Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Antifungal prophylaxis and pre-emptive therapy: When and how?

The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches

Systemic antifungal treatment after posaconazole prophylaxis: results from the SEIFEM 2010-C survey.

OBJECTIVES: To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis. METHODS: From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925. RESULTS: In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, ∼30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre-emptive groups showed no significant differences regarding the attributable and overall mortalities. CONCLUSIONS: This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used

Prophylaxis and treatment of invasive fungal infections in hematological patients

The evidence from the literature strongly support antifungal prophylaxis in high risk haematological patients, such as patients with AML during remission induction chemotherapy and alloHSCT patients. Current antifungal prophylaxis guidelines for high risk patients recommend azoles (fluconazole, posaconazole, voriconazole) and echinocandins (micafungin) with the strongest level of evidence. In terms of treatment, the choice between empiric therapy (or fever driven) and pre-emptive therapy (or diagnostic driven) is still debated. Not a single therapeutic strategy is appropriate in every patients, in particular empirical antifungal therapy may be recommended in patients at very high risk, while a pre-emptive approach may be advised for those at standard risk. In order to exploit the synergistic and/or additive effect of two antifungal drugs it's possible to combine two agents that work with different mechanisms of action (e.g. echinocandins + azoles or polyenes). Once the treatment has been initiated we should consider the therapeutic drug monitoring (TDM) of the drugs, especially when the pharmacokinetic variability is high and the dose-concentration effect relationships is not predictable (e.g. for itraconazole, voriconazole and posaconazole)

The intensity of competition after patent expiry in pharmaceuticals. A cross-country analysis

This paper shows that the relationships between the dynamics of drug priees, patent expiry, and competition by multisource drugs vary significantly across countries. A clear distinction seems to emerge. On the one side, systems that rely on market based competition (particularly the US) promote a clear distinction between firms that act as innovators and firms that act as imitators after patent expiry. Original products enjoy premium prices under patent protection, and face fierce price competition after patent expiry. On the contrary, systems that rely on administered prices (particularly France and Italy) nurture strategies of pre-emptive brand proliferation and horizontal differentiation by imitative brand name products, well before patent expiry. Our work confirms that that systems that rely on administered prices have tended to stifle price competition, to protect less efficient companies, and to encourage strategies of incremental innovation and imitation

Pharmacogenomics in treatment of depression and psychosis: an update

Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation

Meta-Analysis and Cost Comparison of Empirical versus Pre-Emptive Antifungal Strategies in Hematologic Malignancy Patients with High-Risk Febrile Neutropenia

Background: Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. Methods: We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran’s Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. Results: Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27–0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36–1.87) or overall mortality (RR 0.95, 95% CI 0.46–1.99). The pre-emptive strategy cost $324 less (95$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. Conclusions: Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals

‘County lines’: racism, safeguarding and statecraft in Britain

Government policies relating to dealers in ‘county lines’ drugs trafficking cases have been welcomed as a departure from punitive approaches to drugs and ‘gang’ policing, in that those on the bottom rung of the drugs economy of heroin and crack cocaine are no longer treated as criminals but as potential victims and ‘modern slaves’ in need of protection. However, our research suggests not so much a radical break with previous modes of policing as that the term ‘county lines’ emerged as a logical extension of the government’s racist and classist language surrounding ‘gangs’, knife crime and youth violence. Policies implemented in the name of safeguarding the vulnerable also act as a gateway for criminalisation not just under drugs laws but also modern slavery legislation. The government’s discovery of, and responses to, ‘county lines’ hinge on a moral crisis in the making, which ultimately deepens the state’s pre-emptive and violent criminalisation of the ‘Black criminal other’ at a time of deep political crisis

Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery (Protocol)

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate in adult participants undergoing all types of surgery, the effects of pre-emptive and preventive non-steroidal anti-inflammatory drugs (NSAIDs) compared with post-incision NSAIDs for reducing postoperative pain and opioid consumption