DISKUSI KASUS 1BLOK MEDICAL RESEARCH PROGRAME 3A Multi-Center Randomised Controlled Trial of Gatifloxacin versus Azithromycin for the Treatment of Uncomplicated Typhoid Fever in Children and Adults in Vietnam

Kelompok 8Tutor: dr.Wahyu Siswandari,M.Si.Med,Sp.PK

1. Iman Hendrianto G1A0100482. Albertus Aditya Budiyanto G1A0100523. Indra Jati Laksana G1A0100574. Elisabeth Serafiyani G1A0011795. Rizka Dana Prastiwi G1A0100806. Novita Lusiana G1A0100817. Provita Rahmawati G1A0100828. Sania Nadianisa Maruto G1A0100839. Nurul Apriliani G1A010084

KEMENTERIAN PENDIDIKAN DAN KEBUDAYAAN NASIONALUNIVERSITAS JENDERAL SOEDIRMANFAKULTAS KEDOKTERAN & ILMU-ILMU KESEHATAN JURUSAN KEDOKTERAN PURWOKERTO

2013A. Judul Artikel JurnalA Multi-Center Randomised Controlled Trial of Gatifloxacin versus Azithromycin for the Treatment of Uncomplicated Typhoid Fever in Children and Adults in VietnamB. Bidang Ilmu PenelitianFarmakologiC. Telaah Kritis1. Judula. Judul mengindikasikan study design randomised trial secara eksplisitDalam 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 Vietnamb. Dalam abstrak terdapat ringkasan tentang design, metode, hasil dan kesimpulan penelitianDalam jurnal ini abstrak sudah menyebutkan dengan lengkap ringkasan tersebutMethods: 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 rasionalYa, dalam jurnal sudah dituliskan secara ilmiah dan rasional pada halaman 1 dan 2 bagian introductionThere 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 spesifikYa, pada paragraf terakhir bagian Introduction terdapat tujuan dan hipotesis penelitian yaitu untuk membandingkan efektivitas gatifloksasin terhadap azithomisin di Vietnam selatanWe 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 Penelitiana. 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 in-patients in southern Vietnam. Perubahan penting metode setelah percobaan permulaan (seperti kriteria kelayakan), dengan alasan : tidak disebutkan dalam jurnalb. Participants Kriteria kelayakan dari partisipan : ada pada halaman 2 sub judul ParticipantsPatients 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 approvalThe 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. IntervensiIntervensi dari masing-masing kelompok secara rinci bagaimana dan kapan penelitian dilakukan terdapat pada halaman 2 subjudul InterventionAccording 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 studyThe 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 outcomee. Besar sampel Bagaimana sampel dikelompokkan : ada pada halaman 3The 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 dilanjutkanf. Randomisasi Metode randomisasi yang digunakan, tipe randomisasiAn 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. AllokasiImplementasig. Blinding : tidak ada karena penelitian ini merupakan penelitian terbukah. Metode StatistikBinary outcomes (clinical failure, microbiological failure, typhoid fever-related 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 terteraDuring 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 analyssedAll 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 estimationPrimary 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 and13/140 (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 [0.381.7]). Figure 4 shows the proportion of patients failing through time after the start of treatment... 5. Pembahasan Keterbatasan penelitian : pada hlaman 9The 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 follow-up[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 relevan6. Kesimpulan