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LAPORAN DISKUSI I

CHECKLIST JURNAL

“A Multi-Center Randomised Controlled Trial of Gatifloxacin versus

Azithromycin for the Treatment of Uncomplicated Typhoid Fever in Children and

Adults in Vietnam”

Tutor : dr. Hidayat Sulistyo,Sp.PA,M.Si.Med

Oleh :

KELOMPOK V

1. DHITA HESTILANA A G1A010011

2. RIZA REVINA G1A010012

3. KHOLIFAH ALHUDA G1A010013

4. ZHITA WAHYU AGRINARTANTI G1A010061

5. DASEP PADILAH G1A010062

6. EVIYANTI RATNA SUMINAR G1A010063

7. META MUKHSININA P G1A010064

8. MEY HARSANTI G1A010065

9. NURVYNDA PRATIWI G1A010066

UNIVERSITAS JENDERAL SOEDIRMAN

FAKULTAS KEDOKTERAN DAN ILMU-ILMU KESEHATAN

PROGRAM PENDIDIKAN DOKTER

PURWOKERTO

2013



CONSORT 2010 CHECKLIST OF INFORMATION TO INCLUDE WHEN

REPORTING A RANDOMISED TRIAL

1. Title and abstract

a. (1a) Identification as a randomised trial in the title: pada judul terdapat

ramdomized trial .

“A Multi-Center Randomised Controlled Trial of Gatifloxacin versus

Azithromycin for the Treatment of Uncomplicated Typhoid Fever in

Children and Adults in Vietnam”

b. (1b) Structured summary of trial design, methods, results, and

conclusions (for specific guidance see CONSORT for abstracts):

tercantum.

Abstract

Background: Drug resistant typhoid fever is a major clinical problem

globally. Many of the first line antibiotics, including the older generation

fluoroquinolones, ciprofloxacin and ofloxacin, are failing.

Objectives: We performed a randomised controlled trial to compare the

efficacy and safety of gatifloxacin (10 mg/kg/day) versus azithromycin (20

mg/kg/day) as a once daily oral dose for 7 days for the treatment of

uncomplicated typhoid fever in children and adults in Vietnam. Methods:

An open-label multi-centre randomised trial with pre-specified per protocol

analysis and intention to treat analysis was conducted. The primary outcome

was fever clearance time, the secondary outcome was overall treatment

failure (clinical or microbiological failure, development of typhoid fever-

related complications, relapse or faecal carriage of S. typhi).

Principal Findings: We enrolled 358 children and adults with suspectedtyphoid fever. There was no death in the study. 287 patients had blood

culture confirmed typhoid fever, 145 patients received gatifloxacin and 142

patients received azithromycin. The median FCT was 106 hours in both

treatment arms (95% Confidence Interval [CI]; 94 – 118 hours for

gatifloxacin versus 88 – 112 hours for azithromycin), (logrank test p = 0.984,

HR [95% CI] = 1.0 [0.80 – 1.26]). Overall treatment failure occurred in

13/145 (9%) patients in the gatifloxacin group and 13/140 (9.3%) patients in



the azithromycin group, (logrank test p = 0.854, HR [95% CI] = 0.93 [0.43 –

2.0]). 96% (254/263) of the Salmonella enterica serovar Typhi isolates were

resistant to nalidixic acid and 58% (153/263) were multidrug resistant.

Conclusions: Both antibiotics showed an excellent efficacy and safety

profile. Both gatifloxacin and azithromycin can be recommended for the

treatment of typhoid fever particularly in regions with high rates

ofmultidrug and nalidixic acid resistance. The cost of a 7-day treatment

course of gatifloxacin is approximately one third of the cost of azithromycin

in Vietnam.

2. Introduction (Background and objectives)

a. (2a) Scientific background and explanation of rationale: tercantum.

1) Prevalensi There are approximately 21 million cases of typhoid fever

annually, with more than 210 000 deaths [1].

2) Target pada program (The emergence of antimicrobial drug

resistance in Salmonella enterica serovar Typhi (S. typhi) is a major

problem particularly in South East Asia and the Indian sub-continent

and challenges our current treatment options[2 – 4]. There is a need

for an efficacious, safe and affordable oral treatment, particularly in

regions with a high proportion of both multidrug and nalidixic acid

resistant S. typhi.).

3) Kesenjangan (konfirmasi penelitian sebelumnya) (Azithromycin, an

azalid antibiotics, has achieved excellent clinical results in the

treatment of MDR and nalidixic acid resistant typhoid fever [7,8].

However azithromycin is expensive. Cefixime has recently failed in

the treatment of nalidixic acid resistant typhoid fever in Nepal (thesedata were not available at the start of this trial) [10]. Of the newer

fluoroquinolones, gatifloxacin is available and affordable in South

and South East Asia including Vietnam [10]. Of all the

fluoroquinolones, gatifloxacin showed the lowest minimum

inhibitory concentrations (MICs) for nalidixic acid resistant S. typhi

from Nepal [11] and Vietnam and a rapid bactericidal effect in time-



kill experiments involving S. typhi isolates with single and double

mutations in the GyrA of S. typhi [6]).

b. (2b) Specific objectives or hypotheses: tercantum namun kurang

detail.

Membandingkan efektifitas gatifloxacin dan azitromisin di Vietnam

selatan.

3. Methods

Trial design

a. (3a) Description of trial design (such as parallel, factorial) including

allocation ratio: tercantum.

Multicenter open-label randomised controlled trial to compare the

efficacy and safety of gatifloxacin versus azithromycin for the

treatment of uncomplicated typhoid fever in children and adult in-

patients in southern Vietnam.

b. (3b) Important changes to methods after trial commencement (such

as eligibility criteria), with reasons : tidak dijelaskan alasannya.

Participants

a. (4a) Eligibility criteria for participants: tercantum.

Kriteria inklusi: tercatat sebagai suspek demam tifoid dan mengisi

informed consent .

Kriteria eksklusi: ibu hamil, bayi di bawah 6 bulan, riwayat

hipersensitivitas terhadap obata-obatan trial, terdapat tanda tifoid berat

(syok, ikterik berat, ensefalopati, konvulsi, perdarahan, perforasi

saluran cerna), tercatat diobati dengan fluorokuinolon, antibiotik

generasi ketiga, antibiotik macrolide selama 1 minggu rawat inap dirumah sakit.

b. (4b) Settings and locations where the data were collected

Interventions: tercatum lokasinya.

Lokasi: penelitian dilakukan di 3 rumah sakit yang berada di Vietnam

selatan (the Hospital for Tropical Diseases in Ho Chi Minh City, at the

Dong Thap Provincial hospital in Cao Lanh, Dong Thap province and at

the An Giang Provincial hospital in Long Xuyen, An Giang province).



(5) The interventions for each group with sufficient details to allow

replication, including how and when they were actually administered

Outcomes

a. (6a) Completely defined pre-specified primary and secondary

outcome measures, including how and when they were assessed:

tercantum.

Outcome primer yakni fever clearance time (FCT), diukur mulai

pertama kali pemberian antibiotik sampai 48 jam berikutnya,

pengukuran dilakukan pada suhu aksiler ≤ 37, 50C. Outcome sekunder

yakni kegagalan terapi (kegagalan klinis, mikrobologi, kekambuhan).

b. (6b) Any changes to trial outcomes after the trial commenced, with

reasons:

Tidak ditemukan, karena tidak ada perubahan outcome dalam

penelitian.

Sample size

a. (7a) How sample size was determined: tercantum.

a. Terbagi menjadi 2 kelompok azitromisin dan gatifloksasin.

Dikalkulasikan sebanyak 139 pasien (detect a Hazard Ratio of 1.40

with twosided alpha of 0.05 and power of 0.80) dengan suspek

demam tifoid untuk masing-masing kelompok kemudian

diasumsikan menjadi 140 pasien.

b. (7b) When applicable, explanation of any interim analyses and

stopping guidelines: tidak tercantum.

Randomisation: Sequence generation

a. (8a) Method used to generate the random allocation sequence:tercantum.

Menggunakan SNOSE (Treatment assignments were folded and kept in

opaque, sealed, sequentially numbered envelopes at all three study

sites).

b. (8b) Type of randomisation; details of any restriction (such as

blocking and block size): tercantum.



Terbentuk dalam Block dengan besar sampel per blok yakni 50 pasien

(These randomised codes were blocked in a size of 50).

Allocation concealment mechanism

(9) Mechanism used to implement the random allocation sequence

(such as sequentially numbered containers), describing any steps

taken to conceal the sequence until interventions were assigned: tidak

tercantum.

Implementation

(10) Who generated the random allocation sequence, who enrolled

participants, and who assigned participants to interventions:

tercantum.

pada jurnal dijelaskan bahwa yang melakukannya adalah dokter sebagai

peneliti. Hal ini ditunjukkan dalam paragraf 2 sub bab prosedur

pengacakan dan intervensi pada halaman 3. Dalam paragraf tersebut

dijelaskan setelah pengecekan kriteria inklusi dan eksklusi dan pemberian

informed consent, peneliti menentukan pengobatan yang diterima pada

probandus.

Blinding

a. (11a) If done, who was blinded after assignment to interventions

(for example, participants, care providers, those assessing

outcomes) and how: tidak tercantum.

b. (11b) If relevant, description of the similarity of interventions: tidak

tercantum.

Statistical methods:

a. (12a) Statistical methods used to compare groups for primary andsecondary outcomes: tercantum.

Menggunakan Fisher’s exact test.

b. (12b) Methods for additional analyses, such as subgroup analyses

and adjusted analyses: tercantum.

Menggunakan kalkulasi Odds ratio (OR) (RR, Hazard Ratio), survival

methods, pre protocol analysis, intention to treat analysis.

4. Results



Participant flow (a diagram is strongly recommended)

a. (13a) For each group, the numbers of participants who were

randomly assigned, received intended treatment, and were analysed

for the primary outcome:

Antara April 2004 dan Agustus 2005, 358 pasien dengan demam tifoid

diduga secara acak menerima baik gatifloksasin atau azitromisin. Dua

ratus delapan puluh delapan dari pasien memiliki darah atau sumsum

tulang dikonfirmasi demam tifoid dan 70 pasien kultur negatif untuk S.

typhi .

b. (13b) For each group, losses and exclusions after randomisation,

together with reasons: tercantum pada gambar 1 pada halaman 5.

Recruitment

a. (14a) Dates defining the periods of recruitment and follow-up:

tercantum namun kurang detail (Between April 2004 and August 2005,

358 patients with suspected typhoid fever were randomised to receive

either gatifloxacin or azithromycin. Two hundred eighty-eight of these

patients had blood or bone marrow confirmed typhoid fever and 70

patients were culture negative for S. Typhi).

b. (14b) Why the trial ended or was stopped

Baseline data

(15) A table showing baseline demographic and clinical characteristics

for each group: tercantum tabel 1 pada halaman 6.

Numbers analysed

(16) For each group, number of participants (denominator) included

in each analysis and whether the analysis was by original assigned

groups: tercantum.

Jumlah partisipan dicantumkan peneliti pada halaman ke-4. Dimana

terdapat 358 pasien yang didapat dari randomisasi yang dianalisa. 287

pasien dengan kultur positif demam tifoid, 145 telah mendapat pengobatan

gatifloxacin dan 142 dengan azithromycin.



Outcomes and estimation

a. (17a) For each primary and secondary outcome, results for each

group, and the estimated effect size and its precision (such as 95%

confidence interval)

b. (17b) For binary outcomes, presentation of both absolute and

relative effect sizes is recommended: tercantum.

Menggunakan angka absolut dalam bentuk pecahan angka kegagalan

per jumlah sampel (Clinical failure occurred in 6/145 (4.3%) patients in

the gatifloxacin group and in 6/140 (4.2%) in the azithromycin group

(p= 1.000, OR [95% CI]= 0.96 [0.25 – 3.7]).

Ancillary analyses

(18) Results of any other analyses performed, including subgroup

analyses and adjusted analyses, distinguishing pre-specified from

exploratory: tidak tercantum

Harms

(19) All important harms or unintended effects in each group (for

specific guidance see CONSORT for harms):

, paragraf 1 dan 2 dibagian “Advers events”

5. Discussion

Limitations

(20) Trial limitations, addressing sources of potential bias,

imprecision, and, if relevant, multiplicity of analyses: tidak tercantum

Generalisability

(21) Generalisability (external validity, applicability) of the trial

findings: tidak tercantum Interpretation

(22) Interpretation consistent with results, balancing benefits and harms, and

considering other relevant evidence: :

intepretasi jurnal sesuai dengan hasil penelitian. Paragraf pertama pada kolom

intepretasi menyatakan bahwa kedua antibiotik (gatifloxacin dan azithromycin)

bekeja baik untuk pengobatan demam tifoid kasus MDR dan resisten asam

nalidixic di Vietnam. Hal tersebut sesuai dengan hasil penelitian yang



menunjukkan hanya sedikit kasus gagal terapi, yaitu 9 % pada pengobatan

gatifloxacin dan 9,3 % pada pengobatan azithromycin. Selain itu, kedua obat

tersebut memberikan penurunan demam dalam waktu cukup singkat, yaitu dengan

melihat hasil rata-rata penurunan demam (FCT) di hari ketujuh (84, 2 % pada

pengobatan gatifloxacin dan 82, 6 % pada pengobatan azithromycin.

Dalam intepretasi hasil penelitian juga menunjukkan keuntungan dan kerugian

yang seimbang serta mempertimbangkan bukti-bukti yang relevan.keuntungan

dan kerugian terdapat pada paragraf 3 hingga 5. Pada pararaf 3 memperlihatkan

bahwa hasil penggunaan gatrifloxacin sebanding dengan hasil memuaskan yang

didapatkan pada penggunaan ofloxacin di Vietnam pada awal tahun 1990, dimana

saat itu rentan resisten terhadap asam nalidixic. Pada paragraf 4 menyatakan

bahwa Gatrifloxacin memiliki afinitas tinggi terhadap GyrA dan sedikit

menghambat mutasi gen GyrA. Akan tetapi penggunaan Gatifloxacin juga

memberikan efek samping. Hal ini diperlihatkan dalam paragraf 5 yang

menyatakan bahwa terdapat beberapa laporan kasus penggunaan gatrifloxacin

berhubungan denga terjadinya dysglicemia pada pasien DM tipe 2 da overweight.

Akan tetapi pada penelitian ini, tidak dilaporkan adanya kasus dysglicemia. Hasil

penelitian tersebut sama seperti penelitian sebelumnya di daerah Nepal yang

menggunakan gatrifloxacin dan tidak ada laporan terjadinya dysglicemia (paragraf

7).

6. Other information

Registration

(23) Registration number and name of trial registry: tidak tercantum

Protocol(24) Where the full trial protocol can be accessed, if available:

Protokol penelitian dicantumkan oleh peneliti pada halaman ke-10.

Protocol S1: Trial Protocol

Found at: doc: 10.371/journal.pone.0002188.s001 (0.07 MB DOC)

Funding



(25) Sources of funding and other support (such as supply of drugs),

role of funders:

Sumber pendanaan pada penelitian ini berasal dari Welcome Trust, UK.

Sponsor tidak memegang peraan dalam desain, analisa, atau publikasi

penelitian.

laporan diskusi i mrp 3.docx

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