University of Groningen Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic treatments Purba, Abdul

Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic treatments

Purba, Abdul

DOI:

10.33612/diss.128518764

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Publication date: 2020

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Purba, A. (2020). Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic

treatments: Focus on surgical site infection and hospitalized community-acquired pneumonia. University of Groningen. https://doi.org/10.33612/diss.128518764

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Addendum

SUMMARY

Antibiotics are widely used for surgical site infections (SSIs) and hospitalized community-acquired pneumonia (CAP) treatments. Typically, for SSIs and hospitalized CAP, antibiotics are often given before the pathogen has been identified, and their use is not always adequately informed by the antibiotic susceptibility profiles. Prophylactic antibiotics are used for SSI prevention, whereas empirical antibiotics are used for the temporary initial treatment of hospitalized CAP, based on the pathogenic patterns of causes and the patterns of antibiotic sensitivity particular healthcare centers that may or may not be accurate. High intensity of antibiotics without guided microbiological tests can generate resistant organisms, causing therapy failure in individual patients and high medical costs. Diagnostic-based antibiotic treatments using microbiological evaluations may contribute to improved use of prophylactic and empirical antibiotics.

First, we analyzed the cost burden of systemic sepsis infection in Indonesia, looking at focal infections, including pneumonia and postoperative infections such as SSIs. This research was carried out in an integrated manner with respect to surviving and death outcomes and is planned as part of the insurance financing system when universal health coverage (UHC) is introduced in Indonesia. The average hospital cost per surviving and deceased sepsis patient was US$ 1,011 and US$ 1,406 respectively. The national burden of sepsis in 100,000 patients is estimated at US$ 130 million. Sepsis patients with multifocal infections and single focal infections of the lower respiratory tract were estimated as the two groups with the highest economic burden (US$ 48 million and US$ 33 million respectively in 100,000 cases). It is important to consider mortality and focal infection when assessing the burden of sepsis, as there are significant differences in the total cost of care. In a resource-limited context such as Indonesia, where the new UHC system is being implemented, the provision of adequate health services requires a re-evaluation and recalculation of the cost of sepsis. Furthermore, cases of sepsis with multifocal infections and pneumonia should be categorized as high-burden cases; it is cases like these that require price adjustments at the national level when replacing private and public health services.

The policy adopted by the government and clinicians in hospitals for the prevention and control of antibiotic resistance in SSIs and hospitalized CAP needs to be supported by scientific evidence. Pharmacoeconomics provides an integrity evaluation and an interpretation of the extent and accuracy of the handling of SSI and hospitalized CAP patients in the therapeutic context, with appropriate morbidity and mortality targets and outcomes. Clinical microbiological evaluation to identify pathogens in these two diseases and the economic impact on patients’ outcomes need to be analyzed as part of the pharmacoeconomics when developing a strategy for the use of antibiotics. The strategy implemented needs to be effective, efficient and affordable and to be able to improve patients’ quality of life.

The first part of this thesis contains a comprehensive discussion of SSIs based on a review of 20 studies of the effectiveness and cost of prophylactic antibiotics for patients who are about to undergo surgery, in order to prevent postoperative SSI events (Chapter 3). Indeed, the preoperative phase is an important period when it comes to preventing SSIs. Prophylactic antibiotics help to

reduce the level of SSI, leading to a reduction in the time and cost of hospitalization. Preoperative prophylactic antibiotics are given both locally and systemically, and this has been examined in several studies on preventing SSIs. Among the studies reviewed, there were 14 trial-based studies; the others were model-based studies. The incidence of SSIs in the trial-based study ranged from 0 to 71%, with average hospital care costs of between US$ 482 and US$ 22,130. A cohort study using prophylactic antibiotics to prevent SSIs in primary hip replacement yielded pharmacoeconomics outcomes with an estimated cost of US$ 121,000/QALY. In clinical practice, the selection of prophylactic antibiotic agents also needs to take evidence on the microbiological costs and results into account, in addition to effectiveness and safety. The most recent scientific evidence on the use of antibiotics for SSI prophylaxis is presented in Chapter 3 from the perspective of pharmacoeconomics and epidemiological microbiological findings. Twenty-four bacteria were identified as agents causing SSI. Gram-negative bacteria are the dominant cause of SSIs, especially in general surgery, neurosurgery, cardiothoracic surgery, and obstetric surgery patients.

The impact of SSI disease on hospital admission, length of stay and cost has been analyzed in-depth, including predictors of length-of-stay outcomes and of SSI outcomes, which are discussed in Chapter 4. Of a total of 12,285 patients in an academic hospital in the Netherlands, 343 SSI patients (87%) needed a hospital stay after surgery. The average length of stay is around 12 days, with an estimated cost per hospital admission of € 9,016. Independent variables related to SSI outcome were patient’s age > 65 years (OR: 1.334; 95% CI: 1.036-1.720), prophylactic antibiotic use (OR: 0.424; 95% CI: 0.344-0.537), and comorbid cancer (OR: 2,050; 95% CI: 1,473-2,854). In addition, patients suffering from SSI showed a prolonged length of stay (HR: 0.742; 95% CI: 0.679-0.809).

The third part of this thesis discusses hospitalized CAP in-depth and the pathogens responsible, in order to assess therapeutic effectiveness. The characteristics of the germs that cause pneumonia are analyzed in Chapter 5. The epidemiology study of the etiology of hospitalized CAP due to bacterial infections in Indonesia shows that one-fifth are multiple drug-resistant organisms (MDROs). Resistance to ciprofloxacin and amoxicillin/clavulanate reached 82%.

Acinetobacter baumannii was a bacterium that was found to be multiresistant to some antibiotics.

Several factors, such as a history of inappropriate use and the use of unprescribed antibiotics in the community, can cause multiresistant infections. In addition, patients with diabetes, heart disease, cancer, kidney disorders, liver disorders, and immune disorders also trigger community pneumonia with drug resistance. We recommend the third-generation drug cephalosporin as an empirical antibiotic in national guidelines, since the sensitivity rate remained high (67-82%).

The risk of death in cases of pneumonia depends on the following three factors: the patient’s condition, bacterial factors, and treatment. The mortality rate increased significantly in patients with severe hospitalized CAP and those who did not show any improvement after day three. Most of the severe pneumonia that requires hospital treatment is suffered by male patients aged 56 years and above. Symptoms that often arise are shortness of breath (98%), fever (96%), cough (74%), and chest discomfort (21%). Patients with cancer and those with weak immunity are more likely to fall prey to this severe hospitalized CAP, so it requires close clinical observation. An MDRO infection may be suspected if the patient has received therapy but there is no clinical improvement,

for example, the patient is still complaining of dyspnea and fever. Clinical assessment 72 hours after the administration of empirical antibiotics is a reliable integrated assessment indicator of hospitalized CAP. In combination with the pneumonia severity index (PSI), this 72-hour clinical assessment helps to predict mortality outcomes.

Hospitalized CAP patients treated in hospitals generally had serious symptoms that required intensive observation and inpatient treatment. The focus during observation in the inpatient room was the selection of appropriate antibiotics, based on the results of microbiological cultures of both sputum and blood, to prevent further antibiotic resistance. Treatment based on culture evaluation and antibiotic susceptibility testing provides benefits in terms of reduced cost and extended life expectancy. The recommended strategy for the use of empirical treatment is discontinuation the antibiotic administration if the culture results are negative and the patient shows a clinical improvement (Chapter 6). The implementation of germ culture in pneumonia cases can save as much as US$ 1,067 per patient and increase life expectancy in all cases. Giving patients culture-based treatment (CBT), especially in intensive care, would save US$ 1,792 per patient, along with a higher life expectancy than without CBT. Interestingly, in the elderly group, CBT not only mediates the right antibiotic choices and saves a cost of US$ 3,828 per patient, it also increases life expectancy by one year compared with patients who are not given CBT.

The implementation of microbiological culture analysis in developing countries with a high incidence of CAP, such as Indonesia, needs to be considered. Since 2014, Indonesia has implemented a national health insurance system (Jaminan Kesehatan Nasional, JKN) to manage spending on treatment. Given the current limitations on administering cost-based antibiotics to pneumonia patients, CBT could be used for CAP patients receiving treatment in hospitals in Indonesia. Bacterial culture analysis makes the administration of antibiotics in the treatment of pneumonia more precise, hence it can ultimately reduce the cost of care and increase life expectancy, especially in the case of elderly patients, those with immune disorders and those with concomitant diseases.

Additional analysis of antibiotic uses for empirical treatment, Chapter 6 analyzes the cost burden of systemic sepsis infection by considering focal infections including pneumonia and postoperative infections such as SSIs. This research was carried out in an integrated manner with respect to life and death outcomes and is projected in the insurance financing system in the era of universal health coverage (UHC) in Indonesia. The average hospital cost per living sepsis and deceased patient was US$ 1,011 and US$ 1,406, respectively. The national burden of sepsis in 100,000 patients is estimated at US$ 130 million. Sepsis patients with multifocal infections and single focal infections of the lower respiratory tract infections are estimated as the two with the highest economic burden (US$ 48 million and US$ 33 million, respectively, in 100,000 cases). It is important to consider mortality and focal infection in the assessment of the burden of sepsis because there are significant differences in the total cost of care. In a resource-limited context such as in Indonesia, where the new UHC system is implemented, the provision of adequate health services requires a re-evaluation and re-calculation of prices for sepsis. Furthermore, cases of sepsis with multifocal infections and pneumonia should be categorized as high-burden sepsis

cases, reflecting the clearest examples that require national price adjustments for the replacement of private and public health services.

SAMENVATTING

Antibiotica worden vaak gebruikt om postoperatieve wondinfecties (POWI’s) en community-acquired pneumonie (CAP) waarvoor een ziekenhuisopname plaatsvindt (gehospitaliseerde CAP) te voorkomen. Deze aandoeningen dienen te worden onderzocht, aangezien antibiotica worden toegediend nog voordat de ziekteverwekker is geïdentificeerd en het niet bekend is voor welke antibiotica de ziekteverwekker gevoelig is. Antibiotica worden profylactisch toegediend om POWI’s te voorkomen. Antibiotica worden daarentegen empirisch toegepast als initiële behandeling voor gehospitaliseerde CAP. Deze empirische behandeling is gebaseerd op het patroon van ziekteverwekkers en hun gevoeligheid voor antibiotica in een bepaalde zorginstelling. Hierbij dient als kanttekening te worden geplaatst dat het toedienen van hoge doseringen antibiotica zonder microbiologische onderbouwing kan leiden tot resistente micro-organismen. Hierdoor kan de behandeling bij individuele patiënten mislukken en kunnen de medische kosten hoog oplopen.

Het beleid van de overheid en klinisch werkzame artsen om antibioticaresistentie bij POWI’s en gehospitaliseerde CAP te voorkomen en te bestrijden dient wetenschappelijk te worden onderbouwd. Aan de hand van farmaco-economie kan een volledigheidsonderzoek en een interpretatie van de reikwijdte en nauwkeurigheid van het beleid bij POWI’s en gehospitaliseerde CAP plaatsvinden binnen een therapeutische setting. Daarin kunnen de juiste doelstellingen en uitkomsten op het gebied van morbiditeit en mortaliteit worden opgenomen. Een antibioticabeleid dient te zijn gestoeld op een farmaco-economische evaluatie bestaande uit een klinisch microbiologische evaluatie om de ziekteverwekkers van POWI’s en gehospitaliseerde CAP te identificeren en een analyse van de economische gevolgen voor de patiëntuitkomsten. Het beleid dient effectief, efficiënt en betaalbaar te zijn. Daarnaast dient de kwaliteit van leven van de patiënten door het beleid te worden bevorderd.

De preoperatieve fase is van groot belang bij het voorkomen van POWI’s. Door het profylactisch toedienen van antibiotica kan het aantal POWI’s worden verminderd. Hierdoor nemen het aantal opnamedagen en de opnamekosten af. Het preoperatief toedienen van antibioticaprofylaxe vindt zowel lokaal als systemisch plaats. Dit is onderzocht in een aantal studies naar de preventie van POWI’s. In het eerste deel van dit proefschrift vindt een uitgebreide bespreking plaats van POWI’s op basis van een overzichtsstudie. In deze studie worden twintig onderzoeken beschreven naar de effectiviteit en kosten van het profylactisch toedienen van antibiotica voorafgaand aan een operatie met als doel het voorkomen van POWI’s (Hoofdstuk 3). Veertien van de onderzoeken waren ‘trial-based’; de overige waren ‘model-based’. De incidentie van POWI’s in de ‘trial-based’-studies varieerde van 0 tot 71%. De ziekenhuiskosten in deze ‘trial-based’-studies bedroegen gemiddeld US$482 tot US$22.130. In een cohortstudie waarin antibioticaprofylaxe werd toegediend bij het plaatsen van een eerste (primaire) heupprothese om POWI’s te voorkomen, werden de kosten op basis van een farmaco-economische analyse geschat op US$121.000/QALY. In de klinische praktijk dient de keuze voor de profylactisch toe te dienen antibiotica niet alleen gebaseerd te zijn op de effectiviteit en veiligheid van de antibiotica, maar ook op de kosten en resultaten

van microbiologische diagnostiek. In Hoofdstuk 3 worden de meest recente wetenschappelijke gegevens betreffende het toedienen van antibioticaprofylaxe bij POWI’s gepresenteerd op basis van farmaco-economisch onderzoek en epidemiologisch microbiologische bevindingen. Van vierentwintig bacteriën werd vastgesteld dat ze POWI’s kunnen veroorzaken. Het betreft overwegend Gram-negatieve bacteriën, die met name POWI’s kunnen veroorzaken bij algemene chirurgische, neurochirurgische, cardio-thoracale en obstetrische ingrepen.

In Hoofdstuk 4 bespreken we de resultaten van een uitgebreide analyse van de relatie tussen POWI’s en ziekenhuisopnamen, opnameduur en opnamekosten. Daarnaast hebben we onderzoek gedaan naar eventuele voorspellers van de opnameduur en het optreden van POWI’s. In een academisch ziekenhuis in Nederland werden in totaal 12.285 patiënten behandeld. Driehonderddrieënveertig van hen (87%) moesten na een chirurgische ingreep worden opgenomen vanwege een POWI. De gemiddelde opnameduur bedroeg ongeveer twaalf dagen. Een ziekenhuisopname kostte naar schatting $9.016. Onafhankelijke variabelen die verband hielden met POWI’s waren: leeftijd van de patiënt ≥ 65 jaar (OR: 1.334; 95% CI: 1.036-1.720), het toedienen van antibioticaprofylaxe (OR: 0.424; 95% CI: 0.344-0.537) en comorbiditeit in de vorm van een maligniteit (OR: 2.050; 95% CI: 1.473-2.854). Daarnaast bleek dat patiënten met een POWI langer in het ziekenhuis verbleven (HR: 0.742; 95% CI: 0.679-0.809).

In het tweede deel van dit proefschrift komen gehospitaliseerde CAP en de ziekteverwekkers uitgebreid aan bod, met als doel de therapeutische effectiviteit vast te stellen. De eigenschappen van de bacteriën die pneumonie veroorzaken worden onderzocht in Hoofdstuk 4. Uit een epidemiologische studie naar de oorzaak van gehospitaliseerde CAP met een bacteriële verwekker in Indonesië blijkt dat een vijfde van deze infecties wordt veroorzaakt door Multidrug Resistente Organismen (MDRO). Tot 82% van de organismen was resistent tegen ciprofloxacine en amoxicilline/clavulanaat. De bacterie Acinetobacter baumannii bleek resistent te zijn tegen een aantal antibiotica. Infecties met multiresistente bacteriën kunnen ontstaan wanneer bijvoorbeeld antibiotica in het verleden op inadequate wijze zijn gebruikt en wanneer antibiotica zonder recept worden gebruikt binnen de gemeenschap. Daarnaast zijn patiënten met diabetes, hartaandoeningen, oncologische aandoeningen, nierziekten, leverziekten en immuunziekten vatbaar voor CAP veroorzaakt door organismen die resistent zijn tegen antibiotica. Omdat bacteriën gevoelig blijven voor derde generatie cefalosporines (67-82%) adviseren we deze antibiotica als empirische behandeling op te nemen in nationale richtlijnen.

Of een patiënt met pneumonie overlijdt, hangt af van drie factoren, namelijk de conditie waarin de patiënt verkeert, eigenschappen van de bacterie en de behandeling. Patiënten met ernstige gehospitaliseerde CAP en patiënten bij wie geen enkele verbetering werd geconstateerd na de derde dag, hadden een significant hogere kans om te overlijden. Met name mannen ≥56 jaar leden aan ernstige gehospitaliseerde pneumonie. Symptomen die vaak voorkomen zijn kortademigheid (98%), koorts (96%), hoesten (74%) en ongemak en pijn in de borststreek (21%). Patiënten met een oncologische aandoening en patiënten met een verminderde afweer hebben een grotere kans op ernstige gehospitaliseerde CAP. Daarom dient nauwkeurige klinische observatie plaats te vinden. Er dient rekening te worden gehouden met een infectie die wordt

veroorzaakt door Multidrug Resistente Organismen (MDRO) als de patiënt ondanks behandeling klinisch niet vooruitgaat. Hiervan kan bijvoorbeeld sprake zijn bij persisterende kortademigheid en koorts. Gehospitaliseerde CAP kan op betrouwbare wijze worden vastgesteld aan de hand van een klinische beoordeling die tweeënzeventig uur na het empirisch toedienen van antibiotica plaatsvindt. Op basis van deze klinische beoordeling na tweeënzeventig uur in combinatie met de ‘pneumonia severity index’ (PSI) kan worden voorspeld of de patiënt kans loopt te overlijden.

Gehospitaliseerde patiënten met CAP hadden meestal ernstige symptomen waarvoor intensieve observatie en een klinische behandeling nodig was. De observatie in de behandelkamer was gericht op het selecteren van de juiste antibiotica op basis van de uitslagen van sputum- en bloedkweken. Het doel was om verdere resistentie tegen antibiotica tegen te gaan. Behandeling op basis van kweekonderzoek en op basis van een bepaling voor welke antibiotica de ziekteverwekker gevoelig is, leidt tot lagere kosten en een hogere levensverwachting van de patiënt. Bij een empirische behandeling is het raadzaam het gebruik van antibiotica te beëindigen indien de kweekuitslagen negatief zijn en de patiënt klinisch vooruitgaat. De implementatie van kweekonderzoek bij patiënten met een pneumonie kan leiden tot een kostenbesparing van US$1.067 per patiënt en een hogere levensverwachting van alle patiënten. Met name op de intensive care leidt behandeling op basis van kweekonderzoek (‘culture-based treatment’, CBT) tot een kostenbesparing van US$1.792 per patiënt en tot een hogere levensverwachting dan wanneer CBT niet wordt gegeven. Bij ouderen leidt CBT niet alleen tot de juiste antibioticakeuze en een kostenbesparing van US$3.828 per patiënt, maar ook tot een toename van de levensverwachting met één jaar vergeleken met het niet toepassen van CBT.

In ontwikkelingslanden met een hoge incidentie van CAP, zoals Indonesië, dient het invoeren van kweekonderzoek te worden overwogen. Sinds 2014 is in Indonesië de Sociale Ziektekostenverzekering (BPJS Kesehatan) in werking getreden om de zorguitgaven te beheersen. CBT zou toepasbaar kunnen zijn bij gehospitaliseerde patiënten met CAP in Indonesië, gelet op de huidige beperkingen om antibiotica op basis van kosten toe te dienen aan patiënten met een pneumonie. Het uitvoeren van kweekonderzoek kan leiden tot gerichtere toepassing van antibiotica bij de behandeling van een pneumonie, met als gevolg lagere zorgkosten en een hogere levensverwachting met name bij oudere patiënten, patiënten met immuunziekten en patiënten met comorbiditeiten.

We hebben de toepassing van antibiotica als empirische behandeling nader onderzocht. In Hoofdstuk 6 hebben we onderzoek gedaan naar de kosten als gevolg van sepsis. Daarbij hebben we gelokaliseerde infecties bestudeerd, waaronder pneumonie en postoperatieve infecties zoals POWI’s. Dit onderzoek, waarin uitkomsten wat betreft leven en overlijden op geïntegreerde wijze in kaart zijn gebracht, is opgezet in het kader van de financiering van de invoering van een universele ziektekostenverzekering (‘universal health coverage’, UHC) in Indonesië. Voor patiënten die sepsis overleefden bedroegen de ziekenhuiskosten gemiddeld $1.011. Voor patiënten die overleden aan sepsis bedroegen de ziekenhuiskosten daarentegen gemiddeld $1.406. Op nationaal niveau worden de kosten als gevolg van sepsis geschat op $130.000.000 per 100.000 patiënten. De ziektebeelden die gepaard gaan met de hoogste kosten zijn sepsis op basis van

infecties in meerdere organen ($48.000.000 per 100.000 patiënten) en sepsis op basis van een gelokaliseerde infectie in de onderste luchtwegen ($33.000.000 per 100.000 patiënten). Bij het vaststellen van de kosten van sepsis dienen de mortaliteitcijfers en de lokalisatie van de infecties te worden meegewogen, aangezien er significante verschillen zijn in de totale zorgkosten. In landen zoals Indonesië, waar de middelen beperkt zijn en een nieuwe universele ziektekostenverzekering wordt ingevoerd, moeten de kosten als gevolg van sepsis opnieuw worden geëvalueerd en berekend om adequate gezondheidszorg te kunnen verlenen. Sepsis op basis van infecties in meerdere organen en sepsis op basis van een pneumonie moeten als een hoge kostenpost worden beschouwd. Deze ziektebeelden maken een prijsaanpassing op nationaal niveau noodzakelijk bij het vervangen van het particuliere en openbare gezondheidszorgstelsel.

RINGKASAN

Obat yang digunakan secara luas untuk pencegahan infeksi daerah operasi (IDO) dan penyakit pneumonia komuniti adalah antibiotik. Pembahasan IDO dan pneumonia komuniti menjadi hal yang penting dibahas karena penggunaan antibiotik untuk kedua penyakit ini diberikan lebih awal sebelum patogen teridentifikasi dan belum mengetahui kerentanannya terhadap antibiotik yang diberikan. Antibiotik profilaksis digunakan untuk pencegahan IDO sedangkan antibiotik empirik digunakan untuk pengobatan sementara pneumonia komuniti berdasar pola patogen penyebab dan pola kepekaan antibiotik di suatu layanan kesehatan. Intensitas penggunaan antibiotik yang tinggi dapat menimbulkan penggunaan antibiotik yang tidak rasional. Masalah besar akibat ketidakrasionalan penggunaan antibiotik adalah resistensi obat yang menyebabkan kegagalan terapi dan biaya pengobatan yang tinggi.

Implementasi strategi yang dilakukan pemerintah dan pemegang kebijakan klinis di rumah sakit dalam pencegahan dan pengendalian resistensi antibiotik pada IDO dan penumonia komuniti harus didukung oleh bukti ilmiah. Evaluasi farmakoekonomi secara integritas memberikan interpretasi sejauh mana ketepatan dan efektivitas penangan pasien IDO dan pneumonia komuniti dalam konteks terapi dengan target yang tepat dan luaran morbiditas dan mortalitas. Analisis evaluasi mikrobiologi klinik terhadap identifikasi patogen pada kedua penyakit tersebut merupakan bagian dari farmakoekonomi yang dipertimbangkan untuk menyusun strategi dalam penggunaan antibiotik. Strategi yang diimplementasikan diharapkan efektif, efisien, terjangkau, dan dapat meningkatkan kualitas hidup pasien.

Penggunaan antibiotik profilaksis membantu mengurangi tingkat IDO, yang mengarah pada pengurangan waktu dan biaya rawat inap. Antibiotik profilaksis pra operasi yang diberikan baik secara lokal maupun sistemik perlu dipertimbangkan dalam mencegah IDO. Pada bagian pertama tesis ini, IDO dibahas secara komprehensif melalui review 20 studi terkait efektivitas dan biaya dari penggunaan antibiotik profilaksis untuk pasien yang akan menjalani operasi dalam mencegah IDO pascaoperasi (Bab 3). Dari studi yang direview, terdapat 14 studi berbasis riset pada populasi, dan yang lainnya adalah studi berbasis model. Insiden IDO pada studi populasi berkisar antara 0 hingga 71% dengan biaya rerata perawatan rumah sakit sebesar antara US$482 hingga US$22.130. Pada studi model kohort penggunaan antibiotik profilaksis untuk pencegahan IDO pada tindakan primary hip-replacement menunjukkan estimasi biaya sebesar US$121,000/QALY. Fase pra operasi adalah periode penting untuk mencegah IDO. Dalam praktik klinis, selain efektivitas dan keamanan, pemilihan agen antibiotik profilaksis juga harus mempertimbangkan bukti yang berkaitan dengan biaya dan hasil mikrobiologis. Bukti ilmiah terkini terkait dengan penggunaan antibiotik untuk profilaksis IDO ditampilkan pada Bab 3 dengan perspektif farmakoekonomi dan epidemiologi temuan mikrobiologis. Dua puluh empat bakteri diidentifikasi sebagai agen penyebab SSI. Bakteri Gram negatif adalah penyebab dominan SSI terutama pada pasien dengan tindakan bedah umum, bedah saraf, bedah kardiotoraks dan operasi obstetrik.

Penyakit IDO berdampak terhadap kejadian hospital readmission, lama rawat inap, dan biaya. Dampak tersebut dianalisis secara mendalam dengan analisis faktor prediktor luaran lamanya

perawatan di rumah sakit dan faktor prediktor luaran terjadinya IDO yang dibahas dalam Bab 3. Dari total 12.285 pasien di suatu rumah sakit di Belanda, sebanyak 343 pasien IDO (87%) memerlukan perawatan tinggal di rumah sakit setelah operasi. Lama rawat rata-rata sekitar 12 hari dengan estimasi biaya per masuk rumah sakit sebesar € 9.016. Variabel independen yang terkait dengan luaran terjadinya IDO adalah usia pasien >65 tahun (OR: 1,334; 95%CI: 1,036-1,720), penggunaan antibiotik profilaksis (OR: 0,424; 95%CI: 0,344-0,537), dan pasien yang memiliki komorbid penyakit kanker (OR: 2.050; 95%CI: 1.473-2.854). Selain itu, pasien yang menderita IDO menunjukkan lama rawat yang berkepanjangan (HR: 0,742; 95% CI: 0,679-0,809).

Bagian kedua membahas secara mendalam pneumonia komuniti dari patogen penyebab penyakit untuk menilai efektivitas terapi. Karakteristik kuman penyebab pneumonia dianalisis pada Bab 4. Epidemiologi etiologi pneumonia komuniti dengan infeksi bakteri di Indonesia menunjukkan seperlimanya merupakan multiple drug resistant organism (MDRO). Resistensi terhadap ciprofloxacin dan amoxicillin/clavulanate mencapai 82%. Acinetobacter baumannii merupakan bakteri yang dijumpai multiresisten terhadap antibiotik ini. Beberapa faktor seperti riwayat penggunaan antibiotik yang tidak tepat dan tanpa resep dokter di komunitas dapat menyebabkan infeksi yang multiresisten ini. Pasien dengan diabetes, penyakit jantung, kanker, gangguan ginjal, gangguan liver dan gangguan imunitas juga menjadi faktor pencetus terjadinya pneumonia komuniti dengan resistensi obat. Pada studi ini merekomendasikan cephalosporin generasi ketiga untuk pedoman lokal karena tingkat sensitivitasnya masih tinggi (67-82%)

Risiko kematian pada kasus pneumonia tergantung dari tiga faktor, yakni kondisi pasien, karakteristik bakteri, dan terapinya. Tingkat kematian meningkat secara bermakna pada pasien dengan pneumonia komuniti yang berat dan pada pasien yang tidak menunjukkan perbaikan setelah hari ke tiga. Sebagian besar pneumonia berat yang membutuhkan perawatan di rumah sakit diderita oleh pasien laki-laki dengan usia 56 tahun keatas. Gejala yang sering timbul adalah sesak napas (98%), demam (96%), batuk (74%), dan rasa tidak nyaman di dada (21%). Pasien dengan kanker dan pasien dengan imunitas yang lemah lebih rentan jatuh dalam kondisi pneumonia komuniti berat ini sehingga memerlukan observasi klinis yang ketat. Kecurigaan terhadap infeksi MDRO dapat ditelusuri ketika pasien sudah mendapatkan terapi namun tidak ada perbaikan klinis, misalnya pasien masih mengeluh sesak dan demam. Penilaian klinis 72 jam setelah pemberian antibiotik empirik sebagai indikator penilaian terintegrasi yang dapat diandalkan untuk pasien pneumonia komuniti yang dirawat di rumah sakit. Bersama pengukuran indeks keparahan pneumonia (pneumonia severity index, PSI), penialian klinis 72 jam ini membantu memprediksi luaran kematian.

Manfaat pemeriksaan kultur baik dari dahak maupun darah dalam pengobatan pneumonia di rumah sakit dibahas dalam Bab 5. Sebelum ada hasil kultur, pasien diberi antibiotik sesuai dengan pola kuman yang sering muncul sebagai penyebab pneumonia. Setelah ada hasil kultur dari individu pasien, pemberian antibiotik dapat disesuaikan dengan hasil kultur tersebut dan sensitivitasnya terhadap antibiotik. Kami evaluasi pasien saat pulang dari perawatan ke dalam 2 kategori yaitu sembuh atau meninggal. Kami menilai usia harapan hidup pasien yang pulih dari perawatan.

Pasien infeksi yang dirawat di rumah sakit pada umumnya memiliki gejala yang sudah serius sehingga memerlukan observasi dan pengobatan di ruang rawat inap yang dikaji oleh tenaga medis setiap hari. Hal yang menjadi fokus selama observasi di ruang rawat inap adalah pemilihan antibiotik yang tepat sesuai dengan hasil kultur kuman dari dahak dan darah untuk mencegah resistensi antibiotik lebih lanjut. Hasil penelitian menunjukkan bahwa pengobatan berdasarkan evaluasi kultur yang disertai uji kerentanan terhadap antibiotik memberikan manfaat dalam hal pengurangan biaya dan memperpanjang usia harapan hidup. Setelah hasil kultur kuman diserahkan kepada dokter, pasien diberi antibiotik yang sesuai dengan kondisi pasien, kuman penyebab, kekebalan antibiotik, dan biaya. Pemberian antibiotik dihentikan jika hasilnya negatif dan jika pada diri pasien terdapat perbaikan klinis. Implementasi kultur kuman pada kasus pneumonia dapat menghemat biaya sebesar US$1.067 (sekitar Rp.15 juta) per pasien dan meningkatkan harapan hidup dalam semua kasus. Kultur kuman dan hasil kepekaan terhadap antibiotik pada pasien yang dirawat di ruang intensif akan menghemat US$ 1.792 (sekitar Rp. 25 juta) per pasien dan menambah usia harapan hidup lebih tinggi daripada tanpa kultur. Menariknya, pada kelompok usia lanjut, kultur kuman membantu memberikan pilihan antibiotik yang tepat dan menghemat biaya sebesar US$3.828 (sekitar Rp.53 juta) per pasien dan juga meningkatkan harapan hidup satu tahun lebih lama daripada pasien yang tidak dievaluasi dengan kultur kuman.

Setelah mengetahui manfaat analisis kultur kuman terhadap biaya dan harapan hidup pasien sebagaimana hasil penelitian di atas, maka implementasi analisis kultur kuman di negara-negara berkembang dengan angka kejadian pneumonia yang tinggi, seperti Indonesia, harus dipertimbangkan. Sejak 2014, Indonesia telah menerapkan sistem jaminan kesehatan nasional (JKN) dalam mengelola pengeluaran terkait pembiayaan untuk pengobatan. Dengan mempertimbangkan keterbatasan saat ini dalam pemberian antibiotik berbasis biaya pada pasien pneumonia, maka kultur kuman dapat diterapkan untuk pasien pneumonia yang mendapat perawatan di rumah sakit di Indonesia. Melalui analisis kultur kuman ini maka pemberian antibiotik pada pengobatan pneumonia menjadi lebih tepat sehingga pada akhirnya dapat mengurangi biaya perawatan dan meningkatkan usia harapan hidup terutama pada kasus pasien usia lanjut, pasien dengan kondisi gangguan imun dan pasien dengan penyakit penyerta.

Bab 6 menganalisis beban biaya akibat infeksi sistemik sepsis dengan mempertimbangkan infeksi fokal termasuk pneumonia dan infeksi pasca operasi seperti IDO. Penelitian ini dilakukan secara integrasi terhadap luaran hidup dan kematian serta diproyeksikan pada sistem pembiayaan asuransi di era universal health coverage (UHC) di Indonesia. Biaya rata-rata rumah sakit yang dikeluarkan per pasien sepsis yang masih hidup dan yang meninggal masing-masing adalah US$1.011 dan US$ 1.406. Beban nasional sepsis pada 100.000 pasien diperkirakan mencapai US$130 juta. Pasien sepsis dengan infeksi multifokal dan infeksi fokal tunggal infeksi saluran pernapasan bawah diperkirakan sebagai dua peringkat teratas beban ekonomi tertinggi (US$48 juta dan US$33 juta, masing-masing, dalam 100.000 kasus). Sepsis dengan infeksi kardiovaskular diperkirakan menjamin harga nasional tertinggi yang diusulkan untuk penggantian (US$4.256).

Mempertimbangkan mortalitas dan infeksi fokal dalam penilaian beban sepsis menjadi hal yang penting karena ada perbedaan total biaya perawatan yang bermakna. Dalam konteks sumber

daya yang terbatas seperti di Indonesia, di mana sistem UHC yang baru diimplementasikan, penyediaan layanan kesehatan yang memadai memerlukan evaluasi dan perhitungan ulang paket pembayaran untuk sepsis. Lebih jauh, dalam konteks kasus sepsis dengan infeksi multifokal dan pneumonia harus dikategorikan sebagai kasus sepsis dengan beban tinggi, yang mencerminkan contoh paling jelas yang memerlukan penyesuaian standard biaya nasional untuk klaim pembayaran di layanan kesehatan sektor pemerintah dan swasta.

ACKNOWLEDGMENT

Syukur Alhamdulillahirobbil’alamin. This achievement is a great gift from Alloh SWT to complete my PhD. First of all, I would like to thank Mama Titiek Hariyati, and Papa alm. John Eddy Purba, for your sincere prayer and endless love.

Being a single son, father of three children, husband, civil servant, an organizational leader, and a clinical consultant, it would not have been possible to do a journey of PhD at three departments without the presence of many people who have never stopped giving supports and sincere prayers for my success.

I am very grateful to have dedicated promotors Prof. Maarten J. Postma and Prof. Alex W. Friedrich, and my co-promotor Dr. Jan-Willem H. Dik to supervise me being an independent and innovative researcher at the University of Groningen and the University Medical Center Groningen.

Dear respected promotor, Prof. Maarten J. Postma,

Wednesday, 20 May 2015, was the first day we met at the Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta. You gave an introductory lecture on pharmacoeconomics, afterward, with dr. Jarir (Pak Itob), we discussed a research topic of antimicrobial stewardship for my PhD project. I would like to express my deepest gratitude to you for giving me an opportunity as a PhD student at the Unit of Pharmacotherapy, Pharmacoepidemiology, and Pharmacoeconomics, and at the Department of Health Sciences, UMCG. When I came to you for the first meeting, I brought a 4-page proposal representing my ambitious work. After the meeting, I realized that I needed to be wise and simply to see what was essential to be implemented for my country with a resource-limited setting. I remember that you had a great dream of your Indonesian students someday successfully having roles giving benefits to the community. During my PhD trajectory, you trained me on how science works and how to be wise in respecting life. You were always there in the time when I most needed you despite your busy schedule. You are an awesome teacher showing me how to turn complicated concepts into a lot easier and simpler ones. Every meeting, I always got clear explanations from you and afterward felt reassured. When I did not understand, you used your whiteboard or took a paper to make a simulation. When I needed 15 minutes, you gave me 30-45 minutes. I enjoyed working with an open-minded person like you. You gave freedom of thought so that a series of research topics could be packaged in something meaningful.

The invaluable experience was learning how to publish in Q1 journals. We have four published articles in Q1 journals with minor revisions. By this, you taught me how to manage PhD time, and then I could make it complete three years ten months with a total of six publications. Also, I would like to acknowledge you for your willingness to become an adjunct professor and giving some lectures at our campus of Nederlandsch Indishe Artsenschool (NIAS), at the Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Airlangga, Indonesia, in 2018-2019. You showed me the awesome relationship between a supervisor and a promovendus. I

am grateful that you taught me how to think comprehensively, logically, critically, not only in the academic field but also at a more personal level, including how to manage time for relaxation. You are such a multitalented teacher and thank you for playing squash and swimming with me. Absolutely, it was the valuable moments, and I realize how lucky I was to work with you. For all of this, I would like to send my gratitude and looking forward to seeing you in the future.

Dear respected promotor, Prof. Alex W. Friedrich,

We met for the first time at an online meeting via Webex on Tuesday, 20 October 2015. I would like to express my deepest gratitude to you for giving me an opportunity as a PhD at the Department of Medical Microbiology, UMCG. You have inspired me a lot with your passion for conducting research and making a great collaboration. You always supported me to have collaboration research and have some courses related to pharmacoeconomics, antimicrobial stewardship, and infection prevention. I would like to thank you for your time to supervise me and having constructive discussions. You always replied to my emails even you have busy schedules. When you open your working desktop, I was honored to see the PowerPoint I presented at the first meeting. With this, you made me motivated to do my PhD on the schedule. From you, I have learnt much about clinical microbiology, antimicrobial resistance, and also how to make a vast network.

Dear respected co-promotor, Jan-Willem Hendrik Dik

On Wednesday, 4 May 2016, after I had a meeting with the international office staff, I came to you at the Department of Medical Microbiology (MMB), UMCG, to start my PhD journey. You showed my first place at the office 2.056 deBrug with great friends: Erley, Maria, Mart, Rendy, Ana Carolina, Huub, Ilona, and Jelte. At the moment, you were busy finalizing your thesis. After you achieved your PhD, you have a career in Amsterdam. Even though you were not in Groningen, you always made a regular monthly meeting with me at UMCG to discuss my PhD progress, to clarify the data, to validate the research input, and to see any possible solutions for the difficulties during the work. I felt how lucky I was to work with you, who could make a bridge between pharmacoeconomics and microbiology. I would like to express my deepest gratitude to you for your supports, time, hope, countless discussions, and wise advice throughout all the phases of my PhD.

I would like to acknowledge the reading committee: Prof. Kuntaman, dr., MS., Sp.MK(K), Prof. B. Wilffert, and Prof. J.C. Wilschut, for willing to read and assess this thesis, and also many thanks for considering me continuing the next steps to have a defense.

To my friendly paranymphs, Erley and Rifqi. Thank you very much for your contributions to prepare all of the defense-related issues. You are so very organized people to make my defense memorable. I highly appreciate it. Also, I would like to thank Mas Joko and Mas Deni for helping me and the paranymphs to make my big day held successfully.

I would especially like to acknowledge the Directorate General of Resources for Science, Technology and Higher Education (DIKTI), Ministry of Research, Technology, and Higher Education, Republic of Indonesia, for the financial support. To Prof. dr. Ali Ghufron Mukti, I would like to thank you for your supports and prayer. To BPPLN DIKTI staff: alm. Bu Fine Resyalia, Bu Anis Apriliawati, Septian Maryanto, Pak Sabar, and Pak Pujianto, I would like to thank you for assisting and relieving me from all administration hurdles, and for your constant support during my PhD.

I would like to thank all colleagues and friends from the Unit of Global Health, Department of Health Sciences: Simon van der Pol, Simon van der Schans, Abrham Wondimu Dagne, Mb. Afifah Machlaurin, Tanja Fens, Jurjen van der Schans, Mas M Rifqi Rokhman, Mb. Ajeng Viska Icanervilia, Mas Angga Prawira Kautsar, Kang Deni Iskandar, and Jap for friendship, cooperation, research collaboration, and all technical and non-technical supports. Working at office 615 was fantastic. It was a very convenient office to talk, to discuss, and to share knowledge. I felt welcome anytime, so I had a good time to finalize my thesis. We will certainly keep in touch. I would like to send a special word of thankfulness to Simon van der Pol for organizing ISPOR students, solving non-academic matters, and your kind advice about the way to assess life-expectancy in cost-effectiveness analyses.

Also, I would like to thank all people in the Department of Health Sciences: Janneke, Obbe, Prof. Menno, Prof. Sandra, Femke, Patricia, Lindy, Matheus, Joke, Nicole, Loes, Alex, Pepijn, Haltze, Jitse, Andrea, Jaap, Kor Brongers, Gabriel, Harriet, Tialda, Jelle, Janne, Regien, Yuwei, Lotte, Siobhan, Henk-Jan, Lisette, Carin, Janine, Joyce. The most exciting thing was we have fruit breaks, outings, drinks and a small birthday party for everyone. The research topic in this department was very diverse and dynamic. I also would like to thank Josue Almansa Ortiz for checking the statistic results. A huge thank you to the secretaries: Janneke, Obbe, Rieta, and Hanneke for assisting and relieving me from all administration hurdles. To Mb. Hana, thank you for sharing stories, jokes, and tips for staying in Holland, always be healthy and take care.

To my kindly MMB friends: Erley, Maria, Mart, Rendy, Ana Carolina, Huub, Ilona, Natacha, Christina, Giuseppe, Jelte, Leonard, Hayley, Nilay, Christian, Matthijs, Henry, Linda, Silvia, Paola, Prof. Bhanu, Ieneke, Mathilde, Sigrid, Monika, Caroline, Judith, Henk, and Ank, I would like to thank you for having lunch together, celebrating a new publication, and sharing happiness during my years of working at UMCG. We will certainly keep in touch. A special thanks to Linda, Erley, Maria, Ana, Christina, and Christian, you always motivate and support me during my PhD. I am thankful for your time to talk and discuss everything with you. Also, to Christian, thank you for involving in the SSI study and helping me to understand using R. To Henk and Ank, I would like to express my acknowledgment for all of your helps to handle administration issues and for sharing non-academic matters. I wish you all the best in life and looking forward to seeing you in the future.

I would like to thank all colleagues and friends from the Unit of Pharmacotherapy, Pharmacoepidemiology, and Pharmacoeconomics: Prof. Bob, Prof. Elko, Jannie, Abrham, Mb. Ira Sianturi, Tanja, Mas Fajri, Mas Ivan, Mas Akbar, Christian, Jurjen, Eva, Taichi, Pepijn, Mb. Neily, Pieter, Ury, Mb. Tia, Mb. Lusi, Qi, Mas Riswandy, Mas Didik, Mb. Sofa, Mb. Doti, Aizati, Atiqul, and Bert. You made me feel welcome in working at the office. Thank you for lunch together and sharing knowledge. We will certainly keep in touch. A special thank you to the secretary, Jannie Schoonveld, for all arrangements you had made for me.

To my respected teacher from Universitas Gadjah Mada: alm Prof. Iwan Dwiprahasto, Prof. Mustofa, dr. Indwiani Astuti, Bu Erna, and Pak Jarir, I would like to express an enormous thank you for your kindness and attention. To dr. Jarir, you were my favorite teacher from Yogyakarta. I cannot show how much my gratitude is with your attention giving from I did my master up to now I did my PhD. I am very grateful to have a teacher like you, so smart and a very nice person. You taught me pharmacoeconomics and also introduced me to Prof. Postma. Again, thank you very much for your kindness and all your supports.

Dear Ury, thank you very much for your everlasting friendship and togetherness. I have known you since we did a Master program in Yogyakarta. We had togetherness moments from doing presentations, having discussions, and working in the lab. Besides academic matters, we had plenty of experiences when we stayed in Yogyakarta. We had lunch, dinner, and time for swimming, and traveling. Afterward, you continued your PhD at RuG, and then you introduced me to Prof. Postma. Although your thesis had a different topic from mine, we conducted a nice study, and then finally, we had one awesome paper published in a Q1 journal. I wish you a successful person and always welcome when you visit Surabaya.

Dear Tim Zwaagstra and Renzo Tuinsma, thank you for your kindness and guidance during my PhD period. You made links for research collaboration between Groningen and Surabaya. I believe we will still keep in touch to implement the agreement for student and staff exchanges.

My special word of thankfulness goes to Mas Joko for everlasting friendship and togetherness. I am grateful to know you. We met on the bus going to the Introductory PhD event. To me, you are a nice brother and very helpful - no rejections from you when I need help. I would like to express my gratitude to you for taking care of my children and my mother when I went abroad. Also, I would say many thanks for jamaah sholat, togetherness involving in organizations, lunch together, sharing your knowledge, time, patience, prayers, and all support that I can not mention one by one. Also, to me, you are so cool. You have five children, and you will have finalized your PhD this year. I wish you a successful PhD.

To the awesome neighbors of BBBO families: Mas Joko & Mb Uci’s family, Mas Afif, Mas Ivan & Mb Dita’s family, Mas Amak & Mb. Putri’s family, Mb. Icha & Mas Erdi’s family, Mas Agung & Mb Inna’s family, Mas Riswandy & Mb Cici’s family, Mas Adyatmika & Mb Nuri’s family, Mas Romy’s family, Mas Angga, Kang Deni, Mas Sem, Mb. Sarah, Mb. Zamrotul Izzah, Annas, Bayan, Malik, Mas Haris, Mas Agung, Mb. Tania, Mb. Defa, Mb. Valina and Mas Aldo, Mb. Btari, and Mb. Afi for warmest welcome and togetherness for sharing the happiness. I felt much at home because of the cozy atmosphere and the lovely moments of togetherness with all of you and your children. Someday, we could make silaturahim and BBQ again with our children in Indonesia, inshaAlloh. Also, Mas Alfian, thank you for being part of Nieuwe Ebbingestraat 59b, and playing with Ahsan and Annisa. I wish you successful people and see you in the future in Surabaya.

In particular, for my friends who involved in the Indonesia student association (Perhimpunan Pelajar Indonesia - PPI) Groningen 2016-2017, especially for those participating in the Health Division: Mb. Marina Ika Irianti, dr. Didin, dr. Salva, Mas Joko, Mas Didik, Ury, Mas Alfian, Mas Riswandy, Mas Akbar, Mb. Sofa, Mas Ivan, Mb. Anggreni, Mas Frans Simanjuntak, Mb. Citra, Mb. Amirah, Mas Yudi, Mas Ananditya (from the University of Wageningen), Mas Lukman, Mas Mikhael Manurung (from Leiden University Medical Center - LUMC), as a coordinator for the division, I am very thankful that we together successfully developed a proposal of some inputs for the new Indonesian Universal Health Coverage (UHC) implementation. The proposal was granted by the President of PPI Groningen (Mas Amak) and the coordinator of the division for strategic issues and scientific study (Mb. Titissari). Also, I would like to thank Prof. Hartono, Prof. Ari Probandari, and dr. Brian Wasita for participating in the Indonesian Science Café 2 at UMCG, where the meeting focused on the health issues in the UHC era.

I am delighted to have an opportunity to be a leader of the organization of deGromiest from 2017 to 2018. I would like to thank all deGromiest staff: Mas Joko, Mb. Inna, Mb. Nuril, Mas Lathif. To Kinderen deGromiest staff: Mb. Uchi, Mb. Amalina, Bu Rini, Mb. Monik, Mb. Irma, Mb. Nadia, Mb. Sannya, Mb. Anisah, Mb. Arum, Mb. Ghina, and Retno, I would like to thank you very much for being teachers and making creativities for kids that they had moments for interaction with each other. Of course, they enjoyed learning Islam and Indonesian culture in Groningen. To Mas Rai, Mas Ghozi, Mas Afif, I would like to thank you for coordinating the weekly meeting for tadarus keliling and kultum – Darlingku. To Mas Jabbar, Mas Lathif, dr. Didin, Mas Akbar, and Mas. Habibie, I would like to thank you very much for coordinating Sholat Jumat. To Mb. Yosi, Mb. Monik, Mas Fajar, Mas Amak, Mas Lana, Mas Yudi, Mb. Sofa, Mas Azkario, and dr, Didin, I would like to thank you for your supports to maintain the Buletin deGromiest I and II by providing update news and inspiring stories with an attractive design. To Mas Yudi and Mas Azkario, I would like to thank you for handling the website that gives fruitful information to the public. To Mas Agung, Mas Lathif, Mas Panji, and Mas Joko, I would like to thank you for coordinating the events of Iedul Fitri, Halal bi Halal, and Sholat Iedul Adha). To Mas Azka M, I would like to thank you for organizing deGromiest visiting SGB Utrecht for KALAMI event. To Mas Ghozi, Mas Joko, Mas Haris, and Mas Ivan, I would

like to thank you for coordinating deGromiest to have an initial draft of AD/ART. To Mas Ega, I would like to say a special thank you for being a coordinator for Hajj together with seven families and four kids. In addition, I would like to thank Ust. Agus Suranto and Pak Said from EuroMuslim Amsterdam for teaching us to do Umroh and Hajj and guiding during in Mecca and Madinah. Also, many thanks to Ust Cholis and Ust. Eko for sharing knowledge and experience.

To other Indonesian friends: Pak Tatang & Bu Rohmah, Mas Auliya & Mb. Neily, Mb. Nur Qomariyah, Mb. Ira, Mas Ronny Prabowo, Mb. Erna, Mas Azis & Mb. Amalina, Mas Bino & Mb. Susan, Mas Rully & Mb. Intan, Mas Kuswanto & Mb. Fitria, Mas Hegar & Mb. Anisa, Bhimo, Deka, dr. Fundhy, dr. Mahendra, Mas Ristiono & Mb. Afifah, Mas Yopi & Mb. Dewi, dr. Budi Darmawan & Mb. Nonny, Mas Adhi, Mas Azzam & Mb. Ghina, Ust. Naufal & Mb. Moza, Mas Ali Syari’ati & Mb. Liany, Mas Harry & Mb. Fiska, Mas Dimas & Mb. Anya, Mas Ali Abdurrahman & Mb. Yosi, Mas Fean, Mas Tri Efriadi, Mb. Masyitha, Mas Aunurrofik, Mas Prayoga, Mas Yusran, Mas Zaki & Mb. Nadia, Ust. Fika & Mb. Nisak, Mb. Pretty, Mas Gerry, Mb. Endira, Mas Zaenal & Mb. Ayu, Pak Asmoro & Bu Rini, Mas Cholis & Mb. Jean, Mb. Inda & Mas Feri, Mas Romy & Mb. Arlina, Mas Kadek & Mb. Laksmi, Mas Habibie & Mb. Ma’wa, Mas Krisna & Mb. Icha, Mas Adityo, Mas Mega & Mb. Irma, Mas Lathief & Mb. Septi, Mas Lana & Mb. Arum, Mas Azka Mujib & Mb. Aidina, Mas Surya & Mb. Yasaroh, Mas Ade & Mb. Cika, Mas Akbar & Mb. Andis, and to all Indonesian seniors: Uwak Asiyah, Om Meno and Bachtiar in Delfzijl; Om Archi and Tante Mary in Robijnstraat; Budhe Arie and Om Herman in Hoogezand; Budhe Nunung, Pakdhe Said and Vincent in Bankastraat; Mb. Hellen’s family, Bu Elvira’s family, Bu Nur’s family, Bu Roos’ family, Mb. Ade & Mas Joesoef, Mb. Siti’s family, Mb. Atika and Salim’s family, Mb. Eny’s family, Mb. Amalia’s family. Mb. Sindhu’s family, Mb. Ria’s family, Mb. Rani’s family, and Om Dedi’s family in Amsterdam, I would like to many thanks for warm welcome and making Netherlands more special to me. I felt at home having a huge family that I could find big supports and help at any time.

To all co-authors: Maarten J. Postma, Alex W. Friedrich, Jan-Willem Dik, Nina Mariana, Gestina Aliska, Sonny Hadi Wijaya, Riyanti Retno Wulandari, Usman Hadi, Hamzah, Cahyo Wibisono Nugroho Jurjen van der Schans, Didik Setiawan, Erik Bathoorn, Christian F Luz, BTF van der Gun, Purwantyastuti, Armen Muchtar, Laksmi Wulandari, Alfian Nur Rosyid, Priyo Budi Purwono, Tjip S van der Werf, Annette d’Arqom, and my hard-working students: Rahmat Sayyid Zharfan, and Ahmad Lukman Hakim, I would like to many thanks for your thoughtful guidance on my papers and the great collaborations. Moreover, the deepest gratitude to Prof. Tjip S van der Werf for countless constructive discussions and sharing your exciting journey from Indonesia. A special word of thankfulness to Pak Hendro Suprayogi and Bu Rosita Prananingtias, who managed all the data collections. Also, I would like to express many thanks to everyone involved in my study from Prof. Dr. Sulianti Saroso Hospital, Dr. Soetomo General Academic Hospital in Surabaya, Universitas Airlangga Hospital, Dr. M. Djamil Hospital. I hope that all what we did will have plenty of fruitful contributions and benefits to the community.

To people working at the Drug and Therapeutics Committee (Komite Farmasi dan Terapi) Dr. Soetomo Hospital: Dr. Hamzah, dr. Fendik, Prof. Kuntaman, apt. Ali, apt. Yahya, apt. Woro, Bu Hermin, Bu Nur, Pak Yuwono, and Mb. Nia, I would like to thank all of you for supporting me in doing research for my PhD. I would like to appreciate all of you. Although I was doing a study abroad, we could stay in touch. Then, we successfully developed a national guideline for antimicrobial stewardship implementation in the hospital.

To WHO secretariat and consultants who involved in the technical expert working on essential medicine list (EML) for surgical antibiotic prophylaxis: Prof. Benedetta Allegranzi, Dr. Peter Bischoff, Mr. Carl Coleman, Jerome Delauzun, Dr. Benedikt Huttner, Dr. Stijn de Jonge, Dr. Nicola Margrini, and Mr. Paul Roger, Pilar Ramin-Prado (WHO Pan American Office - PAHO), Prof. Dale W. Bratzler, Prof. Hanan Balkhy, Prof. Adrian Brink, Dr. Adrian Brink, Dr. Nizam Damani, Prof. E. Patchen Dellinger, Dr. Mazen Ferwana, Prof. Daniela Filipescu, Prof. Lindsay Grayson, Prof. Stephan Harbarth, Dr. Joost Hopman, Prof. Shaheen Mehtar, Prof. Bisola Onajin Obembe, Dr. Leonardo Pagani, Dr. Giampietro Pellizer, Prof. Evelina Tacconelli, I would like to express my gratitude to have a meeting with all of you in Geneva. Afterward, we had dinner, and a moment to share all of your experiences handling antimicrobial resistance.

I would like to thank all my respected teachers, my seniors, my colleagues from Universitas Airlangga, especially for all people at the Department of Pharmacology and Therapy, Faculty of Medicine, UNAIR: Prof. Achmad Basori, dr. Roostantia, dr. alm Moh Teguh Wahjudi, dr. Haryanto Husein, drg. Indriyatni Uno, dr. Rahardjo, dr. Ramadhani, dr. alm. Sunarni Zakaria, apt. Nuraini Farida, dr. Arifa Mustika, dr. Bambang Hermanto, dr. Widayat, dr. Endang Isbandiyati, apt. Abdul Mughni, dr. Nurmawati Fatimah, dr. Ratna Sofaria Munir, dr. Maftuchah Rochmanti, dr. Sri, dr. M. Fathul Qorib, dr. Yuani Setiawati, dr. Danti Nur Indiastuti, dr. Nurina Hasanatuludhiyah, dr. Annette d’Arqom, dr. Maulana Antiyan Empitu, dr. Firas Farisi Alkaff, Bu Nana, Bu Tari, Pak Didik, Bu Erti, Pak Joko, Pak Udin, Pak Bibit, for your supports and prayers. Also, I would like to express my deepest gratitude to all of you for your understanding of allowing me to have school in Yogyakarta, Jakarta, and Groningen. I wish you all the best in all of our steps forward. To the Rector of my home university: Prof. Nasih, the Dean: Prof. Dr. Sutojo, dr., Sp.U(K), and other respected teachers: Prof. Djoko Santoso, Sp.PD, Prof. Dr. David S. Perdanakusuma, dr., Sp.BP-RE(K), Prof. Dr. Budi Santoso, dr., Sp.OG (K), Prof. Dr. Ni Made, dr., MS., Sp.MK(K), and to all my respected teachers, I would like to thank you for your supports and consideration. Also, to all people involving my success during my PhD period: Bu Rini, Pak Fadli, Bu Nurul, Mb. Endah, Mb. Ella, Bu Peni, Bu Ani, Bu Dyah, and Bu Triana, I would like to thank you for your supports and helps so that I did my PhD successfully.

I would like to express my deepest gratitude to my beloved father, Papa alm. John Eddy Purba, and my mother, Mama Titiek Hariyati for your endless prayer, love, and encouragement. To Papa, I apologize for not being on your side when you had a difficult time. When I flew to Netherland to start my PhD in May 2016, you looked strong and healthy. Four months later, you had experienced with cancer, and you did not allow me to know your condition since you considered me focusing on my study. Afterward, I had news that you fell into a serious critical state and had the last breathing, but I was still in Groningen. I did not expect that the warmest hug at the airport in May 2016 was the last hug from you. I wish Alloh loves you and brings us together in His heaven. Untuk Mama, terima kasih atas kasih sayang yang tidak pernah putus, doa yang sungguh-sungguh, keikhlasan dan pengertiannya yang luar biasa, serta semua dukungan yang diberikan kepada kami sekeluarga. Kelembutan tanganmu membuat Khairul yang kecil dulu telah tumbuh menjadi seseorang yang haus akan ilmu. Mohon maaf jika selama ini saya sering jauh secara fisik. Terima kasih telah merawat Papa hingga Papa sedo. Terima kasih juga telah memberi perhatian kasih sayang kepada cucu. Patut mencontoh Mama yang sabar menghadapi realita, dan tidak pernah putus asa dalam berdoa. Sekali lagi terima kasih banyak atas semuanya. Semoga Mama selalu sehat, mendapat ridho dan keberkahan dari Alloh SWT. Untuk Ibu Unsidah, terima kasih atas doa, kesabaran, dan dukungannya semoga Ibu selalu sehat dan mendapat ridho dan keberkahan dari Alloh SWT.

Untuk kakakku tercinta, Mb. Inna, Mas Erman, Mb. Rini, Mas Yanto, Mb. Prapti, Mas Slamet, Mb. Yani, Mas Nur, Mb. Wachid, Mb. Pipit, dan Mas Bhakti; adikku tercinta, Mifta dan Helga, dan juga keponakanku: Mahren, Andre, Tiara, Vania, Akbar, Arif, Ahmad, Latif, and Ishom, terima kasih banyak atas doa, tenaga, waktu, pikiran, keikhlasan, kesabaran, dan dukungannya yang diberikan kepada saya dan keluarga saya. Terima kasih sebesar-besarnya telah merawat Papa di rumah, rumah sakit, dan mendampingi saat-saat sulitnya. Terima kasih juga menjaga Mama, Ibu, Retno, Annisa and Ahsan selama saya mengambil studi di Jogja, Jakarta, dan Groningen, serta mengajak jalan-jalan Annisa dan Ahsan, menghibur dan membawa kehangatan serta kebersamaan keluarga. Semoga Alloh SWT memberikan limpahan kasih sayang, keberkahan, kesehatan dan kesuksesan untuk kita semua.

A very special appreciation and many great thanks go to my dearest wife, Retno, for your endless love, patience, thoughts, sincere prayers, and time to be part of my life. Also, many thanks for understanding my complicated rhythms and always being on my side during my difficult time. I am thankful for all of your kindness and smiles that treated my fatigue. It was very often to leave you since I had to have higher education qualifications for my further career. It was not easy for you to take care of our children by yourself in Surabaya for six years: two years when I did a master in Yogyakarta, three years when I did a specialization program in Jakarta, and one year when I did my first year of PhD in Groningen. Absolutely, your presence made me motivated to do PhD. Thank you so much for hearing me at any time I need. Thanks for leaving your job and choosing togetherness with me and with our children: Annisa, Ahsan, and Mafaza, to live in the

place with an extreme climate, freezing in the winter (we believe that there is nothing above Groningen); and in the summer, we had almost 19 hours fasting in the Month of Ramadhan. After a year in Groningen, surprisingly, you made my life colorful to have a newborn, baby Mafaza, in Groningen. When you were going to deliver, I brought you with all things of your and baby’s needs to UMCG by bike in the morning. Of course, it was such an amazing and unforgettable moment. Unbelievable, we have made many stories that can tell our children someday. To my children: Annisa, Ahsan, and Mafaza, many thanks for giving supports and endless sincere prayer to your parents. To Annisa and Ahsan, you successfully managed your study at Dutch basis school in the morning and Netherland-Indonesia elementary school in the evening. To all of my children, I wish all of you a successful person with an excellent attitude. We wish Alloh gives His Rahmat and Blessing to all of us and keeps our hearts to everlasting love.

I realize that a lot of people involving in my success. To anyone who is not mentioned in this part, I would like to express my deepest gratitude, and I wish you all the best.

Thank you! Bedankt! Terima Kasih! Groningen, February 2020 Abdul Khairul Rizki Purba

CURRICULUM VITAE

Abdul Khairul Rizki Purba, dr., M.Sc., Sp.FK-Clin. Pharmacologist Nationality: Indonesian

Email: khairul_purba@fk.unair.ac.id / a.k.r.purba@umcg.nl

Higher education Year

Medical Doctor (dr.) Faculty of Medicine, Universitas Airlangga, Indonesia

Sep 2001 – Dec 2007 M.Sc in Pharmacology

and Therapy

Faculty of Medicine, Universitas Gadjah Mada, Indonesia

Sep 2010 – Jun 2012 Sp.FK – Clinical

pharmacologist

Universitas Indonesia, Indonesia

(Ciptomangunkusumo, Harapan Kita, and Persahabatan Hospitals)

Jul 2012 – Jun 2015

Non-degree Center for Clinical and Translational Research, Faculty of Medicine, Kyushu University, Japan

Sep – Oct 2015 PhD in Medical Sciences University Medical Center Groningen,

University of Groningen, the Netherlands

May 2016 – Feb 2020

Professional memberships

Indonesian Medical Doctor Association (IDI) Indonesian Pharmacologist Association (IKAFI)

Indonesian Clinical Pharmacologist Association (PERDAFKI)

European Society Clinical Microbiology and Infectious Disease (ESCMID-Europe) International society for Pharmacoeconomics and outcome research (ISPOR-Europe)

Courses and scientific meetings Place Year

ISPOR Europe 2019 Copenhagen, Denmark 2019 Understanding survival modelling with application to

health technology assessments (HTA)

Copenhagen, Denmark 2019 Bayesian network meta-analysis –

Cochrane-Netherlands

Utrecht, the Netherlands 2019 Fitting the structure to the task: Choosing the right

dynamic simulation model to inform decisions about health care

Copenhagen, Denmark 2019

Value of information analyses Copenhagen, Denmark 2019 Mapping to estimate utility values from non-preference

based outcome measures

Copenhagen, Denmark 2019

Courses and scientific meetings Place Year Pharmacokinetics and pharmacodynamics of

antibiotics: optimal-dose achievement Rotterdam, the Netherlands 2019 Advance course of Statistical Methods in Economic

Evaluation for health technology assessments (HTA)

York University, UK 2019 Foundation course of Statistical Methods in Economic

Evaluation for health technology assessments (HTA)

York University, UK 2019 Use of propensity scores in observational studies of

treatment effects

Copenhagen, Denmark 2019 Advanced methods for addressing selection bias in

real-world effectiveness and cost-effectiveness studies Copenhagen, Denmark 2019 Writing a thesis using word University of Groningen, the

Netherlands 2018 ISPOR Europe 2018 Barcelona, Spain 2018 Pharmacoeconomic Modelling-Application Barcelona, Spain 2018 National Seminar of Health Technology Assessment in

Drug Use (as a speaker)

Universitas Airlangga, Indonesia

2018 1st International Scientific Meeting on Clinical

Microbiology and Infectious Disease (as a speaker) Universitas Airlangga, Indonesia 2018 Pharmacokinetics and pharmacodynamics of

antibiotics (as a speaker) Indonesian Society of Medical Microbiology and Infectious Disease

2018

Bayesian Analysis for HTA – Overview and Applications ISPOR-Barcelona, Spain 2018 Advanced Methods for Cost-Effectiveness Analysis:

Meeting Decision Makers’ Requirements

York University, UK 2018 Modelling in Health Technology Assessment UMCG, the Netherlands 2018 Phase II and III clinical trials GSMS, UMCG, the Netherlands 2018 Antimicrobial stewardship: principles and practice Istanbul, Turkey 2017 Systematic reviews and meta-analysis GSMS, UMCG, the Netherlands 2018 R statistics GSMS, UMCG, the Netherlands 2018 Medical statistics GSMS, UMCG, the Netherlands 2018 Excel Advanced RuG, the Netherlands 2017 Advanced in genetic epidemiology GSMS, UMCG, the Netherlands 2017 Epidemiology and applied statistics GSMS, UMCG, the Netherlands 2017 Advanced Pharmaco-epidemiology GSMS, UMCG, the Netherlands 2017

Courses and scientific meetings Place Year Good research practice: GCP/GLP GSMS, UMCG, the Netherlands 2017 Managing your PhD GSMS, UMCG, the Netherlands 2017 Ethics of Research and Scientific Integrity for

Researchers

GSMS, UMCG, the Netherlands 2017 Pharmacoeconomics course GSMS, UMCG, the Netherlands 2016 Modelling in Health Technology Assessment GSMS, UMCG, the Netherlands 2016 Pubmed and Embase search strategy for reviews CMB, UMCG, the Netherlands 2016 RefWorks CMB, UMCG, the Netherlands 2016 Pharmacovigilance and Monitoring of side effects in

hospitals

World Health Organization (WHO) and BPOM

2015 Sosialisasi Gerakan Masyarakat Cerdas Menggunaan

Obat (GeMa CerMat)

Minstry of Health, Republic of Indonesia

2015 Essential pain management Indonesian Medical Doctor

Association 2014 TLC fingerprint Biofarmaka, IPB Bogor 2014 Bioavailability and bioequivalence (BaBe) Universitas Indonesia 2014 Pharmacokinetics & pharmacodynamics modeling:

concept and application of antibiotic use in infection management

UNAIR and Erasmus Medical Center, Rotterdam

2014

Course on publishing in international journals Universitas Airlangga and

Erasmus University 2013 Western blot Cancer chemoprevention

research center, UGM

2012 Course and Workshop Good Clinical Practice Research Hospital for

Tropical-Infectious Disease, IASMED and Universitas Airlangga

2012

Workshop on Introduction to Clinical Research Institute of Tropical Medicine, Antwerp, Belgium

2012 Frontier in Biomedical Science: From Gene to

Applications

Universitas Gadjah Mada 2011 Immunopharmacology Indonesian Pharmacologist

Association

2010 TOT tutor & instructor Problem Based Learning Universitas Airlangga 2010 Applied Approach plus Universitas Airlangga 2009

Technology of immunization for disease of infectious

and cancer Universitas Airlangga & Dutch foundation 2009 Neonates Life Support Hospital of DR. Soetomo,

Surabaya 2008 Advanced Cardiac Life Support Indonesian Heart Association 2008 Microsoft Office Community based Training

and Learning Center 2008 Training for occupational health Yogyakarta 2008 Primary Trauma Care Management World Federation of Societies

of Anaesthesiologists 2005 Integrated Management in Cancer PKTP 2004

LIST OF PUBLICATIONS

Purba AKR, Setiawan D, Bathoorn E, Postma MJ, Dik JW, Friedrich AW. Prevention of surgical site infections: A systematic review of cost analyses in the use of prophylactic antibiotics.

Frontiers in Pharmacology, 2018; 9(776): 1-18. doi: 10.3389/fphar.2018.00776. https://www.ncbi.

nlm.nih.gov/pmc/articles/PMC6060435/.

Purba AK, Ascobat P, Muchtar A, Wulandari L, Rosyid AN, Purwono PB, van der Werf TS, Friedrich AW, Postma MJ. Multidrug-resistant infections among hospitalized adults with community-acquired pneumonia in an Indonesian tertiary referral hospital. Infect Drug Resist, 2019(12): 3663-3675. doi: 10.2174/IDR.S217842. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6883944/

Purba AKR, Ascobat P, Muchtar A, Wulandari L, Dik JW, d’Arqom A, Postma MJ. Cost-effectiveness of culture-based versus empirical antibiotic treatment for hospitalized adults with community-acquired pneumonia in Indonesia: A real-world patient-database study.

Clinicoecon Outcomes Res, 2019(11): 729-739. doi: 10.2147/CEOR.S224619. https://www.ncbi.

nlm.nih.gov/pmc/articles/PMC6890194/

Zarfan RS, Hakim AL, Purba AKR, Sulistiawan SS, Soemedi BP. Albumin, Leukosit, and Protombin as Predictors of Sepsis Mortality among Adult Patients in Soetomo General Hospital, Surabaya, Indonesia. Indonesian Journal of Anaesthesiology and Reanimation, 2019; 1(1): 8-12. doi: 10.20473/ijar.V1I12019.8-12. https://e-journal.unair.ac.id/IJAR/article/view/12705 Arifin B, Probandari A, Purba AKR, Perwitasari DA, Schuiling-Veninga CCM, Atthobari J, Krabbe PFM, Postma MJ. ‘Diabetes is a gift from God’ a qualitative study coping with diabetes distress by Indonesian outpatients. Qual Life Res, 2020: 29(1): 109-125. doi:10.1007/s11136-019-02299-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962255/.

Purba AKR, Mariana N, Aliska G, et al. The burden and costs of sepsis and reimbursement of its treatment in a developing country: An observational study on focal infections in Indonesia [published online ahead of print, 2020 May 5]. Int J Infect Dis. 2020;S1201-9712(20)30294-0. doi:10.1016/j.ijid.2020.04.075. https://pubmed.ncbi.nlm.nih.gov/32387377/

Purba AKR, Mariana N, Aliska G, Wulandari RR, Wijaya SH, Postma MJ. National burden of sepsis in Indonesia: An analysis based on focal infections. Value in health, 2019(22): Supplement 3, page S655. https://doi.org/10.1016/j.jval.2019.09.1339

A.K.R. Purba, P. Purwantyastuti, A. Muchtar, L. Wulandari, A. d’Arqom, J.W.H. Dik, M.J. Postma, PIN131 Cost-effectiveness of culture-based versus empirical antibiotic treatment for hospitalized adults with community-acquired pneumonia in indonesia: a real-world patient-database study, Value in Health, Vol. 22, Supplement 3, 2019, Page S660, https://doi. org/10.1016/j.jval.2019.09.1372.

Purba AKR. Resistensi obat pada kasus pneumonia (Drug resistance among pneumonia cases). December 2019. UNAIR news. http://news.unair.ac.id/2019/12/19/resistensi-obat-pada-kasus-pneumonia/.

Purba AKR. Manfaat pemeriksaan kultur kuman pada pasien pneumonia (The benefits of specimen culture among pneumonia patients). UNAIR news. December 2019. http://news.