Recent advances in addressing the market failure of new antimicrobials: Learnings from NICE's subscription-style payment model.

Background: Antimicrobial resistance (AMR) is a growing threat to global health. With pathogenic bacteria inevitably becoming more resistant to existing antimicrobials, mortality and costs due to AMR will significantly increase over the next few decades if adequate action is not taken. A major challenge in addressing AMR is the lack of financial incentives for manufacturers to invest in developing new antimicrobials. This is partly because current approaches in health technology assessment (HTA) and standard modeling methods fail to capture the full value of antimicrobials. Aim: We explore recent reimbursement and payment frameworks, particularly pull incentives, aimed to address the market failures in antimicrobials. We focus on the "subscription-style" payment model recently used in the UK and discuss the learnings for other European countries. Methods: A pragmatic literature review was conducted to identify recent initiatives and frameworks between 2012 and 2021, across seven European markets. The National Institute for Health and Care Excellence (NICE) technology appraisals for cefiderocol and for ceftazidime with avibactam were reviewed to evaluate how the new UK model has been applied in practice and identify the key challenges. Conclusion: The UK and Sweden are the first European countries to pilot the feasibility of implementing pull incentives through fully and partially delinked payment models, respectively. The NICE appraisals highlighted the complexity and large areas of uncertainty of modeling antimicrobials. If HTA and value-based pricing are part of the future in tackling the market failure in AMR, European-level efforts may be needed to overcome some of the key challenges.

Biomonitoring of chlorpyrifos exposure and health risk assessment among applicators on rice farms in Ghana.

Chlorpyrifos is a neurotoxic insecticide that is widely used in the agricultural sector of Ghana. The main objective of this study was to evaluate the levels of chlorpyrifos exposure and health risk among applicators (n = 21) on irrigated rice farms in Ghana, based on a typical application event. Pre- and post-application urine samples (24-h) were collected from the applicators and analysed for 3,5,6-trichloro-2-pyridinol (TCP), using LC-MS/MS. The levels of chlorpyrifos-absorbed dose with the applicators were estimated from the urinary TCP levels. Prior to application, the median absorbed dose of chlorpyrifos (background exposure) with the applicators was 0.2 µg/kg/day (range 0.05 to 2 µg/kg/day). Following application, the median absorbed dose of chlorpyrifos (application exposure) increased 30-fold to 6 µg/kg/day (range 0.7 to 74 µg/kg/day). The mean elimination half-life (t1/2) of chlorpyrifos was calculated to be 50 h. Hazard quotient (HQ) values (HQ > 1) obtained with the chronic (10 µg/kg/day) and acute (100 µg/kg/day) guideline values of the WHO suggested no risk of chronic or acute health effects, respectively, among both the median and 5% highly exposed groups. However, HQ values (HQ > 1) obtained with the chronic (0.3 µg/kg/day) and acute (5 µg/kg/day) guideline values of the USEPA suggested risk of chronic and acute health effects, respectively, among both the median and 5% highly exposed groups. The quantity of chlorpyrifos formulation applied, spraying duration, and the number of spray tanks applied significantly correlated with the absorbed dose levels of chlorpyrifos from application exposure. Therefore, these factors suggest means to reduce exposure and consequent health risk among the applicators.

Biological monitoring of chlorpyrifos exposure to rice farmers in Vietnam.

Chlorpyrifos is the most common organophosphate insecticide registered for use in Vietnam and is widely used in agriculture, particularly rice farming. However, chlorpyrifos exposure to and adverse effects on farmers has not been evaluated. In this study, biological monitoring of chlorpyrifos exposure in a group of rice farmers was conducted after a typical application event using back-pack spraying. Urine samples (24 h) were collected from the rice farmers before and post insecticide application. Samples were analysed for 3,5,6-trichloropyridinol (TCP), the major urinary metabolite of chlorpyrifos, using an enzymatic pre-treatment before extraction followed by HPLC-MS/MS. Absorbed Daily Dose (ADD) of chlorpyrifos for farmers were then estimated from urinary TCP levels, expressed as µg g(-1)creatinine. The analytical method for urinary TCP had a low detection limit (0.6 µg L(-1)), acceptable recovery values (80-114%), and low relative percentage differences in duplicate and repeated samples. Post-application chlorpyrifos ADD of farmers varied from 0.4 to 94.2 µg kg(-1) (body weight) d(-1) with a mean of 19.4 µg kg(-1) d(-1) which was approximately 80-fold higher than the mean baseline exposure level (0.24 µg kg(-1) d(-1)). Hazard Quotients (ratio of the mean ADD for rice farmers to acute oral reference dose) calculated using acute oral reference doses recommended by United States and Australian agencies varied from 2.1 (Australian NRA), 4.2 (US EPA) to 6.9 (ATSDR). Biological monitoring using HPLC-MS/MS analysis of urinary TCP (24 h) was found to be an effective method for measuring chlorpyrifos exposure among farmers. This case study found that Vietnamese rice farmers had relatively high exposures to chlorpyrifos after application, which were likely to have adverse health effects.

The burden of moderate/severe premenstrual syndrome and premenstrual dysphoric disorder in a cohort of Latin American women.

OBJECTIVES: The aim of this study was to investigate the relationship between symptom severity, cost, and impairment in women with moderate/severe premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) in a Latin American setting. METHODS: A model was constructed based on analysis of an observational dataset. Data were included from four Latin American countries. Responder-level data were analysed according to four categories of symptom severity: Category 1 comprised Daily Record of Severity of Problems score 21 to 41.9, Category 2 score was 42 to 62.9, Category 3 score was 63 to 83.9, and Category 4 was a score of 84 or higher. Burden was estimated in terms of impact on job and activities using the modified work productivity and impairment questionnaire and affect on quality of life using the SF-12 questionnaire. Costs were estimated in Brazilian reals from a Brazilian private health care and societal perspective. The outputs of the analysis were estimates of burden, mean annual cost and affect on quality of life (as measured by quality adjusted life years) by symptom severity. Confidence intervals around key outcomes were generated through nonparametric bootstrapping. RESULTS: Analysis suggests a significant cost burden associated with moderate/severe PMS and PMDD with mean per patient annual costs estimated at 1618 BRL (95% confidence interval 957-2,481). Although the relationship between cost, quality of life, and severity was not clear, analysis showed a consistent relationship between disease severity and measures of disease burden (job and daily activity). Burden on activities increased with disease severity. CONCLUSIONS: Our analysis, conducted from a Latin American perspective, suggests a significant burden and an increasing impairment associated with moderate/severe PMS and PMDD.

Human methyl parathion poisoning.

BACKGROUND: Methyl parathion is classed as an extremely hazardous pesticide with a rodent LD50 of 6 to 24 mg/kg. It has been banned in numerous countries, but there are few reports of acute methyl parathion poisoning. METHODS: Plasma cholinesterase and acetylcholinesterase were measured in blood. Methyl parathion and the major metabolite 4-nitrophenol where measured in serum and urine. Based on the available concentration-time data, the pharmacokinetic parameters of methyl parathion were estimated for this patient. CASE REPORT AND RESULTS: A 29-year-old male ingested 50 to 100mL (12 to 24 g) of methyl parathion causing delayed and prolonged suppression of acetylcholinesterase but almost no clinical effects. Absorption was predicted to last for 30 hours and the bioavailability appeared to be very low. CONCLUSIONS: Although it is feasible the patient ingested much less, a tenth of his alleged ingestion dose is more than the oral LD50 in rats. Methyl parathion appears to be less toxic in humans than parathion for similar amounts ingested, which is not consistent with the two pesticides having similar rodent LD50.

Intentional self-poisoning with the chlorophenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA).

STUDY OBJECTIVE: Data on poisoning with MCPA (4-chloro-2-methyl-phenoxyacetic acid) are limited to 6 case reports. Our objective is to describe outcomes from intentional self-poisoning with MCPA in a prospective case series of 181 patients presenting to hospitals in Sri Lanka. METHODS: Patient information was collected by on-site study physicians as part of an ongoing prospective cohort study of poisoned patients. Medical history, clinical details, and blood samples were obtained prospectively. RESULTS: Overall clinical toxicity was minimal in 85% of patients, including mild gastrointestinal symptoms in 44% of patients. More severe clinical signs of chlorophenoxy poisoning reported previously, such as rhabdomyolysis, renal dysfunction, and coma, also occurred but were uncommon. Eight patients died (4.4%). Most deaths occurred suddenly from cardiorespiratory arrest within 48 hours of poisoning; the pathophysiological mechanism of death was not apparent. The correlation between admission plasma MCPA concentration and clinical markers of severity of toxicity (physical signs, symptoms, and increased creatine kinase level) was poor. CONCLUSION: Intentional self-poisoning with MCPA generally causes mild toxicity, but cardiorespiratory arrest and death may occur. All patients should receive routine resuscitation and supportive care. It seems reasonable to correct acidosis and maintain an adequate urine output, but there is insufficient evidence to support other specific interventions. Our data do not support a clinical role for measurement of plasma MCPA in the acute management of poisoning, and insufficient data were available to fully examine the utility of measured electrolytes and creatine kinase levels.