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5.1.2 Cephalosporins, cephamycins and other beta-lactams (เฉพาะกลม Carbapenems)
หมำยเหต: US FDA label indication คอขอบงใชทไดรบกำรอนมตโดยองคกำรอำหำรและยำสหรฐอเมรกำ, Non US FDA labeled indication คอขอบงใชทไมไดรบกำรอนมตจำกองคกำรอำหำรและยำสหรฐอเมรกำแตมขอมลกำรใชยำในขอบงใชดงกลำว Micromedex Efficacy; ตวยอ E = effective, F = evidence favors efficacy, I = evidence is inconclusive, Micromedex recommendations class; I = กำรใชยำทผ ปวยทกคนจะไดรบประโยชนและควรเลอกใชเปนล ำดบแรก, IIa = ผ ปวยสวนใหญไดรบประโยชนจำกกำรใชยำ, IIb = ผ ปวยบำงกลมไดรบประโยชนจำกกำรใชยำ แนะน ำใหพจำรณำกำรใชเปนบำงกรณ, III = กำรใชยำไมมประโยชนตอผ ปวย ควรหลกเลยง Micromedex strength of evidence; Category A = มหลกฐำนทเปน meta-analysis
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จำก randomized control trial (RCT) ทมคณภำพ หรอ RCT ทมผ เขำรวมกำรศกษำจ ำนวนมำก, B = มหลกฐำนทเปน meta-analysis จำก RCT ทขดแยงกน หรอ RCT ทมคณภำพต ำ หรอไมใชกำรทดลองแบบ RCT, C = expert opinion, case report หรอ case series
carbapenem เหมอนกน เนองจำกมฤทธดตอเชอ P. aeruginosa(2) และลดอตรำกำรเหนยวน ำใหเกดกำรชกในผ ปวย meningitis(3) ปจจบนกำรดอยำตำนจลชพของเชอแบคทเรยชนดแกรมลบในโรงพยำบำลเปนปญหำทพบมำกขนในภมภำคเอเชยแปซฟก(1) โดยมเชอกอโรคทส ำคญคอ P. aeruginosa, Acinetobacter baumannii และ extended-spectrum β -lactamase (ESBL) producing Enterobacteriaceae WHO(12) ไดท ำกำรส ำรวจ Antibiotic-resistant bacteria in European Union Member States, Iceland and Norway ในป 2007 พบวำมกำรตดเชอ Carbapenem-resistance P. aeruginosa คดเปนรอยละ 3 ท ำใหมอตรำกำรตำยเพมขนรอยละ 7 ของจ ำนวนผ ปวยโรคตดเชอทงหมด ในขณะทกำรศกษำของ Tam VH และคณะ(13) กลำววำควำมชกของกำรตดเชอ P. aeruginosa ทดอยำหลำยชนดในกระแสเลอดมอตรำประมำณ 10–17% จำกป ค.ศ. 2005 – 2007 ในประเทศสหรฐอเมรกำ
ในป ค.ศ. 2010 งำนวจยชอ “In vitro activity of doripenem and other carbapenems against contemporary gram-negative pathogens isolated from hospitalised patients in the Asia-Pacific region: results of the COMPACT Asia-Pacific Study” รำยงำนถงคำ MIC90 ในกำรยบยงเชอ P. aeruginosa ของยำ
non-susceptibility to Doripenem (1, 14) ผ วจยสรปวำจำกกำรศกษำในหลอดทดลอง Doripenem มฤทธใกลเคยงหรออำจดกวำ Meropenem และมฤทธดกวำ Imipenem อยำงนอย 4 เทำ ในกำรตอตำนเชอ Enterobacteriaceae ส ำหรบกำรก ำจดเชอ P. aeruginosa Doripenem เปนยำทมประสทธภำพมำกทสดในกลม carbapenems อยำงไรกตำม ผลจำกกำรทดสอบในหลอดทดลองนอำจไมสมพนธกบผลลพธทำงคลนกทตองกำรเสมอไป Abstract The Comparative Activity of Carbapenems Testing (COMPACT) Study was designed to determine the in vitro potency of doripenem compared with imipenem and meropenem against a large number of contemporary Gram-negative pathogens from more than 100 centres across Europe and the Asia-Pacific region and to assess the reliability of E-test methodology for doripenem minimum inhibitory concentration (MIC) determination against these pathogens. Data from eight countries within the Asia-Pacific region, which collected 1612 bacterial isolates, are presented here. E-test methodology was found to be a reliable method for MIC determination. Doripenem showed in vitro activity similar to or better than meropenem and at least four-fold better than imipenem against Enterobacteriaceae. Against Pseudomonas aeruginosa, doripenem was also the most active of the three carbapenems in vitro. However, in vitro results do not necessarily correlate with clinical outcome.
สบคนจำก Pubmed เมอวนท 11 พฤษภำคม 2555 โดยใช search term คอ "pseudomonas"[MeSH Terms] OR "pseudomonas"[All Fields]) AND resistance[Title] AND ("carbapenems"[MeSH Terms] OR "carbapenem"[All feilds] พบผลลพธทงหมด 241 รำยกำร
กำรศกษำของ Tam VH และคณะ(15) ไดสรปกลไกกำรดอยำตำนจลชพของเชอ Pseudomonas aeruginosa ไวดงตำรำง Table 1 Common mechanisms of antibiotic resistance in Pseudomonas aeruginosa. Isolates may express and/or harbor multiple mechanisms leading to a multidrug-resistant phenotype.
สบคนจำก Pubmed เมอวนท 11 พฤษภำคม 2555 โดยใช search term คอ "pseudomonas"[MeSH Terms] OR "pseudomonas"[All Fields]) AND resistant[All Fields] AND ("doripenem"[Supplementary Concept] OR "doripenem"[All Fields] พบผลลพธทงหมด 85 รำยกำร
Bazan JA และคณะ(16) กลำวถงกำรดอยำของ Carbapenem วำสำมำรถเกดขนไดจำกหลำยกลไก ส ำหรบ Imipenem กบ Meropenem เชอจะไมตอบสนองตอยำไดเมอเกดกำรดอยำเพยงกลไกเดยว เชน ลดกำรสรำง protein porin (OprD) แตยำ Doripenem จะมคำ MIC ทสงขน หำกเกดกำรดอยำไดตองผำนหลำยกลไกรวมกน
สอดคลองกบกำรศกษำของ Nicasio AM และคณะ(17) ทกลำววำ doripenem มคณสมบตเหมอน Carbapenems ตวอน คอ ทนตอเอนไซม β-lactamase หลำยชนด เชน AmpC หรอ ESBL แตมบำงชนดทสำมำรถท ำลำยยำ Doripenem ไดแก β-lactamases of Ambler class A (KPC and SME), C (VIM) และ D (OXA) แตกลไกดงกลำวนพบไดนอยในเชอ P. aeruginosa แตจะท ำใหมเชอทคำ MIC เพมขนหลำยเทำแตยงไมสงเพยงพอทแยกไดวำเปนกำรดอยำ กลไกอนๆทพบมำกในกำรดอยำของ P. aeruginosa ไดแก loss of porin channels และ efflux overexpression กำรดอยำของ Doripenem จะตองมกำรดอผำน 2 กลไกขนไปจงจะถอวำ
สบคนจำก pubmed เมอวนท 12 พฤษภำคม 2555 โดยใช Search term คอ ("acinetobacter baumannii"[MeSH Terms] OR ("acinetobacter"[All Fields] AND "baumannii"[All Fields]) OR "acinetobacter baumannii"[All Fields]) AND resistant[All Fields] AND mechanism[All Fields] AND ("carbapenems"[MeSH Terms] OR "carbapenems"[All Fields] OR "carbapenem"[All Fields]) พบผลลพธจ ำนวน 37 รำยกำร
2) เปนกำรศกษำของ Lerma FA(9) ป ค.ศ. 2009 ทท ำกำร Review ถงคณสมบตของยำ Doripenem ในดำนตำงๆและรวบรวมผลกำรทดลองแบบ In vitro ไว โดยจะเหนไดวำยำมคำ MIC สงขน เมอน ำมำทดลอบกบเชอดอยำทกๆชนด ดงแสดงในตำรำง Table 3 In vitro activity of doripenem against various species of Gram-negative microorganisms (9)
doripenem ในกำรรกษำ complicated intra-abdominal infections (cIAI) และ nosocomial pneumonia/ ventilator-associated pneumonia (NP/VAP) ทเกดจำกกำรตดเชอ P. aeruginosa กบกลมผ ปวยทไดรบยำเปรยบเทยบตวอน ผลกำรศกษำพบวำผลลพธทำงคลนก เชน clinical success rate ในกลมทไดรบ doripenem มแนวโนมดกวำกลมเปรยบเทยบในทง 2 ขอบงใช ทงนผ วจยไดกลำวถงขอจ ำกดของงำนวจยซงท ำใหไมสำมำรถน ำขอมลไปใชอำงองในประชำกรกลมใหญ (ไมสำมำรถเขำถงเอกสำรฉบบเตมได) Objective: Pseudomonas aeruginosa is a difficult-to-treat bacterial pathogen often isolated from patients with serious nosocomial infections. The goal of this analysis is to present the clinical and microbiologic effectiveness of doripenem in the treatment of infections due to P. aeruginosa. Research design and methods: A meta-analysis was conducted on the subset of subjects enrolled in four randomized phase III clinical trials of doripenem in subjects with complicated intra-abdominal infections (cIAI) and nosocomial pneumonia/ventilator-associated pneumonia (NP/VAP) due to P. aeruginosa. Clinical and microbiologic success was determined by infection and across the two infections. Results: Clinical success rates for modified intent-to-treat (mITT) subjects with P. aeruginosa in the cIAI and NP/VAP groups were 78.7% (37/47) and 59.6% (31/52), respectively, following treatment with doripenem versus 74.3% (26/35) and 32.8% (19/58), respectively, for subjects in the comparator groups (p < 0.05 for difference in success rates across infection types). Microbiologic eradication rates also favored doripenem, although the differences did not achieve statistical significance. The weighted difference (doripenem minus comparator) for the mITT population in clinical success rates between doripenem and the comparator agents was 16.0% (95% CI: 3.1%, 29.0%) and for microbiologic eradication rates was 9.1% (95% CI: -4.2%, 22.3%). The proportion of subjects reporting one or more treatment-emergent adverse events or serious adverse events was similar for doripenem and the comparator agents. Fourteen doripenem and 14 comparator subjects died during the study. Limitations of this retrospective meta-analysis also include the qualitative heterogeneity of the data, and a selected, narrow population of moderately ill clinical trial subjects included in the analysis. Due to limitations, these data may not be generalizable to all populations and should be considered hypothesis generating. Conclusion: The weighted difference in clinical success rates for subjects with cIAI and NP/VAP infections caused by P. aeruginosa was in favor of doripenem, with the relative benefit of doripenem compared with the comparator agents similar across the two infections.
1. Efficacy and safety of intravenous infusion of doripenem versus imipenem in ventilator-associated pneumonia: A multicenter, randomized study(6)
Ventilator-associated pneumonia (N = 531) Setting: Intensive care units
doripenem 500 mg q 8 hr (4-hr IV infusion)
imipenem 500 mg q 6 hr or 1000 mg q 8 hr (30 – 60 min IV infusion)
Primary outcome: Clinical cure rates and clinical cure rates in the clinical modified intent-to-treat (cMITT)
- Clinical cure rates = 68.3% (doripenem) and 64.2% (imipenem) in the clinically evaluable and 59.0% (doripenem) and 57.8% (imipenem) in the cMITT populations - In patients with Pseudomonas aeruginosa Clinical cure = 80.0% (doripenem) and 42.9% (imipenem) (p not significant); microbiological cure = 65.0% (doripenem) and 37.5% (imipenem).
2. Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: A phase III, prospective, multicenter, randomized, double-blind, noninferiority study (7)
Hospitalized adult patients with Complicated intra-abdominal infections (N = 476)
doripenem 500 mg IV q 8 hr
meropenem 1 g IV q 8 hr
Primary outcome: Clinical cure rate at 21-60 days after the completion of study drug therapy Secondary outcome: All adverse events
Primary outcome: - Clinical cure rates of doripenem = 85.9% and imipenem = 85.3%, the corresponding treatment difference was 0.6% (95% CI, -7.7% to 9.0%) - Clinical cure rates were not significantly different between the 2 treatment arms in key subgroups (eg, age, sex, race, baseline Acute Physiology and Chronic Health Evaluation II score, primary infection site) Secondary outcome: - Drug discontinuation resulted from AEs in doripenem arm = 5.1% and meropenem arm = 2.1%
Studies Patient Interventions Comparator Outcome Result
3. Medical resource utilization among patients with ventilator-associated pneumonia: pooled analysis of randomized studies of doripenem versus comparators(8)
Ventilator-associated pneumonia
At least 1 dose of doripenem in the phase III studies (n = 312)
piperacillin/tazobactam (study 1) and imipenem (study 2) (n = 313)
- durations of mechanical ventilation - intensive care unit (ICU) stay - hospitalization - All cause mortality
- Median durations of mechanical ventilation (Doripenem 7 days vs. comparators 10 days; P = 0.008) - ICU stays in Doripenem group were 12 days and Comparators 13 days (P = 0.065) - Hospitalization (Doripenem 22 vs. Comparators 26 days; P = 0.010) - Mortality rate in Doripenem group 51/312 [16%] vs. Comparators 47/313 [15%]; P = 0.648)
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3.4. ขอมลจากรายการยาในตางประเทศ 3.4.1. WHO Model List of Essential Medicines 2011
ยงไมมกำรบรรจ Doripenem ไวในรำยกำรยำ สวน Imipenem powders for injection: 250 mg (as monohydrate) + 250 mg (as sodium salt), 500 mg (as monohydrate) + 500 mg (as sodium salt) in vial สำมำรถใชไดส ำหรบ treatment of life-threatening hospital based infection due to suspected or proven multidrug-resistant infection ในขณะท Meropenem สำมำรถใชไดเพยงขอบงใชเดยวคอ Treatment of meningitis and is licensed for use in children over the age of 3 months 3.4.2. Lothian Joint Formulary
4) Dosing of doripenem for P. aeruginosa infections (MicroMedex 2012) Bacteremia associated with intravascular line: (due to Escherichia coli and Klebsiella species,
extended-spectrum beta-lactamase positive) 500 mg IV every 8 hours [2] Infectious disease of abdomen, Complicated: 500 mg IV over 1 hour every 8 hours for 5 to 14
days; duration includes at least 3 days of IV therapy and switch to appropriate oral therapy [3] Pyelonephritis: 500 mg IV over 1 hour every 8 hours for 10 days (or up to 14 days with concurrent
bacteremia); duration includes at least 3 days of IV therapy and switch to appropriate oral therapy [3]
Urinary tract infectious disease, Complicated: 500 mg IV over 1 hour every 8 hours for 10 days (or up to 14 days with concurrent bacteremia); duration includes at least 3 days of IV therapy and switch to appropriate oral therapy [3]
5) Calculation of budget impact Price per course = 1,251.90 ฿/vial * 3 vial/day * days สมมตฐาน
- Isolation number จำก NARST ทกรำยทดอตอ imipenem จะม 29.4% (Jones, et al., 2004) ทยงไวตอ doripenem
- Isolation number ของผ ปวยทตดเชอ P. aeruginosa ถอเปน underestimate เนองจำกกำรสงขอมลใหกบ NARST นนไมไดท ำทกโรงพยำบำล
ตำรำงท 11 คำใชจำยดำนยำทเพมขนเมอน ำ doripenem ไวในบญช จ๒ ตำมเงอนไข ใชในผปวยทตดเชอ Pseudomonas aeruginosa ซงดอตอ imipenem และ meropenem แตยงไวตอ doripenem Duration of treatment Budget implication vary by percent resistance Lowest (12%) Average (16%) highest (19%) 5 days 8,938,303 12,919,861 20,990,382 10 days 17,876,606 25,839,721 41,980,764 14 days 25,027,249 36,175,610 58,773,069
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