A systematic review of antibiotic drug shortages and the strategies employed for managing these shortages.

BACKGROUND: There is a need to examine the impact of increasingly prevalent antibiotic shortages on patient outcomes and on the emergence and spread of antimicrobial resistance (AMR). OBJECTIVES: To: 1) assess patterns and causes of shortages, 2) investigate the effect of shortages on health systems and patient outcomes, and 3) identify strategies for forecasting and managing shortages. DATA SOURCES: PubMed/MEDLINE, EMBASE, Scopus, and Web of Science. STUDY ELIGIBILITY CRITERIA: Studies published in English during January 2000-July 2023. PARTICIPANTS: Healthcare, policy and strategic teams managing and responding to shortages. Patient populations (adult and children) affected by shortages. INTERVENTIONS: Strategies, policies, and mitigation options for managing and responding to antibiotic drug shortages. RISK OF BIAS: Methodological quality of included studies was reviewed using the most appropriate tool from Joanna Briggs Institute critical appraisal tool for each study design. METHODS: Data synthesis was qualitative and quantitative using descriptive statistics. RESULTS: The final analysis included 74 studies (61/74, 82.4% high-income countries). Shortages were most reported for piperacillin-tazobactam (21/74, 28.4%) with most of the reported antibiotics being in the WHO Watch category (27/54, 51%). Frequent cause of shortages was disruption in manufacturing including supply of active pharmaceutical ingredient and raw materials. Clinical implications of shortages included increased length of hospital stay, treatment failure after using inferior alternative agents and negative impact on antimicrobial stewardship programmes (AMS). Robust economic impact analysis of shortages is unavailable. Successfully reported mitigation strategies were driven by AMS and infectious diseases teams in hospitals. CONCLUSIONS: Antibiotic shortages are directly or indirectly driven by economic viability and reliance on single source ingredients. The limited data on clinical outcomes indicates mixed effect with some infections becoming more difficult to treat, though there is no robust data on the impact of shortages on AMR. The mitigation strategies to manage shortages rely heavily on AMS teams.

Field based research in the era of the pandemic in resource limited settings: challenges and lessons for the future.

The coronavirus pandemic that began in December 2019, has had an unprecedented impact on the global economy, health systems and infrastructure, in addition to being responsible for significant mortality and morbidity worldwide. The "new normal" has brought along, unforeseen challenges for the scientific community, owing to obstructions in conducting field-based research in lieu of minimizing exposure through in-person contact. This has had greater ramifications for the LMICs, adding to the already existing concerns. As a response to COVID-19 related movement restrictions, public health researchers across countries had to switch to remote data collections methods. However, impediments like lack of awareness and skepticism among participants, dependence on paper-based prescriptions, dearth of digitized patient records, gaps in connectivity, reliance on smart phones, concerns with participant privacy at home and greater loss to follow-up act as hurdles to carrying out a research study virtually, especially in resource-limited settings. Promoting health literacy through science communication, ensuring digitization of health records in hospitals, and employing measures to encourage research participation among the general public are some steps to tackle barriers to remote research in the long term. COVID-19 may not be a health emergency anymore, but we are not immune to future pandemics. A more holistic approach to research by turning obstacles into opportunities will not just ensure a more comprehensive public health response in the coming time, but also bolster the existing infrastructure for a stronger healthcare system for countries.

Dipeptidyl peptidase 4 (DPP-4) inhibitors and the risk of lung cancer: current evidence and future directions.

INTRODUCTION: Recent evidence has linked long-term use of angiotensin converting enzyme (ACE) inhibitors with the risk of developing lung cancer by increasing levels of substance P (SP) and bradykinin in lung tissue. DPP-4 inhibitors, by virtue of their mechanism of action, may increase the level of SP and pose a similar risk of incident lung cancer. Concomitant use of DPP-4 inhibitors and ACE inhibitors may further exaggerate this plausible risk. AREA COVERED: Here we discuss both direct and indirect evidence involving mechanisms by which DPP-4 inhibitors may increase the risk of lung cancer in treated patients. We highlight that increased levels of SP with DPP-4 inhibitor monotherapy and raised levels of both SP and bradykinin with add-on ACE inhibitor therapy may further enhance this risk. EXPERT OPINION: DPP-4 inhibitors are prescribed in type-2 diabetes mellitus patients with or without cardiovascular disease. When used together, ACE inhibitors and DPP-4 inhibitors may act synergistically and further amplify the lung cancer risk. Consequently, physicians should consider this plausible association while prescribing them concomitantly especially in high-risk individuals. Well-planned research studies are required to assess the association of DPP-4 inhibitors with lung cancer and other adverse effects linked to increased levels of SP and bradykinin.

Recombinant protein subunit COVID-19 vaccine-induced Guillain-Barré Syndrome in an adolescent: A case report.

Guillain-Barré Syndrome (GBS), an autoimmune neurological disease of peripheral nerves, has been causally associated with COVID-19 vaccination in adults. However, no such report has been published so far in children. We describe a 13-year-old female child who presented to the emergency department with complaints of bilateral upper limb, lower limb and truncal weakness over 3 days following first dose of recombinant protein subunit COVID-19 vaccine (Corbevax). Clinical examination and nerve conduction studies showed pure motor axonal polyneuropathy with absent compound muscle action potential (CMAP) in all sampled nerves of upper and lower limbs which was consistent with the diagnosis of GBS after ruling out possible alternative aetiologies. A temporal association between first dose of protein subunit COVID-19 vaccine administered a day prior and symptom onset was noted. The causality assessment using the World Health Organization (WHO) tool for adverse event following immunization (AEFI) assessment indicated vaccine product-related reaction categorized as A1. The patient's clinical condition improved after seven sessions of plasmapheresis. The purpose of this report is to create awareness among health care professionals about COVID-19 vaccine-induced GBS in children as early diagnosis and management can be critical in avoiding complications and improving patient outcomes.

Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID-19) in India.

Healthcare workers (HCWs) and frontline workers were recommended hydroxychloroquine (HCQ) 400 mg twice a day on day 1, followed by 400 mg once weekly for the next 7 weeks, as prophylaxis against COVID-19. There was limited information on the population pharmacokinetics (popPK) of HCQ in an Indian setting when administered for prophylaxis against COVID-19, and hence this study was proposed. It was a multicentric prospective study conducted at 3 sites in India wherein HCWs who were already on HCQ prophylaxis, who were about to start prophylaxis or who had stopped the prophylaxis for any reason were enrolled. Each participant gave 2 to 6 blood samples at different time points and whole-blood HCQ concentrations were assayed using liquid chromatography with tandem mass spectrometry (LC MS/MS). popPK analysis was performed using PUMAS 1.1.0. A total of N = 338 blood samples from N = 121 participants were included in the popPK analysis. A 2-compartment structural model with linear elimination was able to explain the observed data. Body weight was found to be a significant covariate influencing drug clearance. The final model was assessed using goodness-of-fit plots, a visual predictive check and a bootstrap, all of which confirmed that the model was appropriate. Simulations based on the current regimen showed that trough values were below the half-maximal effective concentration (EC50) of 0.7 µmol against COVID-19. A new weight-based dosage regimen was proposed to maintain the trough concentration above the EC50 threshold.

Knowledge, attitude, and practice survey on antimicrobial use and resistance among Indian clinicians: A multicentric, cross-sectional study.

Purpose: This multicentric questionnaire-based study was undertaken to address the lack of systematic background data on the knowledge, attitudes, and practices among Indian physicians related to antimicrobial use and resistance. Materials and Methods: A validated structured study questionnaire was used for capturing respondent particulars, antimicrobial prescribing habits, knowledge of antimicrobial resistance (AMR), ways of choosing and learning about antibiotics, agreement or disagreement with certain perceptions regarding antibiotics, selection of antibiotics in specific settings, and suggestions regarding rationalizing antimicrobial use in the practice setting. Summary statistical analysis of the pooled data was done. Results: Five hundred and six respondents with a mean (standard deviation) age of 31.4 (8.71) years participated in the study. Three hundred and twenty-seven were medical and 179 surgical discipline clinicians. Overall, the theoretical knowledge about antimicrobials was satisfactory, but areas of concern were noted in the attitude and practice domains. A substantial proportion of participants failed to identify the correct choice of antibiotics in the case-based scenarios. 38.33% reported not attending a single continuing medical education on antimicrobials during the past year. Statistically significant differences were not observed in the KAP quotient scores between medical and surgical discipline respondents. Conclusions: Despite satisfactory background knowledge regarding the rational use of antimicrobials and AMR patterns, there are discrepancies in the physicians' prescribing attitude and thus strengthen the case for instituting specific interventions to improve antimicrobial prescribing.

System for administering and monitoring hydroxychloroquine prophylaxis for COVID-19 in accordance with a national advisory: preliminary experience of a tertiary care institute in India.

BACKGROUND: Hydroxychloroquine (HCQ) was one of the earliest drugs to be recommended for tackling the COVID-19 threat leading to its widespread usage. We provide preliminary findings of the system, established in a tertiary care academic center for the administration of HCQ prophylaxis to healthcare workers (HCW) based on Indian Council of Medical Research (ICMR) advisory. METHODS: A dedicated clinical pharmacology and internal medicine team screened for contraindications, administered informed consent, maintained compliance and monitored for adverse events. RESULTS: Among the 194 HCWs screened for ruling out contraindications for prophylaxis, 9 were excluded and 185 were initiated on HCQ. A total of 55 adverse events were seen in 38 (20.5%) HCWs out of which 70.9%, 29.1% were mild and moderate & none were severe. Before the completion of therapy, a total of 23 participants discontinued. Change in QTc interval on day 2 was 5 (IQR: -3.75, 11) ms and the end of week 1 was 15 ms (IQR: 2, 18). Out of the 5 HCW who turned positive for COVID-19, 2 were on HCQ. CONCLUSION: HCQ prophylaxis was found to be safe and well tolerated in HCW when administered after appropriate screening and with monitoring for adverse events.

Assessment of Appropriateness of Antimicrobial Therapy in Resource-Constrained Settings: Development and Piloting of a Novel Tool-AmRAT.

Inappropriate antimicrobial prescribing is considered to be the leading cause of high burden of antimicrobial resistance (AMR) in resource-constrained lower- and middle-income countries. Under its global action plan, the World Health Organization has envisaged tackling the AMR threat through promotion of rational antibiotic use among prescribers. Given the lack of consensus definitions and other associated challenges, we sought to devise and validate an Antimicrobial Rationality Assessment Tool-AmRAT-for standardizing the assessment of appropriateness of antimicrobial prescribing. A consensus algorithm was developed by a multidisciplinary team consisting of intensivists, internal medicine practitioners, clinical pharmacologists, and infectious disease experts. The tool was piloted by 10 raters belonging to three groups of antimicrobial stewardship (AMS) personnel: Master of Pharmacology (M.Sc.) (n = 3, group A), Doctor of Medicine (MD) residents (n = 3, group B), and DM residents in clinical pharmacology (n = 4, group C) using retrospective patient data from 30 audit and feedback forms collected as part of an existing AMS program. Percentage agreement and the kappa (κ) coefficients were used to measure inter-rater agreements amongst themselves and with expert opinion. Sensitivity and specificity estimates were analyzed comparing their assessments against the gold standard. For the overall assessment of rationality, the mean percent agreement with experts was 76.7% for group A, 68.9% for group B, and 77.5% for group C. The kappa values indicated moderate agreement for all raters in group A (κ 0.47-0.57), and fair to moderate in group B (κ 0.22-0.46) as well as group C (κ 0.37-0.60). Sensitivity and specificity for the same were 80% and 68.6%, respectively. Though evaluated by raters with diverse educational background and variable AMS experience in this pilot study, our tool demonstrated high percent agreement and good sensitivity and specificity, assuring confidence in its utility for assessing appropriateness of antimicrobial prescriptions in resource-constrained healthcare environments.

Concomitant use of dexamethasone and tetracyclines: a potential therapeutic option for the management of severe COVID-19 infection?

Introduction: The global coronavirus disease-2019 (COVID-19) pandemic has posed a critical challenge to the research community as well as to the healthcare systems. Severe COVID-19 patients are at a higher risk of developing serious complications and mortality. There is a dire need for safe and effective pharmacotherapy for addressing unmet needs of these patients. Concomitant use of dexamethasone and tetracyclines, by virtue of their immunomodulatory and other relevant pharmacological properties, offers a potential strategy for synergy aimed at improving clinical outcomes.Areas covered: Here we review the potential benefits of combining dexamethasone and tetracyclines (minocycline or doxycycline) for the management of severe COVID-19 patients. We have critically examined the evidence obtained from in silico, experimental, and clinical research. We have also discussed the plausible mechanisms, advantages, and drawbacks of this proposed combination therapy for managing severe COVID-19.Expert opinion: The concomitant use of dexamethasone and one of the tetracyclines among severe COVID-19 patients offers several advantages in terms of additive immunomodulatory effects, cost-effectiveness, wide-availability, and well-known pharmacological properties including adverse-effect profile and contraindications. There is an urgent need to facilitate pilot studies followed by well-designed and adequately-powered multicentric clinical trials to generate conclusive evidence related to utility of this approach.

Minocycline for the management of multiple sclerosis: repositioning potential, opportunities, and challenges.

INTRODUCTION: Multiple sclerosis (MS) is a chronic demyelinating inflammatory disorder with variable clinical and pathologic characteristics reflecting multiple underlying pathophysiologic mechanisms. Repositioning of existing drugs for the new indications offers several advantages including significant reduction in the cost and time of drug development and exemption from early phase clinical trials. Minocycline has been reported to exhibit immunomodulation in several pre-clinical and clinical studies through suppression of migratory inflammatory cells, modulation of peripheral immune response, and inhibition of microglial activation within the CNS. AREAS COVERED: Here, the authors review the repositioning potential of minocycline for the treatment of MS along with appraisal of the evidence obtained from preclinical and clinical research. The authors also discuss the advantages and potential safety concerns related to the use of minocycline for the management of MS. EXPERT OPINION: Minocycline offers several distinct advantages in terms of well-known safety profile, lower cost of therapy, widespread availability, and being available as an oral formulation. The authors call upon the public and private funders to facilitate well designed and adequately powered randomized clinical trials that can provide conclusive evidence regarding the safety and efficacy of minocycline in patients with MS.

Deciphering the COVID-19 cytokine storm: Systematic review and meta-analysis.

INTRODUCTION: The coronavirus pandemic has affected more than 20 million people so far. Elevated cytokines and suppressed immune responses have been hypothesized to set off a cytokine storm, contributing to ARDS, multiple-organ failure and, in the most severe cases, death. We aimed to quantify the differences in the circulating levels of major inflammatory and immunological markers between severe and nonsevere COVID-19 patients. METHODS: Relevant studies were identified from PubMed, EMBASE, Web of Science, SCOPUS and preprint servers. Risk of bias was assessed for each study, using appropriate checklists. All studies were described qualitatively and a subset was included in the meta-analysis, using forest plots. RESULTS: Based on 23 studies, mean cytokine levels were significantly higher (IL-6: MD, 19.55 pg/mL; CI, 14.80, 24.30; IL-8: MD, 19.18 pg/mL; CI, 2.94, 35.43; IL-10: MD, 3.66 pg/mL; CI, 2.41, 4.92; IL-2R: MD, 521.36 U/mL; CI, 87.15, 955.57; and TNF-alpha: MD, 1.11 pg/mL; CI, 0.07, 2.15) and T-lymphocyte levels were significantly lower (CD4+ T cells: MD, -165.28 cells/µL; CI, -207.58, -122.97; CD8+ T cells: MD, -106.51 cells/µL; CI, -128.59, -84.43) among severe cases as compared to nonsevere ones. There was heterogeneity across studies due to small sample sizes and nonuniformity in outcome assessment and varied definitions of disease severity. The overall quality of studies was sub-optimal. CONCLUSION: Severe COVID-19 is characterized by significantly increased levels of pro-inflammatory cytokines and reduced T lymphocytes. Well-designed and adequately powered prospective studies are needed to amplify the current evidence and provide definitive answers to dilemmas regarding timing and type of anti-COVID-19 therapy particularly in severe patients.

Hydroxychloroquine for the treatment and prophylaxis of COVID-19: The journey so far and the road ahead.

As mortality and morbidity from novel coronavirus disease (COVID-19) continue to mount worldwide, the scientific community as well as public health systems are under immense pressure to contain the pandemic as well as to develop effective medical countermeasures. Meanwhile, desperation has driven prescribers, researchers as well as administrators to recommend and try therapies supported by little or no reliable evidence. Recently, hydroxychloroquine-sulfate (HCQS) has got significant media and political attention for the treatment as well as prophylaxis of COVID-19 despite the lack of convincing and unequivocal data supporting its efficacy and safety in these patients. This has unfortunately, yet foreseeably led to several controversies and confusion among the medical fraternity, the patient community as well as the general public. Based on the available studies, many with high risk of bias, relatively small sample sizes, and abbreviated follow-ups, HCQS is unlikely to be of dramatic benefit in COVID-19 patients and yet has the potential to cause harm, particularly when used in combination with azithromycin or other medications in high risk individuals with comorbidities. Although definitive data from larger well-controlled randomized trials will be forthcoming in the future, and we may be able to identify specific patient subpopulations likely to benefit from hydroxychloroquine, till that time it will be prudent to prescribe it within investigational trial settings with close safety monitoring. Here we review the current evidence and developments related to the use of HCQS in COVID-19 patients and highlight the importance of risk-benefit assessment and rational use of HCQS during this devastating pandemic.

A multicentric knowledge-attitude-practice survey in the community about antimicrobial use and resistance in India.

BACKGROUND: To address the reasons for inappropriate use of antimicrobials, it is important to understand the knowledge, attitude and practices (KAP) of all pertinent stakeholders. This multicentric survey is aimed at understanding the KAP quotients of the community regarding antimicrobial use and antimicrobial resistance (AMR), as such information is lacking in India. METHODS: A cross-sectional survey was conducted by face-to-face interviews across five centers in India using a validated, field-tested questionnaire incorporating KAP domain questions. Scores were appropriately assigned to the questions. RESULTS: The mean (SD) age of the respondents was 35.2 (12.61) y and 62% had a graduate or higher level of education. The median (IQR) KAP scores were 10 (8-12), 5 (3-5) and 2 (2-3) out of a maximum of 18, 5 and 6, respectively. Higher educational and socioeconomic levels were associated with better attitude scores, but knowledge levels were comparable. Correlations between KAP scores were poor. CONCLUSIONS: This study reveals that laypeople have appropriate knowledge and attitude regarding antibiotic use and AMR to some degree but there are important lacunae and practices are often wanting. These issues need to be addressed in sustained public awareness and motivation campaigns to improve the rational use of antibiotics in India.

Developing a latent class analysis model to identify at-risk populations among people using medicine without prescription.

INTRODUCTION: There exist limited strategies to address the issue of topical medication without prescription (MWP) use. MATERIAL AND METHODS: A survey with pre-coded questionnaires was conducted with 210 patients following up in the dermatology clinic of a tertiary care center. The knowledge and attitude scores were regressed against demographics and exploratory practice questions, and latent class analysis was carried out to check any particular set of characteristics associated with study subpopulations. RESULTS: Forty-seven (22%) participants were found using topical antimicrobial containing MWP. Participants with good knowledge score had 3.41 (95% C.I. = 1.68-7.33), 2.99 (1.37-6.73), and 2.49 (1.26-5.15) times association with opting of distance as the prime reason for availing topical MWP, habit of always reading the accompanying drug leaflet, and understanding that OTC topical medication may change the effect of the already prescribed drugs. Participants with good attitude score showed 2.76 (1.50-5.13) times association with limiting the use of steroid containing topical MWP. Latent class analysis identified one subset of participants having lesser knowledge and attitude scores and quoted financial reasons for the procurement of MWP; however, it was found to have greater income as compared to remaining participants. CONCLUSION: The strategy to identify the target patient audience so as to deliver patient education intervention programs, regarding safe and effective use of MWP was built.

Statin use and safety concerns: an overview of the past, present, and the future.

INTRODUCTION: Dyslipidemia is a significant risk factor for cardiovascular disorders and contributes to significant morbidity and mortality associated with CAD and stroke worldwide. Statins are the most commonly prescribed drugs for the prevention and management of dyslipidemia globally. Although they provide immense therapeutic benefit, they are associated with clinically significant adverse effects, predominantly muscle, nerve, liver, and cognition-related besides new-onset diabetes. This has sparked various controversies, bringing to the fore, ambiguities that continue to exist in the scientific evidence, in relation to statin-associated harms. Therefore, it becomes essential to have a better understanding of safety issues related to statin use in various populations. AREAS COVERED: This review describes the most common adverse effects of statins, examines available evidence and highlights the role of ethnicity, lipophilicity and other biological factors that could mediate and/or influence the relationship. MEDLINE was searched via PubMed to obtain relevant articles on dyslipidemia and statin safety. EXPERT OPINION: The effectiveness of statins is presently unmatched. Further research is warranted to gain insights into the diverse pharmacological effects of statins in various population subgroups. This would assist prescribers in making better informed decisions. Specific treatment strategies for vulnerable groups can significantly attenuate harms, improve risk-benefit ratios, and ultimately enhance patient experience.