) in the treatment of early syphilis among HIV-infected patients has rarely been evaluated in the era of combination ART.. Consecutive HIV-infected patients with early syphilis, who received 2 g single-dose azithromycin or 2.4 MU benzathine penicillin G, between 2007 and 2014, were prospectively observed. Genotypic resistance to macrolides was determined in Treponema pallidum isolates identified from clinical specimens using PCR assays. Rapid plasma reagin (RPR) titres were determined at baseline and every 3 months after treatment. Primary outcome was a decline of RPR titre by ≥4-fold at 12 months after treatment.. During the study period, 162 HIV-infected patients with early syphilis received benzathine penicillin G and 237 patients received azithromycin. At 12 months follow-up, the serological response rate for penicillin and azithromycin groups was 61.1% and 56.5% (P = 0.41), respectively; respective response rate was 61.1% and 65.9% (P = 0.49) if we only included patients infected with T. pallidum not harbouring macrolide resistance in the azithromycin group. In multivariate analysis, RPR titres ≥1:32 (OR 2.56; 95% CI 1.55-4.21) and prior syphilis (OR 0.54; 95% CI 0.35-0.81) were predictors of serological response. Most common adverse effects of azithromycin included diarrhoea (52.7%), nausea (22.4%), abdominal pain (18.6%), bloating (17.7%) and lassitude/somnolence (27.4%).. In the setting of a low prevalence of macrolide-resistant T. pallidum, 2 g single-dose azithromycin achieved a similar serological response to benzathine penicillin G in HIV-infected patients with early syphilis. Major adverse effects of azithromycin were gastrointestinal symptoms and lassitude/somnolence.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Genotype; HIV Infections; Humans; Macrolides; Male; Middle Aged; Penicillin G Benzathine; Polymerase Chain Reaction; Prospective Studies; Reagins; Syphilis; Treatment Outcome; Treponema pallidum; Young Adult

Scrub typhus, caused by Orientia tsutsugamushi, has recently emerged in northern China where the disease had not been known to exist. Although doxycycline and azithromycin are the recommended agents for the treatment of scrub typhus, clinical responses depend both on the susceptibilities of various O. tsutsugamushi strains and the severity of the disease. A retrospective analysis was conducted on patients diagnosed with mild scrub typhus from August 2013 to January 2016 in the Affiliated Hospital of Nantong University, northern China. A total of 40 patients who received minocycline treatment and 34 patients who received azithromycin treatment were included in the analysis. All patients except one defervesced within 120 h after initiating antimicrobial therapy. Kaplan-Meier curves in association with log-rank test showed that the median time to defervescence was significantly shorter for the minocycline-treated group than the azithromycin-treated group (P = 0.003). There were no serious adverse events during treatment. No relapse occurred in either group during the 1-month follow-up period. In conclusion, both minocycline and azithromycin are effective and safe for the treatment of mild scrub typhus, but minocycline is more active than azithromycin against O. tsutsugamushi infection acquired in northern China.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Azithromycin; China; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Minocycline; Pregnancy; Retrospective Studies; Scrub Typhus; Time Factors; Treatment Outcome; Young Adult

Topics: Anti-Bacterial Agents; Azithromycin; Cardiovascular Physiological Phenomena; Child; Chronic Disease; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Electrophysiologic Techniques, Cardiac; Female; Humans; Long QT Syndrome; Male; Respiratory Tract Diseases; Spain; Treatment Outcome

The Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated.. In HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance.. The overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p<0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log2 increase, 1.21; confidence interval [CI], 1.04-1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19-0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08-0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the macrolide resistance mutation (A2058G). In subgroup analyses confined to the 75 patients infected with T. pallidum lacking resistance mutation, a statistically significantly lower risk for the Jarisch-Herxheimer reaction following azithromycin treatment was noted.. Treatment with azithromycin was associated with a lower risk for the Jarisch-Herxheimer reaction than that with benzathine penicillin G in HIV-positive patients with early syphilis. Previous benzathine penicillin G therapy for syphilis decreased the risk, whereas higher RPR titres increased the risk, for the reaction.

Topics: Adult; Anti-Bacterial Agents; Azithromycin; Cohort Studies; DNA, Bacterial; DNA, Ribosomal; Drug-Related Side Effects and Adverse Reactions; Female; Fever; HIV Infections; Humans; Incidence; Male; Microbial Sensitivity Tests; Penicillin G Benzathine; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Prospective Studies; RNA, Ribosomal, 23S; Syphilis; Taiwan; Treponema pallidum

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration