Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.

SUMMARYThe World Health Organisation's 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few (n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams (n = 80), 42 (52.5%) differed from traditionally accepted 30%-50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

A pilot study on the rational use of medicines in four tertiary care hospitals through validated World Health Organization prescribing drugs indicators.

BACKGROUND: Appropriate utilization of therapeutic agents is a basic component of the quality of health outcomes for the patients and the community. A pilot study was conducted to evaluate the rational use of medicines and antibiotics, based on World Health Organization (who) prescribing indicators. STUDY DESIGN: We performed a retrospective, descriptive, cross-sectional pilot study in the medical outpatient departments in four tertiary care hospitals of Islamabad, Pakistan, in order to verify the correct prescribing of medicines according to the validated indicators prepared by the World Health Organization (who). METHODS: The Registries of all the prescriptions formulated during the period April 02 2017 - April 01 2018 by the outpatient departments of four tertiary care hospitals (two government funded hospitals (GH-A and GH-B) and two private funded hospitals (PH-C and PH-D) were considered. According to the World Health Organization recommendations, during the following month (April 02 2018 to May 1 2018), 600 prescriptions (150 per hospital) were collected by a random sampling method, verified and analyzed through a statistical tool (SPSS version 22.0). RESULTS: Mean number of medicines per prescription were 4.6 (Optimal value ≤ 2), with the highest value observed in GH-B hospital. Out of these, 350 (58.3%) (Optimal value < 30%) prescriptions consisted of antibiotics and 340 (56.6%) (Optimal value < 25%) prescriptions consisted of injectable medicines, with marked differences between hospitals. About 550 (19.6%) medicines were prescribed by generic name in all selected prescriptions with the lowest value observed in PH-D (9.9%) (Optimal value = 100%). Overall, 88% medicines were prescribed from National essential medicine list/formulary (Optimal value = 100%). All the prescribing core indicators showed significant difference between hospitals (P = 0.001). The most commonly prescribed antibiotic was ceftriaxone (37.4%), followed by ciprofloxacin (15.1%). CONCLUSIONS: Poor adherence to WHO prescribing indicators were observed in all medical outpatient departments in selected hospitals. WHO recommended core interventions should be implemented on trial basis to develop strategies to achieve long-lasting benefits.

Biopharmaceutical optimization in neglected diseases for paediatric patients by applying the provisional paediatric biopharmaceutical classification system.

AIMS: Unavailability and lack of appropriate, effective and safe formulations are common problems in paediatric therapeutics. Key factors such as swallowing abilities, organoleptic preferences and dosage requirements determine the need for optimization of formulations. The provisional Biopharmaceutics Classification System (BCS) can be used in paediatric formulation design as a risk analysis and optimization tool. The objective of this study was to classify six neglected tropical disease drugs following a provisional paediatric BCS (pBCS) classification adapted to three paediatric subpopulations (neonates, infants and children). METHODS: Albendazole, benznidazole, ivermectin, nifurtimox, praziquantel and proguanil were selected from the 5th edition of the Model List of Essential Medicines for Children from the World Health Organization. Paediatric drug solubility classification was based on dose number calculation. Provisional permeability classification was based on log P comparison versus metoprolol log P value, assuming passive diffusion absorption mechanisms and no changes in passive membrane permeability between paediatric patients and adults. pBCS classes were estimated for each drug, according to different doses and volumes adapted for each age stage and were compared to the adult classification. RESULTS: All six drugs were classified into provisional pBCS in the three paediatric subpopulations. Three drugs maintained the same classification as for adults, ivermectin and benznidazole changed solubility class from low to high in neonates and proguanil changed from low to high solubility in all age stages. CONCLUSION: Provisional pBCS classification of these six drugs shows potential changes in the limiting factors in oral absorption in paediatrics, depending on age stage, compared to the adult population. This valuable information will aid the optimization of paediatric dosing and formulations and can identify bioinequivalence risks when comparing different formulations and paediatric populations.

The selection and use of essential medicines.

This report presents the recommendations of the WHO Expert Committee responsible for updating the WHO Model Lists of Essential Medicines. It contains a summary of the Committee's considerations and justifications for additions and changes to the Model Lists, including its recommendations. Annexes to the main report include the revised version of the WHO Model List of Essential Medicines (18th edition) and the WHO Model List of Essential Medicines for Children (4th edition). In addition there is a list of all the items on the Model Lists sorted according to their Anatomical Therapeutic Chemical (ATC) classification codes.

Global aspects of drug development.

About nine million children die every year before they reach the age of 5 years, of conditions largely amendable with existing medicines. Lack of medicines is not the single most important health problem of children, but work to provide children with better access to appropriate medicines is essential for achievement of the child health goals set. Taking into consideration the global aspect in the development of paediatric medicines the benefits of the regional paediatric initiatives can be spread worldwide. This chapter provides insights in the challenges and opportunities of developing paediatric medicines for health needs of children in the developing world. The Essential Medicines List for children first made available in 2008 serves as an example of the many tools available from WHO to improve children's access to the medicines they need.

[Can linking co-payment for drugs to evidence on treatment value improve health outcomes and contain healthcare costs?].

Co-payment strategies are frequently used by health insurers as a measure of containing healthcare costs. However, co-payments may reduce the use of essential drugs in chronically-ill patients. Recently, value-based insurance designs, where co-payments rates are determined by the value of the treatment, have been introduced in the United States. This review summarizes the results of recent studies in the United States, suggesting that reducing co-payments for highly valued treatments and raising co-payments for less effective treatments can lead to better compliance and better outcomes, with the potential of reducing long-term costs. Further research is needed to examine the feasibility of this approach and the long-term impact on quality of care and treatment costs in other healthcare systems, including Israel.

Essential Medicinal Chemistry of Essential Medicines.

Since 1977, the World Health Organization publishes a list of essential medicines, i.e., those that satisfy the priority health care needs of the population and are selected with regard to disease prevalence and public health relevance, evidence of clinical efficacy, and safety, as well as comparative costs and cost-effectiveness. The Essential Medicines List (EML) is an invaluable tool for all countries to select those medicines that have an excellent risk/benefit ratio and that are reputed to be of pivotal importance to health. In the present perspective, we describe the chemical composition and the main features of the small molecules that are included in the EML, spanning from their origin, to their stereochemistry and measure of drug-likeness. Most and foremost, we wish to disseminate the importance of the EML, which can be both a helpful teaching tool in an ever-expanding world of medicines and an inspiration for those involved in pharmaceutical R&D.

The selection and use of essential medicines.

This report presents the recommendations of the WHO Expert Committee responsible for updating the WHO Model List of Essential Medicines. The first part contains a review of the report of the meeting of the Expert Subcommittee on the Selection and Use of Essential Medicines, held in October 2008. It also provides details of new applications for paediatric medicines and summarizes the Committee's considerations and justifications for additions and changes to the Model List, including its recommendations. Part Two of the publication is the report of the second meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines. Annexes include the revised version of the WHO Model List of Essential Medicines (the 16th) and the revised version of the WHO Model List of Essential Medicines for Children (the 2nd). In addition there is a list of all the items on the Model List sorted according to their Anatomical Therapeutic Chemical (ATC) classification codes.

[Review of national and international legal and regulatory mechanisms on the management of drugs and the residues thereof]. / Revisão dos dispositivos legais e normativos internacionais e nacionais sobre gestão de medicamentos e de seus resíduos.

This paper presents a descriptive review of laws and regulations on the management of drugs and the residues thereof adopted by countries in Europe, the Americas and Australia. This review integrates relevant points of official documents of regulatory agencies in these countries, as well as important scientific works. All countries surveyed carry out drug management concomitant with the management of the residues thereof, ranging from awareness programs on the rational use and the risks of drugs through to the collection and safe disposal of such residues. Germany, the USA and Sweden demand a prior assessment of the environmental impact caused by a given drug as a criterion for its registration. Sweden is noteworthy in that it periodically updates a list of essential drugs based on risk assessment and the environmental risks posed by the residues thereof. In Brazil, the legal measures proposed including rational prescription and reverse logistics have not yet been effectively implemented. Prior environmental impact assessment safeguards the risks to human health and the wild biota caused by exposure to drug residues. Therefore, these international models could serve as a basis for discussion and/or legal and regulatory changes in Brazil.

Este trabalho apresenta uma revisão descritiva de leis e normas adotadas pelos países da Europa, das Américas e Austrália sobre gestão de medicamentos e de seus resíduos. Esta revisão integra pontos relevantes de documentos oficiais das agências reguladoras desses países, bem como de trabalhos científicos importantes. Todos os países pesquisados realizam gestão de medicamentos concomitantemente com a gestão de seus resíduos, atuando desde programas de conscientização sobre o uso racional e os riscos dos medicamentos até na coleta e disposição segura de seus resíduos. A Alemanha, os EUA e a Suécia exigem uma avaliação prévia do impacto ambiental provocado pelo medicamento como critério de seu registro. Em destaque, a Suécia que periodicamente atualiza uma lista de medicamentos essenciais baseada na avaliação do risco e do perigo ambiental de seus resíduos. No Brasil, as medidas legais propostas como prescrição racional e logística reversa ainda não foram efetivamente implementadas. A avaliação prévia de impacto ambiental resguarda os riscos à saúde humana e da biota selvagem causados pela exposição aos resíduos de medicamentos. Portanto, esses modelos internacionais poderiam servir de base para discussões e/ou alterações legais e normativas no Brasil.

Prescribing patterns of antimicrobials in the Internal Medicine Department of Ibrahim Malik Teaching Hospital in Khartoum, 2016.

INTRODUCTION: Antimicrobials are among the most commonly prescribed therapeutic agents in hospitals. Irrational use of antimicrobials results in the development of antimicrobial resistance which could lead to life-threatening illnesses. Therefore, the assessment of antimicrobial prescribing and use is of utmost importance. This study aimed to examine the prescribing patterns of antimicrobials in the Internal Medicine Department of Ibrahim Malik Teaching Hospital in Khartoum, Sudan. METHODS: A descriptive, cross-sectional study was conducted using World Health Organization (WHO) indicators for antimicrobial use in hospitals. Systematic random sampling was used to select 245 medical records from the 2613 medical records of patients admitted to the internal medicine department in 2016. Data were collected using a data collection form and a structured interview with the chief pharmacist in the hospital. RESULTS: Of the 245 medical records examined, 201 (82%) patients were prescribed one or more antimicrobial drug. The average number of antimicrobials per patient was (2.1±1.1). The average duration of antimicrobial treatment was (4.9±3.8) days. The generic name was used in (35.6%) of antimicrobials, while (95.5%) of all antimicrobials were prescribed from the national essential medicines list. Overall, there were 421 courses of antimicrobials prescribed. The most frequently prescribed antimicrobials were ceftriaxone (131 courses) and metronidazole (89 courses). Among the documented infectious diseases, the most frequently encountered was pneumonia, followed by malaria. There was no drug and therapeutic committee, hospital formulary or essential medicines list, and standard treatment guidelines for infectious diseases in the hospital. CONCLUSION: The results of the study revealed a high percentage of antimicrobial use in the Internal Medicine Department. Multifaceted interventions are urgently needed to promote rational prescribing of antimicrobials.

[Study considering the use of medicines in children receiving free care]. / Etude de l'utilisation des médicaments chez les enfants dans un contexte de gratuité des soins.

INTRODUCTION: Rational medical prescription is a concern for the health systems and policies of African countries. The purpose of this study was to analyze the use of medicines in children aged 0 to 5 years receiving free care. METHODS: We conducted a cross-sectional study considering the use of medicines in 20 randomly selected health facilities level 1 in Ouagadougou. The reference of the World Health Organization and of the International Network for the Rational Use of Drugs (WHO/INRUD) was used to analyze data. Descriptive statistics were used as the average and standard deviation. Differences were measured using ANOVA test. RESULTS: In total, 1.206 prescriptions were reviewed between April 2016 and March 2017. The number of medicines issued on prescription was 2.9, the percentage of generic medicines prescribed was 88.7% and 97.7% of medicines prescribed were registered on the National List of Essential Medicines. The percentage of consultations during which antibiotics were prescribed was 83.2%, and 9.3% of prescriptions contained at least one injectable product. CONCLUSION: Irrational prescription is mainly relates to the use of antibiotics. Essential alertness should be given to the treatment of children less than 5 years to avoid an excessive consumption of medicines and the emergence of antibiotic resistance.

Evaluating access to oral anti-diabetic medicines: A cross-sectional survey of prices, availability and affordability in Shaanxi Province, Western China.

OBJECTIVES: To assess the availability and affordability of oral anti-diabetic medicines in Shaanxi Province, Western China. METHODS: In 2015, the prices and availability of 8 anti-diabetic medicines covering 31 different dosage forms and strengths were collected in six cities of Shaanxi Province. A total of 72 public hospitals and 72 private pharmacies were sampled, using a modified methodology developed by the World Health Organization (WHO) and Health Action International (HAI). Medicine prices were compared with international reference prices to obtain a median price ratio. For urban residents, affordability was assessed as the lowest-paid unskilled government workers to purchase cost of standard treatment in days' wages; for rural residents, days' net income was used. RESULTS: The mean availabilities of originator brands (OBs) and generics were 34.3% and 28.7% in public hospitals, and 44.1% and 64.4% in the private pharmacies. OBs and the lowest priced generics (LPGs) were procured at 12.38 and 4.52 times the international reference price in public hospitals, and 10.26 and 2.81 times the international reference prices in private pharmacies. Treatments with OBs were unaffordable even for urban residents. The affordability of the LPGs was good, except for acarbose, repaglinide and pioglitazone. CONCLUSIONS: Most anti-diabetic medicines cannot met the WHO's availability target (80% availability) in Shaanxi Province. The high prices of OBs had severely influenced the affordability of medicines, especially for the rural residents. Effective policies should be initiated to ensure the Chinese people a better access to more affordable anti-diabetic medicines.

Implementing an essential medicines list: effects on pricing and utilization in West Bank, Palestine.

The purpose of this article is to examine the effects of implementing an essential medicines list (EML) on medicine prices, utilization and aggregate cost savings in the public sector of West Bank, Palestine. The Palestinian Ministry of Health (MOH) introduced an EML to contain escalating costs and improve appropriate utilization within the public sector. To assess the effects of the EML implementation, we obtained price and utilization data for 76 medicine groups for 1997-2003. We also collected demographic and economic information for the population living in the catchment areas of the MOH health care facilities. After EML implementation, medicine utilization declined by 1.7 defined daily doses (DDDs) per-capita per year, and prices declined by US $0.0013 per DDD. The aggregate cost savings totaled US $5.38 million. We conclude that the EML implementation was successful in containing medicine costs and should continue to increase savings into the future.

Patient satisfaction with prescribed medicines in community health services in China: A cross-sectional survey 6 years after the implementation of the national essential medicines policy.

The National essential medicines policy (NEMP) is promoted by the World Health Organization for affordable medicines that can meet the basic needs of communities. Patient acceptance is essential for achieving the policy goals of the NEMP. This study aimed to assess patient satisfaction with prescribed medicines in community health services under the NEMP context in China. A stratified random sampling strategy was adopted to select 1,037 participants in 40 community health centres from four provinces in China. Patient satisfaction was rated on a five-point Likert scale (from 1 = "very dissatisfied" to 5 = "very satisfied") covering four domains: availability, affordability, effectiveness and safety. The results showed that the participants expressed a moderate degree of satisfaction, with a rating in the range of 66-82 out of a total of 100. Older people, those covered by insurance and those with a lower level of education tended to have higher ratings. While eastern (wealthy) residents were more likely to be concerned with "effectiveness," western (poor) residents were more likely to be concerned with "affordability." Awareness of the NEMP was negatively associated with patient satisfaction after control for other factors.

The International Association for Hospice and Palliative Care list of essential medicines for palliative care.

The World Health Organization (WHO) requested that the International Association for Hospice and Palliative Care (IAHPC) develop a list of essential drugs for palliative care to be included in the WHO list of essential drugs. This report describes the process by which this specialized list was developed and the outcomes of that process.

The selection and use of essential medicines.

This report presents the recommendations of the WHO Expert Committee responsible for updating the WHO Model List of Essential Medicines. The first part contains a summary of the Committee's considerations and justifications for additions and changes to the Model List, including its recommendations. Annexes to the main report include the revised version of the WHO Model List of Essential Medicines (the 15th) and a list of all items on the Model List sorted according to their 5-level Anatomical Therapeutic Chemical (ATC) classification codes. Other annexes cover the proposed procedure for updating and disseminating the WHO Model List of Essential Medicines, and the revised procedure for updating the content of the Interagency Emergency Health Kit.

Acute isoniazid toxicity and the need for adequate pyridoxine supplies.

A 25-year-old, 54-kg Hispanic man who had recently started multidrug therapy for pulmonary tuberculosis presented in status epilepticus after ingesting 9 g of isoniazid in a suicide attempt. Successful management of this patient required collaboration between several institutions to provide the large amount of necessary intravenous pyridoxine. Ultimately, this single overdose depleted the supply of intravenous pyridoxine for a significant region of the state of Nebraska. Isoniazid is commonly used to treat tuberculosis, but it is encountered relatively infrequently as the cause of an acute overdose. Severe isoniazid overdoses may present as seizure activity that is refractory to conventional antiepileptic therapy. Although intravenous pyridoxine is an effective antidote for isoniazid overdoses in patients presenting with status epilepticus, this agent has few indications and is typically stocked in limited quantities. In regions with large populations of patients who receive antituberculosis therapy, collaborative networks must be created to ensure that adequate supplies of intravenous pyridoxine (> or = 20 g) are available for effective treatment of isoniazid poisonings.

Safer injections following a new national medicine policy in the public sector, Burkina Faso 1995-2000.

BACKGROUND: The common failure of health systems to ensure adequate and sufficient supplies of injection devices may have a negative impact on injection safety. We conducted an assessment in April 2001 to determine to which extent an increase in safe injection practices between 1995 and 2000 was related to the increased access to injection devices because of a new essential medicine policy in Burkina Faso. METHODS: We reviewed outcomes of the new medicine policy implemented in 1995. In April 2001, a retrospective programme review assessed the situation between 1995 and 2000. We visited 52 health care facilities where injections had been observed during a 2000 injection safety assessment and their adjacent operational public pharmaceutical depots. Data collection included structured observations of available injection devices and an estimation of the proportion of prescriptions including at least one injection. We interviewed wholesaler managers at national and regional levels on supply of injection devices to public health facilities. RESULTS: Fifty of 52 (96%) health care facilities were equipped with a pharmaceutical depot selling syringes and needles, 37 (74%) of which had been established between 1995 and 2000. Of 50 pharmaceutical depots, 96% had single-use 5 ml syringes available. At all facilities, patients were buying syringes and needles out of the depot for their injections prescribed at the dispensary. While injection devices were available in greater quantities, the proportion of prescriptions including at least one injection remained stable between 1995 (26.5%) and 2000 (23.8%). CONCLUSION: The implementation of pharmaceutical depots next to public health care facilities increased geographical access to essential medicines and basic supplies, among which syringes and needles, contributing substantially to safer injection practices in the absence of increased use of therapeutic injections.

Overcoming Obstacles To Enable Access To Medicines For Noncommunicable Diseases In Poor Countries.

The modern access-to-medicines movement grew largely out of the civil-society reaction to the HIV/AIDS pandemic three decades ago. While the movement was successful with regard to HIV/AIDS medications, the increasingly urgent challenge to address access to medicines for noncommunicable diseases has lagged behind-and, in some cases, has been forgotten. In this article we first ask what causes the access gap with respect to lifesaving essential noncommunicable disease medicines and then what can be done to close the gap. Using the example of the push for access to antiretrovirals for HIV/AIDS patients for comparison, we highlight the problems of inadequate global financing and procurement for noncommunicable disease medications, intellectual property barriers and concerns raised by the pharmaceutical industry, and challenges to building stronger civil-society organizations and a patient and humanitarian response from the bottom up to demand treatment. We provide targeted policy recommendations, specific to the public sector, the private sector, and civil society, with the goal of improving access to noncommunicable disease medications globally.