DISKUSI KASUS 1

BLOK MEDICAL RESEARCH PROGRAME 3

A Multi-Center Randomised Controlled Trial of Gatifloxacin versus Azithromycin for
the Treatment of Uncomplicated Typhoid Fever in Children and Adults in Vietnam

Kelompok 8
Tutor: dr.Wahyu Siswandari,M.Si.Med,Sp.PK
1.
2.
3.
4.
5.
6.
7.
8.
9.

Iman Hendrianto
Albertus Aditya Budiyanto
Indra Jati Laksana
Elisabeth Serafiyani
Rizka Dana Prastiwi
Novita Lusiana
Provita Rahmawati
Sania Nadianisa Maruto
Nurul Apriliani

G1A010048
G1A010052
G1A010057
G1A001179
G1A010080
G1A010081
G1A010082
G1A010083
G1A010084

KEMENTERIAN PENDIDIKAN DAN KEBUDAYAAN NASIONAL

UNIVERSITAS JENDERAL SOEDIRMAN
FAKULTAS KEDOKTERAN & ILMU-ILMU KESEHATAN
JURUSAN KEDOKTERAN
PURWOKERTO
2013
A. Judul Artikel Jurnal
A Multi-Center Randomised Controlled Trial of Gatifloxacin versus Azithromycin for
the Treatment of Uncomplicated Typhoid Fever in Children and Adults in Vietnam

B. Bidang Ilmu Penelitian

Farmakologi
C. Telaah Kritis
1. Judul
a. Judul mengindikasikan study design randomised trial secara eksplisit
Dalam judul sudah ditunjukkan secara eksplisit
A Multi-Center Randomised Controlled Trial of Gatifloxacin versus
Azithromycin for the Treatment of Uncomplicated Typhoid Fever in Children and
Adults in Vietnam
b. Dalam abstrak terdapat ringkasan tentang design, metode, hasil dan kesimpulan
penelitian
Dalam jurnal ini abstrak sudah menyebutkan dengan lengkap ringkasan tersebut
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 suspected typhoid
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]; 94118 hours for gatifloxacin versus 88112 hours for
azithromycin), (logrank test p = 0.984, HR [95% CI] = 1.0 [0.801.26]). 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 [0.432.0]). 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 zithromycin in Vietnam.
2. Latar belakang (Introduction)
a. Latar belakang dituliskan berdasarkan ilmiah dan dijelaskan dengan rasional
Ya, dalam jurnal sudah dituliskan secara ilmiah dan rasional pada halaman 1 dan
2 bagian introduction
There are approximately 21 million cases of typhoid fever annually, with more
than 210 000 deaths [1]. 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 [24]. There is a need for an efficacious, safe and affordable
oral ....
b. Mencantumkan tujuan atau hipotesis yang spesifik

Ya, pada paragraf terakhir bagian Introduction terdapat tujuan dan hipotesis
penelitian yaitu untuk membandingkan efektivitas gatifloksasin terhadap
azithomisin di Vietnam selatan
We conducted a randomised controlled trial comparing the efficacy of
gatifloxacin to azithromycin in southern Vietnam, an area characterised by a
very high proportion of MDR (88%) and nalidixic acid resistant (93%) S. typhi
isolates [8].
3. Metode Penelitian
a. Trial Desain
- Deskripsi dari trial desain termasuk perbandingan alokasi :

The study was designed as a 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 inpatients in southern Vietnam.
Perubahan penting metode setelah percobaan permulaan (seperti kriteria

kelayakan), dengan alasan : tidak disebutkan dalam jurnal

b. Participants
- Kriteria kelayakan dari partisipan : ada pada halaman 2 sub judul
Participants

Patients were eligible to be included in the study if they had clinically

suspected or culture confirmed uncomplicated typhoid fever and if fully
informed written consent had been obtained. For children, consent was
obtained from the parent. Exclusion criteria were pregnancy, age under 6
months, history of hypersensitivity to either of the trial drugs, any signs of
severe typhoid fever (shock, deep jaundice, encephalopathy, convulsions,
bleeding, suspicion or evidence of gut perforation), or previous reported
treatment with a fluoroquinolone antibiotics, a third generation
ephalosporine or macrolide antibiotics within one week prior to hospital
admission.
Seting dan lokasi pengumpulan data : ada yaitu dilakukan di 3 rumah
sakit. Dinyatakan pada halaman 2 sub judul The study sites and ethical
approval
The study was conducted at three hospitals in the south of Vietnam.
Adult and paediatric patients were recruited at 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.

c. Intervensi
Intervensi dari masing-masing kelompok secara rinci bagaimana dan kapan
penelitian dilakukan terdapat pada halaman 2 subjudul Intervention
According to their randomisation number patients were assigned to oral
treatment with either 20 mg/kg azithromycin (ZithromaxH suspension, Pfizer,

USA; 200 mg/5 mL or ZithromaxH tablets, Pfizer, USA; 500 mg/tablet) or 10

mg/kg gatifloxacin (TequinH, Bristol-Myers Squibb, USA; 400 mg/tablet)
once daily for 7 days. Tablets were cut to obtain the appropriate study
dosage and administered with water. Inevitably, the dose administered was
an estimate of 10 mg/kg/day of gatifloxacin or 20 mg/kg/day of azithromycin
(number of tablets or proportions of tablets were documented in the CRFs).
Gatifloxacin was only available as tablets, which were cut to obtain the
appropriate dosage and crushed if necessary for children. The maximum
dose of azithromycin was 1 g per day. All drugs were purchased
commercially.
d. Outcome
- Menyebutkan secara lengkap pra spesifikasi outcome primer dan sekunder
pada halaman 3 subjudul Outcome of the study
The primary endpoint of the study was the resolution of fever (fever clearance
time, FCT), which was defined as the time from the start of the antibiotic
treatment to when the axillary temperature first fell #37.5uC and remained
there for at least 48 hours. Secondary endpoints were the overall failure to
treatment, which was defined a priori as any of the following: clinical failure
(persistence of fever and symptoms two days after the end of treatment, i.e. on
day 10) or need for re-treatment due to insufficient treatment response as
judged by the treating physician; microbiological failure (positive blood
culture on day 7 to 9 after the start of treatment); the development of typhoid
feverrelated complications during hospital-stay; the occurrence of relapse
(symptoms and signs suggestive of typhoid fever) within 1 month after
completion of treatment or the detection of faecal carriage of S. typhi at the
follow-up visits at 1, 3 and 6 months (to exclude faecal carriage a minimum
of two consecutive follow-up visits had to be attended).
- Tidak ada perubahan pada trial outcome
e. Besar sampel
- Bagaimana sampel dikelompokkan : ada pada halaman 3
The primary outcome measure for the study was the fever clearance time
(FCT). Previous studies that used azithromycin to treat typhoid fever patients,
reported a mean fever clearance time of 130 hours [7] and 139 hours [8].
For gatifloxacin, clinical observations from a small number of typhoid fever
patients were available and indicated a mean FCT of 76 hours. We calculated
that 139 patients with culture-confirmed typhoid fever would be needed in
each treatment arm to detect a Hazard Ratio of 1.40 with twosided alpha of
0.05 and power of 0.80 [14]. Therefore, assuming a median fever clearance
time of 130 hours for azithromycin, the sample size of 140 patients with
culture-confirmed typhoid fever in each arm would give power of at least 0.80
to detect a difference between treatments if the fever clearance time in the
gatifloxacin group was 92 hours or less.
- Hal apa yang bisa menghantikan penelitian dlam penelitian ini tidak ada,
penelitian tetap dilanjutkan
f. Randomisasi
- Metode randomisasi yang digunakan, tipe randomisasi

An administrator independent from the study generated the random number

sequence in Excel using RAND function. These randomised codes were
blocked in a size of 50. Treatment assignments were folded and kept in
opaque, sealed, sequentially numbered envelopes at all three study sites. Due
to logistic reasons randomisation was not stratified by centre.
After all inclusion and exclusion criteria were checked, and
informed consent given, the study doctor opened the
envelope to determine which treatment the subject would
receive. The sealed envelopes were opened in strict numeric
sequence.
- Allokasi
Implementasi
g. Blinding : tidak ada karena penelitian ini merupakan penelitian terbuka
h. Metode Statistik
Binary outcomes (clinical failure, microbiological failure, typhoid feverrelated complications) were compared between the two treatment groups
using Fishers exact test, assuming the worst case scenario (all lost to follow
up treated as failures). The unadjusted Odds Ratio (OR) and Cornfields 95%
confidence interval [15] were calculated to show the relative risk of
developing individual secondary outcomes (clinical, microbiological failure,
typhoid fever-related complications) in the gatifloxacin group compared to
the azithromycin group.
4. Hasil Penelitian
- Partisipan yang digunakan dalam penelitian masing masing kelompok
yang mendapatkan perlakuan dan yang dianalisis terdapat pada halaman 4
dan lebh jelas ada pada diagram halaman 5 dijelaskan bahwa 460 pasien
-

yang memenuhi syarat 358 kemudian dilakukan randomisasi...

Waktu Recruitment dan follow up juga tertera
During the study period, 460 patients were assessed for eligibility (Figure
1). One hundred and two patients were noneligible, the main reason was
the reported previous use of fluoroquinolone, macrolid or third generation
cephalosporin antibiotics (41 patients) in the week before hospitalisation.
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.
One culture positive patients was excluded from the per protocol analysis
(PP), because he had received ciprofloxacin before entry to the trial. The
PP group consisted of 287 patients, 145 in the gatifloxacin group and 142
in the azithromycin group. All PP patients, except two in the azithromycin
group, finished the full course of treatment.
The total number patients visiting the follow-up at 1 month was 275 out of
287 (96%), at 3 months 268 out of 287 (93%), at 6 months 128 out of 287
(44%) patients.

Terdapat tabel yang mencantumkan data demografi dan karakteristik

masing masing kelompok partisipan pada halaman 6

Jumlah partisipan yang dianalisis terdapat pada halaman 4 sibjudul

number analyssed
All 358 randomised patients were analysed in the intention to treat (ITT)
analysis. Two hundred and eighty-seven patients with culture confirmed
typhoid fever, 145 treated with gatifloxacin and 142 with azithromycin,
were analysed in the pre-specified PP analysis.

outcome primer dan sekunder, hasil dari masing masing kelompok dan
estimasi besar efek dan ketepatan terdapat pada halaman 4 subjudul
Outcome and estimation
Primary outcomes. There was no significant difference inthe resolution of
fever (FCT) between the two treatment groups(Table 2).By PP analysis,
the median FCT was 106 hours in both treatment arms (95% Confidence
Interval [CI]; 94118 hours for gatifloxacin versus 88112 hours for
azithromycin), (logrank test p= 0.984, HR [95% CI] =1.0 [0.801.26]).
The Kaplan-Meier survival curve for the fever clearance time is shown in
Figure 2. At day 7, fever clearance rate was 82.8% (95% CI; 76.2%
88.4%) in the gatifloxacin group and 80.5% (95% CI; 73.6 %86.6 %) in
the azithromycin group. In the ITT population, the median FCT was 100
hours in both treatment arms (95% CI; 92106 hours for gatifloxacin
versus 88112 hours for azithromycin), (logrank test p= 0.914, HR [95%
CI] =1.01 [0.821.25]). At day 7, fever clearance rate was 84.2% (95%
CI; 78.5%89%) in the gatifloxacin group and 82.6% (95% CI; 76.5%
87.9%) in the azithromycin group (Figure 3).
Secondary outcomes. There was no death in the study. There was no
significant difference in overall failure to treatment between the two
groups (Table 2). By PP analysis, the number of patients that showed
overall failure to treatment was 13/145 (9%) in the gatifloxacin group and
13/140 (9.3%) in the azithromycin group (logrank test p =0.854, HR
[95% CI]= 0.93 [0.432.0]), or when assuming the worst case scenario,

that all dropped-out patients were failures, 15/142 (10.6%) failures in the
azithromycin group (logrank test p =0.570, HR [95% CI]= 0.81 [0.38
1.7]). Figure 4 shows the proportion of patients failing through time after
the start of treatment...
5. Pembahasan
- Keterbatasan penelitian : pada hlaman 9
The randomisation sequence was generated with a large block size of 50,
which resulted in uneven numbers in the two treatment groups (186 versus
172 patients in the ITT population). One possible limitation was the low
rate of stool cultures positive for S. typhi. Faecal carriage is usually
characterised by intermittent shedding and the stool culture for S. typhi is
not very sensitive. When comparing our data with other studies that
demonstrate that azithromycin is highly efficacious for the treatment of
typhoid fever, we find similar low rates of faecal carriage at followup[7,30].
-

penelitian ini bisa digeneralisasikan untuk cakupan yang lebih luas terkait
validitas eksternal dan bisa diaplikasikan terdapat pada halaman 9 bisa
digunakan dalam wilayah Asia.
The emergence of nalidixic acid resistant S. typhi and S. Paratyphi A with
reduced susceptibility to the fluoroquinolones is a widespread problem
throughout Asia and therefore our study is relevant to the whole region
[2,6]. Many case reports and some randomised controlled trials have
described the worsening clinical response to ciprofloxacin and ofloxacin
[8,27,28]...

dalam penelitian ini sudah sesuai / konsisten antara hasil, keuntungan

dan kerugian sesuai dengan relevan
6. Kesimpulan