University of Groningen

Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic treatmentsPurba, Abdul

DOI:10.33612/diss.128518764

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Citation for published version (APA):Purba, A. (2020). Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotictreatments: Focus on surgical site infection and hospitalized community-acquired pneumonia. University ofGroningen. https://doi.org/10.33612/diss.128518764

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https://doi.org/10.33612/diss.128518764https://research.rug.nl/en/publications/pharmacoeconomics-of-prophylactic-empirical-and-diagnosticbased-antibiotic-treatments(41164690-43a5-4e03-9ebd-64663e40c461).htmlhttps://doi.org/10.33612/diss.128518764

163

Addendum

SummarySamenvattingRingkasanAcknowledgmentsCurriculum VitaeList of publicationsBiography

164

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

Addendum

165

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,

Summary

166

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

Addendum

167

cases, reflecting the clearest examples that require national price adjustments for the replacement

of private and public health services.

Summary

168

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 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

Addendum

169

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

Samenvatting

170

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

Addendum

171

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.

Samenvatting

172

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

Addendum

173

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.

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174

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

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175

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.

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176

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

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177

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.

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178

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.

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179

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.

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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

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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.

Acknowledgement

182

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.

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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

Acknowledgement

184

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

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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 membershipsIndonesian 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

Curriculum Vitae

186

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

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187

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

Curriculum Vitae

188

Courses and scientific meetings Place Year

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

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189

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.unair.ac.id/2019/12/19/manfaat-pemeriksaan-kultur-kuman-pada-pasien-pneumonia/

List of Publications

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BIOGRAPHY

Abdul Khairul Rizki Purba was born on February 22nd, 1984, in

Surabaya, Indonesia. He obtained his Medical Doctor (MD) or a

title of “dokter” in 2007 from the Faculty of Medicine, Universitas

Airlangga (formerly named Nederlandsch Indishe Artsenschool),

with an internship program at Dr. Soetomo General and Academic

Hospital, Surabaya. After graduation, he joined the Hospital of

Petrokimia in Gresik as a physician in the Department of Emergency.

In December 2008, he went back to his almamater of Faculty of

Medicine, Universitas Airlangga, as a lecturer at the Department

of Pharmacology and Therapy. In 2010, he started his Master at

the Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, and

finished it cum laude with research in drug-drug interactions in

cancer treatments under supervisors Prof. Dr. Mustofa, Apt and Dr. Med. Indwiani Astuti, dr. After

graduation from his Master, he wrote a book with his colleagues about drug-drug interactions.

In 2012, he moved to Jakarta to do his medical specialization in clinical pharmacology in Universitas

Indonesia with an internship program in the National Center of General Hospital of Cipto

Mangunkusomo, Jakarta. He conducted clinical research with a topic of pharmacoeconomics of

empirical antibiotic treatments under supervisors Prof. Dr. Purwantyastuti, dr., M.Sc., Sp.FK and

Prof. Dr. Armen Muchtar, dr., MS., Sp.FK. In 2015, he joined in the Drug and Therapeutics Committee

(Komite Farmasi dan Terapi) as a clinical pharmacologist at General Hospital of Dr. Soetomo in

Surabaya.

In 2015, he decided to pursue his doctoral degree in the Netherlands under a grant from the

Directorate General of Higher Education, Ministry of National Education, Republic of Indonesia.

From May 3rd 2016, he officially started working his Ph.D. research at University Medical Center

Groningen (UMCG), University of Groningen. His Ph.D. trajectory was performed with a series

of research focused on pharmacoeconomics of antibiotic treatments under the supervision

of Prof. Dr. Maarten J. Postma and Prof. Dr. Alex W. Friedrich, together with Jan-Willem H. Dik,

Ph.D. The research was conducted under Groningen University Institute for Drug Exploration

(GUIDE) with collaboration between the Department of Medical Microbiology (MMB); the Unit of

Pharmacotherapy, PharmacoEpidemiology, and PharmacoEconomics, Department of Pharmacy;

and the Unit of Global Health, Department of Health Sciences, UMCG. He finished it in February

2020, with a defence on July 8th, 2020. After finalizing his Ph.D., he will continue working as a

lecturer, researcher, and clinical pharmacologist at the Department of Pharmacology and Therapy,

Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia. Also, he has been involving in the

expert working on the Essential Medicine List (EML) for surgical antibiotic prophylaxis in World

Health Organization (WHO), Geneva, Switzerland, since December 2018.

Addendum

Addendum