Tuberculosis and its sequelae: Diagnostic, epidemiological and therapeutic studies

Onno Willem Akkerman

Tuberculosis and its sequelae: Diagnostic, epidemiological and therapeutic studies

Onno Willem Akkerman

Microbes in Health and Disease (MHD)

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Tuberculose (TB) veroorzaakt wereldwijd nog altijd veel ziekte en sterfte. TB is een infectieziekte veroorzaakt door Mycobacterium tuberculosis, of soms, M. bovis. De kweekproef vergt tijd, en een genetische test, de PCR methode, kan de diagnose versnellen. We vergeleken de diagnostische gevoeligheid van verschillende PCR testen onderling. Kleine genetische verschillen tussen bacteriestammen – fingerprints – worden gebruikt om verspreidingspatronen van TB in de bevolking te bestuderen; wij hebben zo’n techniek nader onderzocht. We hebben ook gekeken naar immunologische testen bij besmettingen met TB veroorzaakt door M. bovis.
Multiresistente TB (MDR-TB) vereist behandeling met een selectie van zogenaamde tweedelijns TB middelen waarvoor de bacterie in de kweek nog gevoelig is. Veel van deze geneesmiddelen behoren tot de groep 5 middelen (WHO): ze hebben een onduidelijke of nog onbewezen effectiviteit. We weten vaak ook nog niets over de concentraties van deze geneesmiddelen ter plaatse van de infectie. We pleiten voor meer onderzoek naar MDR-TB, om de overleving te verbeteren en blijvende gevolgen (sequelae) te verminderen.
Veel patiënten die TB overleven houden sequelae over; vaak zijn dat bronchiëctasieën, deformaties met verwijde luchtwegen waarin vaak weer andere infecties ontstaan, met ophoesten van veel vies slijm en soms bloed. Een belangrijke behandeling bij deze luchtweginfecties bij bronchiëctasieën is het inhaleren van bepaalde antibiotica, zoals tobramycine. We beschrijven een model om bloedspiegels en daarmee de algemene toxiciteit te voorspellen na inhalatie van deze antibiotica. Tenslotte hebben we de effecten bestudeerd van het inhaleren van tobramycine door middel van een nieuw inhalatie apparaat.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	van der Werf, Tjipke, Supervisor Kerstjens, Huib, Supervisor Frijlink, Erik, Supervisor van der Zanden, Adri G. M., Co-supervisor, Externe Persoon
Datum van toekenning	11-nov.-2015
Plaats van publicatie	[Groningen]
Uitgever	University of Groningen
Gedrukte ISBN's	978-90-367-8178-7
Elektronische ISBN's	978-90-367-8177-0
Status	Published - 2015

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Title and contents Final publisher's version, 377 KB
Chapter 1 Final publisher's version, 555 KB
Chapter 2A Final publisher's version, 583 KB
Chapter 2B Final publisher's version, 526 KB
Chapter 3B Final publisher's version, 536 KB
Chapter 4A Final publisher's version, 512 KB
Chapter 4B Final publisher's version, 485 KB
Chapter 4C Final publisher's version, 488 KB
Chapter 5A Final publisher's version, 855 KB
Chapter 5B Final publisher's version, 758 KB
Summary Final publisher's version, 486 KB
General discussion andfuture perspectivesFinal publisher's version, 518 KB
SamenvattingFinal publisher's version, 504 KB
About the authorFinal publisher's version, 192 KB
PropositionsFinal publisher's version, 1,07 MB

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title = "Tuberculosis and its sequelae: Diagnostic, epidemiological and therapeutic studies",

abstract = "Tuberculosis (TB) has remained a leading cause of death. TB is caused by Mycobacterium tuberculosis, or by M. bovis. Culture takes time; a genetic amplification test, PCR, helps to establish a rapid diagnosis. We compared several different PCR assays for their sensitivity to diagnose TB. Genetic fingerprinting techniques are used to study the spread of TB in the population. We studied one such fingerprinting technique. Furthermore we looked at the use of an immunological test to detect TB infections by M. bovis.Multidrug-resistant (MDR) TB is bad news for patients; treatment requires second-line TB drugs for which the isolate tests susceptible in culture. Some of these 2nd line drugs are listed among TB drugs with unclear efficacy; in culture they show inhibition of growth but we don{\textquoteright}t know whether these drugs reach sufficient concentrations at the site of infection, and surely no outcome data are available in larger groups of patients. We argue that increased research efforts are needed in MDRTB, to improve outcome, and reduce sequelae. Indeed a large proportion of the patients are left with sequelae after treatment for TB. In this thesis we address the most common sequelae: bronchiectasis, i.e., deformations of the airways with dilatations causing recurrent exacerbations of infections, and bleeding. An important part of the treatment against these exacerbated infections is by the inhalation of certain antibiotics. We developed a model to predict blood drug concentrations after inhalation, thereby predicting systemic toxicity. Furthermore we studied the inhalation of tobramycin using a novel inhalation device.",

author = "Akkerman, \{Onno Willem\}",

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T1 - Tuberculosis and its sequelae

T2 - Diagnostic, epidemiological and therapeutic studies

AU - Akkerman, Onno Willem

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N2 - Tuberculosis (TB) has remained a leading cause of death. TB is caused by Mycobacterium tuberculosis, or by M. bovis. Culture takes time; a genetic amplification test, PCR, helps to establish a rapid diagnosis. We compared several different PCR assays for their sensitivity to diagnose TB. Genetic fingerprinting techniques are used to study the spread of TB in the population. We studied one such fingerprinting technique. Furthermore we looked at the use of an immunological test to detect TB infections by M. bovis.Multidrug-resistant (MDR) TB is bad news for patients; treatment requires second-line TB drugs for which the isolate tests susceptible in culture. Some of these 2nd line drugs are listed among TB drugs with unclear efficacy; in culture they show inhibition of growth but we don’t know whether these drugs reach sufficient concentrations at the site of infection, and surely no outcome data are available in larger groups of patients. We argue that increased research efforts are needed in MDRTB, to improve outcome, and reduce sequelae. Indeed a large proportion of the patients are left with sequelae after treatment for TB. In this thesis we address the most common sequelae: bronchiectasis, i.e., deformations of the airways with dilatations causing recurrent exacerbations of infections, and bleeding. An important part of the treatment against these exacerbated infections is by the inhalation of certain antibiotics. We developed a model to predict blood drug concentrations after inhalation, thereby predicting systemic toxicity. Furthermore we studied the inhalation of tobramycin using a novel inhalation device.

AB - Tuberculosis (TB) has remained a leading cause of death. TB is caused by Mycobacterium tuberculosis, or by M. bovis. Culture takes time; a genetic amplification test, PCR, helps to establish a rapid diagnosis. We compared several different PCR assays for their sensitivity to diagnose TB. Genetic fingerprinting techniques are used to study the spread of TB in the population. We studied one such fingerprinting technique. Furthermore we looked at the use of an immunological test to detect TB infections by M. bovis.Multidrug-resistant (MDR) TB is bad news for patients; treatment requires second-line TB drugs for which the isolate tests susceptible in culture. Some of these 2nd line drugs are listed among TB drugs with unclear efficacy; in culture they show inhibition of growth but we don’t know whether these drugs reach sufficient concentrations at the site of infection, and surely no outcome data are available in larger groups of patients. We argue that increased research efforts are needed in MDRTB, to improve outcome, and reduce sequelae. Indeed a large proportion of the patients are left with sequelae after treatment for TB. In this thesis we address the most common sequelae: bronchiectasis, i.e., deformations of the airways with dilatations causing recurrent exacerbations of infections, and bleeding. An important part of the treatment against these exacerbated infections is by the inhalation of certain antibiotics. We developed a model to predict blood drug concentrations after inhalation, thereby predicting systemic toxicity. Furthermore we studied the inhalation of tobramycin using a novel inhalation device.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-8178-7

PB - University of Groningen

CY - [Groningen]

ER -

Tuberculosis and its sequelae: Diagnostic, epidemiological and therapeutic studies

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