Rational Use of Antibiotics Rational Use of Antibiotics
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anneke dijkmans anneke anneke dijkmans Rational Use of Antibiotics Rational Use of Antibiotics proefschrift ter verkrijging van de graad van Doctor aan de universiteit Leiden, op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker, volgens besluit van het College voor Promoties te verdedigen op donderdag 2 juni 2020 klokke 11:15 uur door Anneke Corinne Dijkmans geboren te Rhenen in 1974 design Caroline de Lint, Voorburg ([email protected]) The publication of this thesis was financially supported by the foundation Centre for Human Drug Research in Leiden, the Netherlands. Promotor Chapter 1 Prof. dr. J. Burggraaf 7 Introduction Co-promotor Chapter 2 Dr. I.M.C. de Visser-Kamerling, chdr, Leiden 21 A simplified oral flucloxacillin absorption test for patients requiring long-term treatment Leden promotiecommissie Prof. dr. A.C.M. Kroes Chapter 3 Prof. dr. L.G. Visser 30 The simplified oral flucloxacillin absorption test: an accurate method Prof. dr. C.M.J.E. Vandenbroucke-Grauls, Amsterdam UMC to identify patients with inadequate oral flucloxacillin absorption Prof. dr. H.A. Verbrugh, Erasmus Medisch Centrum Rotterdam Chapter 4 43 The oral pheneticillin absorption test: an accurate method to identify patients with inadequate oral pheneticillin absorption Chapter 5 51 Rifampin levels in daily practice: the accuracy of a single measurement Chapter 6 65 Colistin: revival of an old polymyxin Chapter 7 83 Colistin methanesulfonate (CMS) infusion solutions are stable over time and suitable for home administration Chapter 8 91 Fosfomycin: pharmacological, clinical and future perspectives Chapter 9 113 Fosfomycin as a potential therapy for the treatment of systemic infections: a population pharmacokinetic model to simulate multiple dosing regimens Chapter 10 131 Pharmacokinetics of fosfomycin in patients with prophylactic treatment for recurrent E. coli urinary tract infection Chapter 11 149 Recaputilation and general discussion 157 Nederlandse samenvatting 164 Publications 167 Curriculum Vitae 168 Dankwoord Chapter 1 introduction Introduction sulphanilamide. Th e sulpha drugs were the fi rst chemical substances that made a real diff erence in the treatment of bacterial infections in particular infections Infectious diseases are much older than mankind and when Homo sapiens arrived caused by streptococcal species. Th e historical importance of sulpha drugs is great, by evolutionary descent, they were vulnerable for infections. However, the exis- and even to date have wide usage in the treatment of systemic or localized infections. tence, causes and mechanisms of diseases due to microscopically small organisms remained obscure for many centuries and it became clear only since the second Antibiotics part of the nineteenth century. Th e transport of ‘contagious material’ was sug- During the time that sulphonamides were available another important gested by Ignaz Semmelweis, who was convinced that transfer of the putrefying development took place when Sir Alexander Fleming did his historical organic materials from a sick woman resulted in puerperal fever in a healthy discovery of penicillin in 192.⁵ While studying a staphylococcal variant, he woman,1 without recognizing the relationship of microorganisms to disease. found one of the culture plates contaminated with a fungus which destroyed the Although the existence of microorganisms had already been revealed as a result of surrounding staphylococcal colonies. Th is accidental rediscovery of the long- van Leeuwenhoek’s development of the microscope, it took two additional centu- known ability of Penicillium fungi to suppress the growth of bacterial cultures ries to recognise that microorganisms could be the cause of diseases, that at least spurred additional research. Fleming investigated the properties of ‘mould some of them were pathogenic to man. Experiments to proof that a microorgan- broth fi ltrates’ which he named penicillin for brevity. He described penicillin as ism could cause a specifi c disease were performed by Robert Koch in 177 with his an antiseptic ‘more powerful than phenol’, and the name ‘penicillin’ has since experiments with Bacillus anthracis.2 Th e next step in Koch’s work was to defi ne been applied to pure antibiotic substances. Aft er this fi rst historic observation the conditions in which a specifi c microorganism could cause a specifi c disease, i.e. it took a decade before penicillin could be suffi ciently purifi ed and produced Koch’s postulates.3 With the application of these postulates a connection was made on an industrial scale. Indeed, only aft er the successful purifi cation and between clinical manifestations of a disease and microorganisms observed under concentration by Chain and Florey in 1940, it became possible to demonstrate the microscope, establishing the causative role of specifi c microorganisms for spe- the importance of penicillin by a clinical trial in 1941. Th ereaft er, in the course cifi c diseases as tuberculosis, anthrax and cholera. of the 20th century numerous new antibiotics were discovered and developed and introduced in daily practice. Antibacterial agents Antibiotics are unique among all other medical drugs. Th ey are the only class of medicines, whose primary target is present in bacterial cells but absent in human Heavy metals cells, i.e. they are highly selective for bacterial cells. Although the value of hygiene In the early sixteenth century heavy metals such as gold and mercury were measures cannot be underestimated, antibiotics have revolutionized human considered as an elixir of life by Paracelsus. In 190 Paul Ehrlich pioneered the use healthcare in a way that only a few other scientifi c discoveries have. Antibiotics of arsenic and 25 years he discovered that arsenical compounds had activity against have not only enabled us to overcome ‘the captain of the men of death’ by saving syphilis, and discovered that compound 0 (Salvarsan; ‘benefi cial arsenic’) was lives of patients with serious infections, these drugs have also played a pivotal role amazingly active against such infection. in major advances in medicine and surgery, a role which is less oft en highlighted Koch reported the in vitro inhibition of tubercle bacilli growth by gold cyanide and yet has paramount signifi cance.⁶ and in 194 a mixture of gold and magnesium was used to treat tuberculosis. Many On the other hand, antibiotics disturb natural ecological niches by exerting publications were written about chrysotherapy for tuberculosis. Believing that selective evolutionary pressure on bacteria present in the niches were they are tuberculosis and rheumatoid arthritis (RA) had a common infectious aetiology, applied, both in the human, the animal and agricultural domains of society as Forester applied gold for the treatment of RA.⁴ Despite the fact that RA turned out well as in the innate environment. As a consequence of exposure to antibiotics the not to be directly caused by microorganisms, chrysotherapy proved to be rather less susceptible and fully resistant mutants of susceptible species survive as do the eff ective and became an established drug in the treatment of RA. intrinsically resistant (see below) species; these surviving cells may subsequently greatly expand their niche. We currently face an era of serious threats to human and Chemotherapeutics animal health due to the world wide emergence of multi-drug resistant bacteria. Based on the idea’s and work of Paul Ehrlich, Mietzsch and Klarer had synthesized Th is threat was always on the horizon. As early as 194, Sir Alexander Fleming Prontosil in 192. Prontosil was not active against bacteria in vitro, but was quite noted that microbes can be ‘educated to resist penicillin’.⁷ Notwithstanding this active in experimentally infected animals. Th e explanation for this discrepancy early observation, only little has been done to prevent the emergence of drug was that Prontosil is a pro-drug metabolized by the recipient to the active agent resistance.⁶,⁷ 8 9 rational use of antibiotics chapter 1 – introduction Antibiotic Resistance Biochemically, several types of resistance mechanisms are observed including an- Antibiotic resistance is recognised as one of the most serious threats to the treat- tibiotic inactivation, target modifi cation, altered permeability and ‘bypass’ met- ment of infectious diseases globally. Already in 199 Calvin M Kunin, an infectious abolic pathways.⁹ It can be stated that resistance emergence is due to a combi- diseases specialist in the USA, wrote a perspective in the Annals of Internal Medicine nation of two groups of factors: warning against a worldwide calamity due to the global emergence of antimicro- 1 Selection of resistant clones as a direct consequence of exposure to antibiotics bial resistance.3⁸ However, only in 2004 this emerging threat fi nally prompted the favouring: World Health Organisation (WHO) to issue a warning that antibiotic resistance • intrinsically resistant bacterial species would seriously impact the opportunities to treat infectious diseases in the future.⁷ • variants of originally susceptible bacteria that have acquired resistance traits In 2015 the WHO published its Global Action Plan on Antimicrobial Resistance, by spontaneous mutations in their genome or by acquisitions of resistance outlining the way for all nations to combat the emergence of resistance, a world- genes through horizontal gene transfer from other bacteria in their vicinity wide eff ort that is currently being implemented in many countries. Th e awareness 2 Expansion and the spread of