Regional variation in the potentially inappropriate first-line use of fluoroquinolones in Canada as a key to antibiotic stewardship? A drug utilization review study

Background Serious adverse effects of fluoroquinolone antibiotics have been described for more than decade. Recently, several drug regulatory agencies have advised restricting their use in milder infections for which other treatments are available, given the potential for disabling and possibly persistent side effects. We aimed to describe variations in fluoroquinolone use for initial treatment of urinary tract infection (UTI), acute bacterial sinusitis (ABS), and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in the outpatient setting across Canada. Methods Using administrative health data from six provinces, we identified ambulatory visits with a diagnosis of uncomplicated UTI, uncomplicated AECOPD or ABS. Antibiotic exposure was determined by the first antibiotic dispensed within 5 days of the visit. Results We identified 4,303,144 uncomplicated UTI events among 2,170,027 women; the proportion of events treated with fluoroquinolones, mostly ciprofloxacin, varied across provinces, ranging from 18.6% (Saskatchewan) to 51.6% (Alberta). Among 3,467,678 ABS events (2,087,934 patients), between 2.2% (Nova Scotia) and 11.2% (Ontario) were dispensed a fluoroquinolone. For 1,319,128 AECOPD events among 598,347 patients, fluoroquinolones, mostly levofloxacin and moxifloxacin, ranged from 5.8% (Nova Scotia) to 35.6% (Ontario). The proportion of uncomplicated UTI and ABS events treated with fluoroquinolones declined over time, whereas it remained relatively stable for AECOPD. Conclusions Fluoroquinolones were commonly used as first-line therapies for uncomplicated UTI and AECOPD. However, their use varied widely across provinces. Drug insurance formulary criteria and enforcement may be a key to facilitating better antibiotic stewardship and limiting potentially inappropriate first-line use of fluoroquinolones.

Off-Label Use of COVID-19 Vaccines from Ethical Issues to Medico-Legal Aspects: An Italian Perspective

During the COVID-19 outbreak, the lack of official recommendations on the treatment has led healthcare workers to use multiple drugs not specifically tested and approved for the new insidious disease. After the availability of the first COVID-19 vaccines (Comirnaty Pfizer-BioNTech and Moderna COVID19 vaccine), an authorization was issued by national and international Drug Regulatory Agencies in order to speed up their introduction on the market and their administration on a large scale. Despite the authorization, the off-label use of these vaccines may still be possible especially to answer specific concerns as the lack of vaccine doses, the delay in the delivery of planned doses or the pressure from public opinion and political influence also in relation to the evolution of the pandemic. This paper aims to assess the possible off-label use of COVID-19 vaccines and the ethical and medico-legal implications of this eventuality. The scope of this paper is to point out the possible consequences of off-label use of COVID-19 vaccines and possible mitigation and preventive measures to be taken by healthcare workers involved in vaccination procedures.

The Nigerian Pharmaceutical Supply Chain: Blockchain Adoption, Counterfeit Drugs and Successful Deployment of COVID-19 Vaccine in Nigeria

Aim: Critically investigating the possibility of adopting blockchain technology within the Nigerian pharmaceutical supply chain to curb the supply of counterfeit drugs. Study Design: The study is qualitative in nature and the primary data were fetched through interviews. Place and Duration of the Study: Conducted within Nigeria for a period of 3 months. Methodology: A qualitative method of data collection was adopted in the study, where some stakeholders were interviewed. The interviews were conducted with employees from different pharmaceutical companies and some drug regulatory agencies in Nigeria. Result: Firstly, this study has ascertained the current prevalence of counterfeit drugs and the reasons for that. The study discovers a very high level of counterfeit drugs and some reasons behind that. Secondly, this study has also found some barriers to blockchain adoption, including the fact that the level of awareness of blockchain technology among stakeholders within the Nigerian pharmaceutical supply chain and the regulatory agencies is very low. Conclusion: It was concluded that the efforts put in developing a viable COVID-19 vaccine could be undermined due to the current nature of the Nigerian pharmaceutical supply chain, the nature of porous borders in place, absence of an apparent drug distribution system, among others. This study also concludes that the supply chain's current structure needs more regulatory and structural interventions by the Nigerian government than blockchain technology. In other words, with the current nature of the supply chain, blockchain technology adoption would not be effective in delivering the said benefits reported by scholars because the atmosphere is not conducive for successful blockchain adoption.

Excipients in the Paediatric Population: A Review

This theoretical study seeks to critically review the use of excipients in the paediatric population. This study is based on the rules and recommendations of European and American drug regulatory agencies. On the one hand, this review describes the most frequent excipients used in paediatric medicine formulations, identifying the compounds that scientific literature has marked as potentially harmful regarding the side effects generated after exposure. On the other hand, this review also highlights the importance of carrying out safety -checks on the excipients, which, in most cases, are linked to toxicity studies. An excipient in the compilation of paediatric population databases is expected to target safety and toxicity, as in the STEP database. Finally, a promising pharmaceutical form for child population, ODT (Orally Disintegrating Tablets), will be studied.

International Regulations for Bioequivalence Approval of Locally Acting Orally Inhaled Drug Products

Bioequivalence (BE) is established between the brand drug and the generic drug to allow the linking of preclinical and clinical testing conducted on the reference listed drug. Regulatory agencies around the globe have come up with the guidance for locally acting orally inhaled drug products (OIDPs) for bioequivalence approaches. The prime intent of the present article is to compare approaches of different international regulatory authorities such as Health Canada, European Medicines Agency and the US Food and Drug Administration that have published guidance related to locally acting OIDPs. Moreover, the Central Drugs Standard Control Organisation, India, has published guidelines for bioavailability and bioequivalence studies. BE recommendations from global regulatory agencies were based on comparison for different parameters, namely inhaler device, formulation, reference product’s selection, in-vitro as well as in-vivo studies (pharmacokinetics, pharmacodynamics, and clinical studies). In the case of in-vivo studies, details about study design, dose choices, inclusion/ exclusion criteria of the subject, study period, endpoint study, and equivalence acceptance criteria were discussed in the present review article.

In vitro quality assessment of ten brands of metronidazole benzoate suspensions marketed in Warri, Nigeria

Therapeutic failure as a result of high incidence of fake, adulterated, counterfeit and substandard drugs usage is a major concern to health practitioners, drug regulatory agencies, drug consumers and the general public in Nigeria. The objective of this study was to carry out in vitro quality assessment/evaluation of ten (10) different brands of metronidazole benzoate suspensions that are marketed in Warri, Nigeria. Metronidazole benzoate suspensions (10 brands) were purchased from some pharmacies in Warri, Nigeria. They were checked for the label information on both the secondary and primary packages, physical examination of the primary containers for tampering/breakage of seal on cap, organoleptic properties, pH, sedimentation volume, flow rate, viscosity, redispersibility and content of active ingredient/assay using standard methods. Results obtained showed that the suspensions had the necessary information on their labels, the containers were not tampered with in order to access or change their content. All the brands tested showed good results for color variation, pH, viscosity, flow rate, sedimentation, and redispersibility. All the brands met with their label claims of metronidazole benzoate content based on British Pharmacopoeia specification [95 - 105 %] except one brand (MET-A), that failed. Generally, nine of the brands representing 90 % met with their label claim and can be considered fit for distribution and consumption.

Proton pump inhibitors – do we know them well and are they really that safe? – part 1

Proton pump inhibitors (PPIs) are one of the most commonly used drug groups. More than 10% of patients being chronically treated in the adult population. Often patients with a high risk of vascular or renal impairment. In addition to the unquestionable effect in the treatment and in the prophylaxis of gastroduodenal diseases, PPIs have been promoted in combination with antithrombotic therapy in order to reduce bleeding in the gastrointestinal tract. In both of these indications, this is a chronic treatment, often for several years. Drug regulatory agencies (EMAs or FDA) warn against chronic PPIs use, warning of a number of serious side effects. However, chronic administration of PPIs is a common practice. It is therefore time to evaluate the benefit and risk of this important drug group. First of all, it should be noted that PPIs operate not only at the level of the classical gastric proton pump (H+/K+ ATPase), but also block the activity of the sister vacuolar proton pump (V-H+-ATPase) in a number of other organs or organelles, namely lysosomes of all somatic cells. Similarly, PPIs block the activity of a number of transporters and metabolic enzymes. Action at this level is likely to surprise the gastroenterologist. There is no doubt about the benefits of PPIs in the indication of treatment and prevention of ulcerative or reflux disease. However, what are the evidence to reduce the risk of gastriontestinal bleeding in antithrombotic treatment? In this area we have data at the level of observational studies, the decrease in the risk of bleeding by about a third is significant. However, with a relatively low incidence of bleeding in the gastrointestinal tract, the absolute decrease in risk is small, hovering at 0.3%. The observed number need to treat is around 250, i.e. for every 250 PPIs treated, we will prevent one bleeding (usually not critical). On the other hand, there are increasingly work that finds a higher incidence of cardiovascular events, renal failure, bronchial asthma and nervous disabilities in chronic PPIs treatment. In a population at high cardiovascular risk, i.e. in a typical population where we add antithrombotic treatment to PPIs, the risk is significant. The number need to harm value is around 50. Thus, in the chronic use of PPIs, the risk outweighs the benefit.

Toward a Regulatory Qualification of Real-World Mobility Performance Biomarkers in Parkinson’s Patients Using Digital Mobility Outcomes

Wearable inertial sensors can be used to monitor mobility in real-world settings over extended periods. Although these technologies are widely used in human movement research, they have not yet been qualified by drug regulatory agencies for their use in regulatory drug trials. This is because the first generation of these sensors was unreliable when used on slow-walking subjects. However, intense research in this area is now offering a new generation of algorithms to quantify Digital Mobility Outcomes so accurate they may be considered as biomarkers in regulatory drug trials. This perspective paper summarises the work in the Mobilise-D consortium around the regulatory qualification of the use of wearable sensors to quantify real-world mobility performance in patients affected by Parkinson’s Disease. The paper describes the qualification strategy and both the technical and clinical validation plans, which have recently received highly supportive qualification advice from the European Medicines Agency. The scope is to provide detailed guidance for the preparation of similar qualification submissions to broaden the use of real-world mobility assessment in regulatory drug trials.

Introducing bedaquiline: experiences from the Challenge TB Project

BACKGROUND: Drug-resistant tuberculosis (DR-TB) remains a global public health crisis. In 2013, the World Health Organization recommended the introduction of bedaquiline (BDQ) for eligible DR-TB patients.METHODS: We conducted a retrospective review and analyses of project reports from 2016 to mid-2019 on the processes, activities implemented, available results on enrolment and interim treatment outcomes, across the 23 Challenge TB (CTB) supported countries.RESULTS: Initial introduction of BDQ-containing regimens in the 23 CTB-supported countries took on average 2 years, with subsequent nation-wide scale-up achieved in Ethiopia and Kyrgyzstan within a short time period. Successful implementation required critical interventions including advocacy, revision of policies and guidelines, capacity building of health care workers, and strengthening of laboratory networks. The number of countries providing BDQ increased from 9 to 23; 9398 patients were enrolled on bedaquiline containing regimens; 71% were culture-negative after 6 months of treatment; and the number of countries reporting serious adverse events increased (from 5 to 18). Major challenges included limited in-country coordination with drug regulatory agencies, unrealistic quantification and drug ordering, weak laboratory networks and reporting systems for drug safety.CONCLUSION: BDQ introduction required a systematic and programmatic approach. The initial time investment helped achieve initial introduction and scale-up of coverage, ownership and sustainability by National TB Programmes.