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IH Pharmacy Live Rounds Journal Article Review

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  1. IH Pharmacy Live RoundsJournal Article Review Jennifer Day, NHA Resident 2009-2010 Kelowna General Hospital October 7, 2009

  2. Journal Article Review Overview • Title, journal, authors, funding • Abstract • Introduction • Methods • Results • Discussion • Critique • General interpretation • Recommendation

  3. Background Title “Moxifloxacin is non-inferior to combination therapy with ceftriaxone plus metronidazole in patients with community-origin complicated intra-abdominal infections” Journal • International Journal of Antimicrobial Agents Publication Timeline • Submitted online March 26, 2009 • Accepted June 26, 2009

  4. Background Authors • Based on a PUBMED search, one of the authors have published similar work in this area Funding Sources • This study was supported by Bayer HealthCare AG

  5. Abstract Int J Antimicrob Ag 2009;39:439-445

  6. Introduction Summary • Rationale to undertake study • Tackle “on-going debate” about the call for changes in empirical antimicrobial therapy in community acquired complicated intra-abdominal infections (cIAIs) • Moxifloxacin has been shown safe and effective and is approved for use in cIAIs • Proven efficacy, once daily dosing, IV and PO, documented safety profile • Now to evaluate the clinical efficacy when compared to “standard” therapy

  7. Introduction Purpose “The current study was conducted to evaluate the clinical efficacy of moxifloxacin in usually non-life threatening infections… with that of a standard combination regimen of ceftriaxone plus metronidazole in patients with cIAI.” Int J Antimicrob Ag 2009;39:439-445

  8. Methods Research hypothesis • “Efficacy of moxifloxacin is not 15% less than the combination of ceftriaxone plus metronidazole for cIAIs”

  9. Methods Design • Multinational, multicentre, prospective, randomised, double-dummy, double blind parallel design clinical trial • Study was approved by the Ethic Committee of Peking Union Medical College Hospital, Beijing, China Setting • Hospitalized patients in Mainland China, Indonesia, South Korea, Malaysia and Hong Kong between October 2005 and January 2007

  10. Methods Population a) Inclusion criteria – hospitalized patients 18 years of age and older; expected duration of treatment with IV ABX of at least 3 days but not longer than 14; confirmed or suspected cIAI with set criteria b) Exclusion criteria – known hypersensitivity to fluoroquinolones, quinolones, beta-lactams or metronidazole; pregnancy or lactation; history of quinolone-related tendon disease or clinically relevant cardiac conditions

  11. Methods Screening/recruitment • Patients were recruited from multi-centered hospitals across Asia • Sampling: Non-probability or probability? • Not mentioned • There was no screening log kept

  12. Methods Treatment allocation • Was the method of generating randomization number sequence appropriate? • Not mentioned • Was there any restrictions on randomization like ”blocking”, or ”stratification” • ...Not mentioned • Was there a method used to ensure concealment of random allocation to each study group? • ............Not mentioned • Who generated the allocation sequence, who enrolled the patients, who assigned patients to each group? • ..................Not mentioned

  13. Methods Blinding • No mention of blinding methods – only double-blinded Interventions • Moxifloxacin arm: moxifloxacin 400 mg IV once daily plus placebo IV • Combo arm: ceftriaxone 2 g IV once daily plus metronidazole 500 mg IV twice daily • Both treatments for a min three days (max 14 days) • No oral step down for either arm

  14. Methods Study definitions • Confirmed cIAI – either gross peritoneal inflammation with purulent exudate within abdominal cavity, intra-abdominal abcess or macroscopic intestinal perforation with diffuse peritonitis following a surgical or percutaneous procedure • Suspected cIAI – radiological evidence of GI perforation or localized collections of potentially infected material; patient scheduled for surgical procedure with in 24 hours of enrolment; presenting with one the following: symptoms (nausea, vomiting), tenderness & guarding, fever (depending on route), leukocytosis

  15. Methods Study definitions con’t • Clinical success – continued resolution or improvement of clinical signs and symptoms related to the infection, not requiring any antimicrobial therapy and without the occurence of wound infections (Per protocol population) • Bacteriological success – absence of the original causative organism on culture obtained from any site within the intra-abdominal cavity or from blood or absence of appropriate culture material for evaluation because the pt had clinically responded and invasive procedures were not needed

  16. Methods Outcome measures - a priori • Primary • To compare the clinical efficacy of moxifloxacin monotherapy to that of a standard combination of ceftriaxone plus metronidazole in patients with cIAI • Secondary • To compare the bacteriological efficacy and safety of the two treament regimens

  17. Methods Study procedures • Two arms, receiving different interventions • Further sub-grouped into ITT, PP and MBV • End-of-therapy (EOT) assessment after the final dose of study medication • Test-of-cure (TOC) visit that took place 10-14 days after EOT assessment • primary efficacy parameter for clinical success • OR specimens taken, cultured, identified and susceptibility tested

  18. Methods Statistical considerations a) Sample size calculation - Based on true failure rate of 20% in the control group and an equivalence delta of 15%, plus adjustment of 10% for multicentre design - Assumed a patient validity rate of 70% - Estimated enrolment of 364 patients (182 pts per arm)

  19. Methods Statistical considerations b) Statistical tests - All statistical tests were two-sided and performed at the 0.05 significance level - For success rates, 95% confidence interval of the difference of two clinical success rates was calculated using Mantel-Haenszel weights based on strata and centre - If the lower limit of this CI was greater than -15, then treatment with moxi was less effective than the combo regimen

  20. Trial Flow Diagram Enrollment? Number Enrolled n = 374 Allocation Moxi n = 181 Combo n = 183 n = 364 13% not included in final analysis ITT n = 180 ITT n = 181 Safety pop’n n = 361 PP n = 171 PP n = 174 Efficacy pop’n n = 345 MBV n = 132 MBV n = 132 Microbiologically valid n = 255

  21. Results Baseline Characteristics • Dates of recruitment: October 2005 – January 2007 • Duration of follow-up: 10-14 days after last ABX • Baseline demographic and clinical characteristics of each group given (next slide) Co-interventions • Did not describe any controlled or uncontrolled co-interventions that may have affected the results • Other medications, conditions, previous antibiotic use

  22. Baseline Characteristics Int J Antimicrob Ag 2009;39:439-445

  23. Results Analysis • Main analysis performed on primary endpoint was “per protocol, efficacy” analysis • “Per protocol”: Patients only analyzed if they were receiving study drug at the end of the trial • Efficacy population (primary outcome) n = 345 • “Intention-to-treat”: Patients analyzed based on the group they were originally randomized into • Safety population (secondary outcome) n = 361

  24. Results Analysis • Primary diagnosis of complicated appendicitis (279/374 – 74.5%) • Primary organism E.coli (155/255 – 60.7%) • B. fragilis, K. pneuomoniae, Pseudomonas aeruginosa • Based primary outcome (efficacy) on PP population • PP patients: meet inclusion criteria, receive study medication for at least 3 days and had an evaluation of clinical response at TOC other than “missing” or “indeterminate” • Not included if clinical assessment not possible due to early withdrawal (AE, protocol violation, withdrawn consent)

  25. Results Int J Antimicrob Ag 2009;39:439-445

  26. Results Safety • Overall incidence of treatment-emergent AE = NS • Moxi: 57/180 (31.7%) • Combo: 44/181 (24.3%) • Discontinuation due to AE = NS • Moxi: 4/180 (2%) • Combo: 3/181 (1.6%) • Non-compliance • Not mentioned • Mortality • No deaths reported during treatment phase • One death due to Candida infection and multi-organ failure in combo group (p=NS)

  27. Discussion Summary (from authors) • Authors reviewed previous trials in this area • Acknowledge that the infections encountered were managed by surgery • Limited role for ABX as mainly preventing surgical site infection • Do discuss E.coli resistance with moxifloxacin • Contribute success rates to surgery interventions and polymicrobial infections where E.coli may not be main pathogenic agent • But don’t ever assess all aspects of study…

  28. Discussion Summary • Authors conclude that moxifloxacin is non-inferior to combination ceftriaxone and metronidazole in treating cIAIs based on one-sided CI not exceeding -15 (15%)

  29. Critique Title and Abstract • Title should state that this is an RCT • Abstract is not structured into headings but provides enough detail for an initial screen Introduction • Limited scientific background provided on epidemiology, morbidity, impact of disease • Needed to provide more rationale for the study to be conducted, and potential significance • No null hypothesis clearly stated, besides in title

  30. Critique Methods • Super study design: P, R, DD, DB trial • Ethical (approved, patient consent) • Data collected over two years (change in resistance patterns?) • May not be representative of Canadians (Asia) • Did not clarify any aspects of patient enrollment • Was sampling consecutive or based on convenience? • Did not clarify any aspects of treatment allocation • Randomization? Sequence? Concealment? • No “loss to follow up” etc. information ever given • Trial may be subject to bias

  31. Critique Methods • Appropriate “double-dummy” blinding sincestudy drugs had different dosing regimens • But did not provide information on what placebo was • Did not provide data that blinding worked • No rationale for duration (max 14 days) or comparisons between arms • No duration means given or comparison of durations • Safety population (ITT) mean was moxi: 5.8; combo: 5.7 days (1-15 day range) • Use of pre-treatment APACHE II score for “non-life-threatening condition”

  32. Critique Methods • No IV to PO step down • Not standard practice • IDSA cIAI guidelines recommend addition of metronidazole to FQ due to increasing resistance of B.fragilis • Especially if previous FQ exposure • Ceftriaxone plus metronidazole indicated for high severity infections • Trial assessed mild to moderate infections • Numbers used for power calculation not referenced

  33. Critique Results • Trial flow diagram provided, but no information on lost patients • 29 patients unaccounted for (29/374, 7.7%) • EOT and TOC never clearly defined • What was assessed at these visits? • F/U WBC? Neuts? Temp? • Important omissions in baseline characteristics • Previous ABX? Medical conditions? Concurrent meds? • Very high cure rates for both arms • Such broad spectrum necessary?

  34. Critique Results • No data on concurrent use of potential confounding co-interventions • Primary analysis was based on an per-protocol analysis of patients receiving drug at end of study, not based on intention-to-treat analysis

  35. Critique Discussion • Fail to discuss important study limitations, which are a threat to the internal validity of study • Fail to discuss concerns around external validity (generalizability) of results to real world or Canadian practice • No assessment of secondary outcomes and very sparse discussion of primary outcome

  36. Critique Discussion • No discussion of cost comparisons between two arms • Justify blinding as it eliminated physician bias as “were physicians allowed to know treatment… and susceptibility data, many patients might have had therapy changed” • Compared results to other non-inferiority studies which involved IV to PO step down

  37. General Interpretation Summary • Funded by manufacturer of moxifloxacin (Bayer) • Significant methodological limitations make this study hypothesis-generating • Results are not made relevant to Canadian practice • In BC in 2008, E.coli reported to have 25% resistance to ciprofloxacin • A larger, well-designed study is required to confirm a benefit on clinically-important endpoints before a widespread change in practice to an agent that may promote microbial resistance, and is more costly

  38. Recommendation Summary • Based this current study, there is insufficient evidence to recommend moxifloxacin as monotherapy in cIAI • This is supported by the IDSA Guidelines for IAI • Hypotheses generated from this study should be tested in larger, well-designed studies • Superiority trial? • Consider moxifloxacin as an alternative option (in combo with metronidazole) when sample C&S are reported back from lab or when first-line treatment fails