1 Generics of antibiotics: are you sure of what you getGenerics of antibiotics: are you sure of what you get ? (with comments about overconsumption and economical aspects) Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology Louvain Drug Research Institute Université catholique de Louvain Brussels, Belgium Séminaire de Médecine Interne - 2 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
2 Disclosures and slides availabilityResearch grants Theravance, Astellas, Targanta, Cerexa/Forest, AstraZeneca, Bayer, GSK, Trius, Rib-X, Eumedica Belgian Science Foundation (F.R.S.-FNRS), Ministry of Health (SPF), and Walloon and Brussels Regions Speaking fees Bayer, GSK, Sanofi, Johnson & Johnson, OM-Pharma Decision-making and consultation bodies General Assembly and steering committee of EUCAST European Medicines Agency (external expert) US National Institutes of Health (grant reviewing) Slides: Lectures 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
3 Information sources for Belgium Last visited: 4 April 2014 Last visited: 4 April 2014 Last visited: 4 April 2014 Last visited: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
4 A well known antibiotic in Belgium…Before patent expiration Site as visited on 6 June 2013 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
5 A well known antibiotic in Belgium…After … 1 2 3 4 5 6 7 Site as visited on 6 June 2013 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
6 But why would you choose a "generic" drug ?Because they are cheaper 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
7 But why would you choose a "generic" drug ?Sustaining EU Healthcare Systems Through Sustainable Generic Competition Greg Perry, EGA Director General - Brussels, 28 April 2009 Last accessed: 16/03/2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
8 Are generics largely in all countries ?Sustaining EU Healthcare Systems Through Sustainable Generic Competition Greg Perry, EGA Director General - Brussels, 28 April 2009 Last accessed: 16/03/2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
9 Are generics largely in all countries ?Communiqué de presse FeBelGen – 21/09/2010 Last acessed: 16/03/2014 Sustaining EU Healthcare Systems Through Sustainable Generic Competition Greg Perry, EGA Director General - Brussels, 28 April 2009 Last accessed: 16/03/2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
10 What shall we discuss? The US and the EU lawsApproach to PK bioequivalence Approach to microbiological equivalence MIC, MPC, heteroresistance … Approach to pharmacodynamic equivalence PK/PD animal models and clinical data Problems related to dissolution and stability Impurities and falcified medicines The hidden risk of "low cost" antibiotics Last visited: 25 March 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
11 The US Law Last accessed: 4 April 2014 FDA works along the provisions of the Drug Price Competition and Patent Term Restoration Act ("Hatch-Waxman Act" [Public Law ]), which encouraged the manufacture of generic drugs Marketers of generic drugs can file an Abbreviated New Drug Application (ANDAs) to seek FDA approval 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
12 US "Abbreviated New Drug Application" Site as visited on 6 June 2013 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
13 FDA requirements in a nutshell *Published literature (for data for which the applicant has no right of reference to the original raw data supporting the application) FDA's findings (safety and effectiveness of the already approved drug) Comparison with the original NCE/NME (New Chemical Entity/New Molecular Entity) application for dosage form, strength, route of administration substitution of an active ingredient in a combination product or change such as different salt, ester, complex, … Bioequivalence study The proposed product does not need to be shown to be clinically better than the previously approved product; however, the application should not be used as a route of approval for poorly bioavailable generic drug products unable to meet the standards for bioequivalence. * (B) (2) Application (Guidance to Industry) Last accessed: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
14 FDA approved generic drugs: "Orange book" ** Site as visited on 6 June 2013 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
15 FDA approved generic drugs: "Orange book" *As in LEVAQUIN® * 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
16 In the European Union * Site as visited on 6 June 2013 – This site has been modified since then but documents are still available through navigation * Legislative act of the European Union that is then translated into country-specific laws for actual implementation, which may vary (in details) between countries (vs regulations that are self-executing and do not require local adaptations) 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
17 The EU Directive By way of derogation from Article 8(3)(i), and without prejudice to the law relating to the protection of industrial and commercial property, the applicant shall not be required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorised under Article 6 for not less than eight years in a Member State or in the Community. ‘generic medicinal product’ shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. … Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines. 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
18 What shall we discuss? The US and the EU lawsApproach to PK bioequivalence Approach to microbiological equivalence MIC, MPC, heteroresistance … Approach to pharmacodynamic equivalence PK/PD animal models and clinical data Dissolution and stability Impurities and falcified medicines The hidden risk of "low cost" drugs Last visited: 15 March 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
19 Bioequivalence: principlesBioequivalence is an accepted surrogate for therapeutic equivalence 1 (including for branded drugs when the mareketed form differs from the form used in development…)2 Primary metrics are 1,3 AUC (area under the plasma concentrationtime profile of the active substance) extent of absorption Cmax (the maximum plasma concentration of the active substance) extent and rate of absorption Tmax (the time when Cmax is reached) rate of absorption 1. Hauschke et al. Bioequivalence Studies in Drug Development – Methods and Applications, John Wiley & Sons Ltd. (UK), 2007. 2. Benet LZ: Understanding bioequivalence testing. Transplant.Proc. 31 (Suppl 3A): 7S-9S, 1999. 3. Niazi SK: Handbook of Bioequivalence Testing, “Drugs and the Pharmaceutical Sciences”, vol. 171, Informa Healthcare (New York), 2007. 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
20 AUC – Cmax – Tmax Cmax Tmax 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
21 AUC – Cmax – Tmax Cmax Tmax AUC 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
22 What if the absorption is decreased ? Cmax AUC 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
23 What if absorption is delayed ? Cmax Tmax 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
24 Criteria of bioequivalence (EMA* / FDA**)Calculate the 90% confidence interval around the geometric mean ratios of both AUC and Cmax for Test (generic) and Reference (innovator). The 90% confidence intervals should, in most cases, be within the 0.80 – 1.25 acceptance limits. 90 % CI around point estimate 0.80 1.25 1.0 ratio Notes: if both AUC and Cmax are within range, the generic should have the same bioavailability than the reference statistical evaluation of Tmax only makes sense if there is a clinically relevant claim for rapid release or action or signs related to adverse effects (see next slide) For drugs with narrow therapeutic index, EMA recommends "tightened acceptance inervals, Health Canada requires 0.9 – 1.12, but FDA accepts 0.8 – 1.25 * Guideline to the Investigation of Bioequivalence, London, 20 January Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** – Last accessed: 4 April 2014 ** Guidance for Industry (BIOEQUIVALENCE GUIDANCE) - Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations – Last accessed: 4 April 2014 – Last accessed: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
25 Is this enough ? Is PK-based bioequivalence (serum concentrations measured after extraction) a real surrogate of equitherapeutic effect(s) ? What about drugs with narrow therapeutic margins ? What about impurities, pharmaceutical aspects, and quality control (beyond the original dossier) ? 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
26 Even the Belgian authorities have some doubts...Mais aucun antibiotique n'est concerné * * voir la liste des médicaments "no switch" dans les dias back-up Last accessed: 16/03/2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
27 What shall we discuss? The EU and US lawsApproach to PK bioequivalence Approach to microbiological and therapeutic equivalence MIC, MPC, heteroresistance … Approach to pharmacodynamic equivalence PK/PD animal models and clinical data Dissolution, stability, Impurities The hidden risk of "low cost" drugs Last visited: 25 March 2014 Last accessed: 29 March 2014 Last visited: 25 March 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
28 Potency (piperacillin)Using the incremental MIC assay (Jones RN et al., Diagn Microbiol Infect Dis 2008; 61:76–79). Moet et al. Diagnostic Microbiology and Infectious Disease 2009;65: 319–322 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
29 MIC values (vancomycin)MICs were often higher than for the reference product… Fujimura & Watanabe J Infect Chemother (2012) 18:421–427 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
30 MIC values (meropenem)MICs determined by arithmetic dilutions for strains displaying MICs ranging from to 128 mg/L (geometric values) Susceptible strains (MIC ≤ 2 mg/L) Intermediate strains (≤ 2 MIC < 8 mg/L) Resistant strains (MIC > 8 mg/L) MERONEM® = meropenem commercialized by AstraZeneca Van Bambeke et al., in preparation 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
31 Post-exposure hetero-resistance (vancomycin)strain recovered from failed vancomycin treatment unexposed ATCC 29213 Rodriguez et al. Antimicrob Agents Chemother. 2012; 56:243–247 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
32 Post-exposure hetero-resistance (vancomycin)post-treatement with one generic (Procln) strain recovered from failed vancomycin treatment unexposed ATCC 29213 initial Rodriguez et al. Antimicrob Agents Chemother. 2012; 56:243–247 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
33 Vancomycin: evidence of non-equivalence in PK/PD animal modelNeutropenic thigh mouse model Vesga et al. Antimicrob Agents Chemother. 2010; 54:3271–3279. 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
34 Oxacillin: evidence of non-equivalence in animal PK/PD modelNeutropenic thigh mouse model Rodriguez et al. BMC Infectious Diseases 2010, 10:153 - 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
35 Gentamicin: evidence of non-equivalence for survival in animalsNeutropenic thigh mouse model Zuluaga et al. PLoS ONE 2010; 5: e doi: /journal.pone 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
36 Clinical alerts (efficacy and safety) ?J Pharmacol Pharmacother Dec;4(Suppl 1):S110-4. 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
37 Clinical alerts (efficacy and safety) ?J Pharmacol Pharmacother Dec;4(Suppl 1):S110-4. 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
38 And what about pharmaceutical quality ?Three simple questions: the generic must have the same solubility / dispersion properties than the original the generic cannot contain more impurities (or give rise to more degradation products) than the original The real content must be controlled 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
39 What shall we discuss ? The EU and US lawsApproach to PK bioequivalence Approach to microbiological and therapeutic equivalence MIC, MPC, heteroresistance … Approach to pharmacodynamic equivalence PK/PD animal models and clinical data Dissolution, stability, impurities The hidden risk of "low cost" drugs Last visited: 25 March 2014 ... Last visited: 25 March 2014 ... Last visited: 25 March 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
40 Dissolution of meropenem in JapanFujimura & Watanabe J Infect Chemother (2012) 18:421–427 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
41 Crystals size of meropenem (Japan)Fujimura & Watanabe J Infect Chemother (2012) 18:421–427 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
42 Dissolution of meropenem in BelgiumDrug concentration : 50 mg/mL (~ solution used for infusion) gentle manual shaking followed by turbidity measures; room temperature Van Bambeke et al., in preparation 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
43 Dissolution of meropenem in BelgiumDrug concentration : 50 mg/mL (~ solution used for infusion) gentle manual shaking followed by turbidity measures; room temperature Van Bambeke et al., in preparation 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
44 Are Primary Health Care Professionals (nurses) happy? (meropenem)Van Bambeke et al., in preparation 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
45 Impurities in meropenem: coloured compoundsare you happy with the colour? Van Bambeke et al., in preparation 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
46 Impurities in meropenem: coloured compoundsVan Bambeke et al., in preparation 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
47 Substandard (wrong) drugs in the world ?Figure 1. Examples of recent accounts of substandard drugs around the world Johnston & Holt. Substandard drugs: a potential crisis for public health. Br J Clin Pharmacol Nov 29. doi: /bcp [Epub ahead of print] PubMed PMID: 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
48 Falsified Medicines: An EU reaction Last visited: 4 April 2014 with an immediate follow-up from the Industry Last visited: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
49 An unanswered question in Belgium...Le 16 mars 2014, j'ai interrogé FeBelGen (via leur site web) pour savoir quelle était la régularité des contrôle de qualité (entre lots et en cas de changement d'origine des produits) Je n'ai pas eu de réponse jusqu'aujourd'hui (4 avril 2014) 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
50 What shall we discuss? The EU and US lawsApproach to PK bioequivalence Approach to microbiological and therapeutic equivalence MIC, MPC, heteroresistance … Approach to pharmacodynamic equivalence PK/PD animal models and clinical data Dissolution, stability, impurities The hidden risks of "low cost" drugs overconsumption lack of innovative research ... and research for those who pay ... 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
51 "Low cost antibiotics" and "prudent use" … The sour Danish experienceJensen et al. J Antimicrob Chemother 2010; 65:1286–1291 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
52 Innovative antibiotic development is abandonedWhaw !!! Boucher H W et al. Clin Infect Dis. 2009;48:1-12 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
53 Innovative antibiotic development is abandonedNo Money, No new antibiotics ! Boucher H W et al. Clin Infect Dis. 2009;48:1-12 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
54 A spiral to death (in Belgium) ?Pour les antibiotiques et les antifongiques, si un médecin/dentiste prescrit un antibiotique ou un antimycosique pour un traitement aigu : sous le principe actif : les règles de la prescription sous DCI sont d’application sous un le nom de la marque : à partir du 1er mai 2012, le pharmacien doit délivrer dans le groupe des « médicaments les moins chers ». Last visited: 4 April 2014 Le coût médicamenteux d'une pneumonie communautaire suivant les recommandations BAPCOC (amoxicilline [3 g par jour en 3 prises pendant 5-7j] n'atteint plus que € … (prix ex.usine: 7 €) Look for amoxicillin – Last visited: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
55 A spiral to death (in Belgium) ?Pour les antibiotiques et les antifongiques, si un médecin/dentiste prescrit un antibiotique ou un antimycosique pour un traitement aigu : sous le principe actif : les règles de la prescription sous DCI sont d’application sous un le nom de la marque : à partir du 1er mai 2012, le pharmacien doit délivrer dans le groupe des « médicaments les moins chers ». Le coût médicamenteux d'une pneumonie communautaire suivant les recommandations BAPCOC (amoxicilline [3 g par jour en 3 prises pendant 5-7j] n'atteint plus que € … (prix ex.usine: 7 €) Cette spirale infernale entraine le départ de tous les innovateurs… 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
56 The "Qualy" of antibiotics (*)The quality-adjusted life year or quality-adjusted life-year (QALY) is a measure of disease burden, including both the quality and the quantity of life lived. It is used in assessing the value for money of a medical intervention. If antibiotics prolong your life of 2 to 10 years, and the cost of one year of your life is 20,000 euros, then the value of the "Qualy" of an antibiotic treatment is 40,000 to 200,000 euros But the real cost of an antibiotic treatment is usually <<< 40,000 euros for a treatment that gives you 2-10 years survival… The cost of an anticancer treatment for 1 year survival is…. up to 20,000 to 70,000 euros… (and the accepted "Qualy" is close to that) Find where is the problem… * inspired by Hollis & Ahmed, Preserving Antibiotics Rationally, New Engl. J. Med. 2013; 369,26: 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
57 Unless Big Brother comes to your help…will this ever be available to YOUR patients Last accessed: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
58 But EU is not too bad either Last accessed: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
59 How can you COMBA(c)T(e) ?https://www.combacte.com/?q=node/32 Last visited: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
60 EU is funding selected hospitals and institutions for research on new antibiotics Last accessed: 4 April 2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
61 Summary / Suggestions The decision to "go for generics" is a political one that may need revision (at political level) to avoid over-use of antibiotics Pharmacokinetic criteria are, so far, the (nearly) only ones adopted and accepted by the Regulatory Authorities (EMA / FDA) Improved criteria for anti-infective drugs (MIC, MPC, animal PK/PD, …) are probably necessary (but are not yet implemented) Antibiotics are cheap (compared to other chemotherapeutic agents), making discussion about costs largely irrelevant … while savings in this area may cause HUGE expenses now and later… Antibiotics might be a good starting point to modify the current legislative framework concerning generics at the level of the EU-Parliament, the US Congress, and Asian Countries Authorities … 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
62 Back-up 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
63 Are generic really comparable ?arithmetic comparison geometric comparison 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
64 Are generic really comparable ?subject# AUC generic A AUC reference AUC generic B A/reference B/reference 1 30.00 31.00 33.00 0.97 1.06 0.94 0.91 24.00 36.00 32.00 0.67 0.89 28.00 37.00 0.76 34.00 0.82 35.00 27.00 1.13 0.87 15.00 25.00 22.00 0.60 0.88 0.95 39.00 0.64 12.00 42.00 0.29 0.71 0.86 0.38 0.90 arithmetic mean 25.92 34.92 31.17 SD 8.26 4.54 4.06 0.26 0.06 geometric mean 24.49 34.63 30.90 CI 90 0.12 0.03 lower 90 0.58 higher 110 0.83 0.92 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
65 Are generic really comparable ?Ratio of AUCs with calculation of the geometric means (point estimates) 90 % CI around point estimate ( ) 0.60 0.80 1.0 1.25 90 % CI around point estimate ( ) 0.60 0.80 1.0 1.25 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
66 Special situations (EU)Narrow therapeutic index drugs In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to %. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the % acceptance interval should also be applied for this parameter. It is not possible to define a set of criteria to categorise drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations. Highly variable drugs or drug products The extent of the widening is defined based upon the within-subject variability seen in the bioequivalence study using scaled-average-bioequivalence according to [U, L] = exp [±k·sWR], where U is the upper limit of the acceptance range, L is the lower limit of the acceptance range, k is the regulatory constant set to and sWR is the within-subject standard deviation of the log-transformed values of Cmax of the reference product (Important: this applies to Cmax only, NOT to AUC) 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
67 No-switch drugs in Belgium Last accessed: 16/03/2014 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
68 Avez-vous des EEN (excipients à effet notoire)?2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
69 Avez-vous des EEN ? 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
70 Avez-vous des EEN ? 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
71 Avez-vous des EEN ? 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
72 Avez-vous des EEN ? 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
73 Avez-vous des EEN ? 2 April 2014CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
74 A recent economic US studyA "natural experiment" in which Meijer, a popular Midwestern retail chain, offered 14-day supplies of certain generic oral antibiotics free of charge to customers with prescriptions from October 2006 (about 2 millions prescraiptins analayzed from 2004 trough 2008) We find that the program increased the filled prescriptions of covered (free) antibiotics while reducing those of not-covered (paid) antibiotics, with an increase in overall antibiotic prescriptions. 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
75 The situation may be worse in veterinary medicine2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
76 The situation may be worse in veterinary medicineIn France, introduction of generics of fluoroquinolones increased their use by 30% in turkey (n=5500) production and 50% in chicken broiler (n=7000) production. The level of resistance in Spain where cheap generics are available is associated with a higher use of fluoroquinolones in poultry and pigs vs Germany, UK, or Denmark where prices are higher and practice better controlled Generic drug promotion in veterinary medicine is not consistent with the general objective opf Public Health authorities to restrict the use of antibiotics in veterinary medicine… 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
77 Unless Big Brother comes to your help…2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
78 Unless Big Brother comes to your help…2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
79 Unless Big Brother comes to your help… 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
80 Unless Big Brother comes to your help… 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
81 Unless Big Brother comes to your help… 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
82 Unless Big Brother comes to your help even in Switzerland… 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
83 Unless Big Brother comes to your help… even in Switzerland 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie
84 Here is what Big Brother helps to develop…Structure of BAL30072 Numerous attempts have been made to introduce iron-binding functional groups into β-lactams since the 1980s, in order to circumvent the limitations imposed by porin mutation or deletion. BAL30072 is a sulfactam, analogous to tigemonam, with a dihydropyridone iron-chelating group. AAC June 2010 vol. 54 no 2 April 2014 CHU Mont-Godinne/Dinant -- Séminaire de médecine interne - Infectiologie