Effectiveness of Short-course Combination Therapy of Cloxacillin with Gentamicin for Right-sided Endocarditis in Intravenous Drug Abusers: A Systematic Review Binod Neupane McMaster University

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Effectiveness of Short-course Combination Therapy
of Cloxacillin with Gentamicin for Right-sided
Endocarditis in Intravenous Drug Abusers A
Systematic ReviewBinod Neupane McMaster
University
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A typical schenerio

• Population P (e.g., smokers, or drug users, or
  elderly male)
• Disease D (Cancer, Diabetes, MI)
• Outcome O (e.g., death, cure)
• Available threapies for the treatment of D in P
  in terms of O
• Therapy of Interest (T) vs. Therapy of
  comparisons (T1, T2, T3)
• e.g., T can be any types of monotherapies (only
  one drug), and T1, T2, T3 can be any, same or
  different, combination (two or more drugs)
  therapies for the disease D
• Suppose there are 6 studies altogether, none of
  them was large enough to conclude the
  effectiveness of any therapy from a single study.
  
• Study 1 (T vs T1) T was more effective
• Study 2 (T vs T2) T2 was more effective
• Study 3 (T vs T2) T was more effective
• Study 4 (T vs T2) T was more effective
• Study 5 (T vs T3) T appeared to be equally
  effective to T3
• Study 6 (T vs T3) T was more effective
• So coflicting evidences......

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What is Systematic Review?

• Systematic review
• a scientific investigation in which original
  studies are its subjects
• it synthesizes the results of multiple primary
  investigations by limiting bias and random error
• (Qualitative) systematic review
• When the results of primary studies are
  summarized but not statistically combined (when
  results of studies can not be combined? How do we
  know it?)
• Meta-analysis (quantitative systematic review)
• If the statistical methods are used to combine
  the results of two or more studies

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Liming bias and random error? How?

• Clearly define the population, disease, outcome
  of interest, and therapy of interest and broadly
  the therapy of comparison (focussed research
  problem!)
• Identify all the relevant studies done so far,
  published or unpublished, in any language (thus
  limiting selection bias, publication bias and
  language bias)
• How to identify them?
• Develop effective search strategy and search
  articles in databases
• Hand-search individual journals and conference
  proceedings scan references of each relevant
  articles, contact experts and industries
• Note Randomized controlled trials are considered
  to be best evidences
• Unknown variables are expected to be controlled

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Liming bias and random error..... Example

• Suppose there are only 5 studies considered in a
  systematic review
• Study 1 (T vs T1) T is more effective
• ... ... ...
• Study 3 (T vs T2) T is more effective
• Study 4 (T vs T2) T is more effective poor
  evidence
• Study 5 (T vs T3) T appeared to be equally
  effective to T3
• ... ... ...
• Study 7 (T vs T3) T is more effective poor
  evidence
• ... ... ...
• Total patients in 5 trials 200, say
• Information from three studies are missing or not
  included in the overview. Does the missing trials
  suggest the same thing about the effectiveness of
  therapy T? Does this overview limits bias or
  random error?
• Good systematic review should identify all are 8
  studies. Suppose the evidences from them are
• Study 1 (T vs T1) T was more effective
• Study 2 (T vs T2) T2 was more effective
  (unpublished)
• Study 3 (T vs T2) T was more effective
• Study 4 (T vs T2) T was more effective (poor
  quality e.g., improper randomization, no
  stratification)

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The method of synthesis of information from
studies

• Suppose, k studies are consider in a systematic
  review
• Suppose, relative risk is the effect measure of
  ith study (RRi, i 1,2, ..., k)
• If studies are heterogeneous, then generally
  study samples might have different
  characteristics or drugs under comparisons are of
  very different types
• Just present the charateristics of patients in
  all reviewed studies and corresponding effect
  measure (Qualitative systematic review)
• If studies are similar (more or less
  homogeneous)
• Also pool RR1, RR2, ..., RRk into a single
  estimate statistically (Meta-analysis)
• Using fixed effect model, or
• Using random effect model

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Test of Homogeneity

• H0 RR1 RR2 ... RRk
• H1 At one of them is different from others
• Ti log(estimate of RRi from ith study)
  log(observed RRi)
• linear
• Vi variance
• Wi 1/Vi weight
• T ?WiTi/ ? Wi, weighted average of Ti
• Q ?Wi (Ti T)2 ?2(k-1)
• Reject H0 if p lt 0.10
• Power of the test is often low

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Dealing with heterogeneity

• Fixed effect moded Ignore heterogeneity
• RR1 RR2 ... RRk RR ( theta), common
  underlying treatment effect
• Ti log(RRi) ? ei, i 1, 2, ..., k
• Random effect moded Incorporate heterogeneity
• Underlying effect vary from trial to trial, that
  is,
• Ti log(RRi) ?i ei, i 1, 2, ..., k
• where, Ti N(?, t?2), i 1, 2, ..., k
• ? log(random effect) t?2 between study
  variance

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Background

• Right-sided endocarditis
• Dominant IE in intravenous drug abusers (1, 2, 3)
• Mostly tricuspid valve is involved (1, 4)
• S. aureus is the dominant infective organism (1,
  4, 6, 5)
• Diagnosis
• Clinical evidence, radiographic finding, and (1)
• Positive blood culture (three or more) (7, 8, 9)
• Positive echocardiogram (Duke criteria) (1, 4,
  8, 9)
• Treatment
• In intraveneous drug abusers (IVDAs) with
  uncomplicated right-sided IE
• compliance with lengthy therapy is often a major
  problem for such population, Short-course
  antibiotic therapies may be adequate (11, 13, 14,
  15)
• combination antibiotic therapy may have an
  enhanced potential synergism (interaction!) when
  compared to the additive effect of each of the
  antibiotics assessed separately (18)
• Cloxacillin is a semisynthetic penicillin widely
  used in nonmethicillin resistant Staphylococcus
  aureus infections.(19) Gentamicin in native valve
  endocarditis is beneficial in earlier
  defervescence of fever and the sterilisation of
  blood cultures.

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Objective

• Objectives
• To determine whether a combination therapy of
  short-course (lt 2 weeks) cloxacillin and
  gentamicin compared to any other drug or placebo
  (combination or monotherapy, short-course or
  longer-course) is effective in treating
  right-sided bacterial endocarditis due to S.
  Aureus in intravenous drug abusers.

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Study Selection Criteria

• Patients
• Intravenous drug abusers with bacterial
  right-sided endocarditis
• Diagnosis criteria
• Clinical symptoms and laboratory test (blood
  culture) and/or echocardiography
• Exclusion
• Patients with extra-pulmonary metastatic
  infection
• Intervention in one treatment arm
• Short-course antibiotic therapy of cloxacillin
  and gentamicin (lt 2 weeks, combination)
• Intervention in Comparison arm
• Any other antibiotic therapy (short- or
  long-course, single or combination)

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Selection criteria

• Outcome
• At least Clinical Cure at the end of therapy,
  assessed by clinical symptoms and at least one
  blood culture.
• Follow up
• at least 2 weeks of follow-up after the
  completion of therapy but within 6 months
• Design type
• (Parallel) Randomized controlled trials (RCTs)
• Study year
• 1966-present
• Setting
• Inpatients
• Publicaition type
• Published or unpublished

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Search strategy for the identification of studies

• Major Databases Ovid search of MEDLINE
  (1996-present) and EMBASE (1980-present) with the
  following text words, corresponding MeSh and
  index terms and exploding them
• Endocarditis
• cloxacillin, gentamicin,
• right or tricuspid or mitral or intravenous
  or injection or parenteral or substance or drug
  abuse/,
• Human(s)/,
• Clinical Trials/, clinical trial(pt), randomized
  controlled trials/
• Combine all related articles of relevant
  articles and limit by random or random
• Hand searches in individual journals and
  conferences proceedings
• Endocarditis limited to random
• Scanning reference lists of relevant atricles,
  reviews, guidelines
• Contact experts, industries
• Google search for conference procedings

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Validation assessment criteria

• Reviewers
• independently examine the articles for quality
  assessment
• cross-reference to screen for additional
  information
• Make decision of whether to "include" or "not
  include"
• Any discrepancy resolved by consensus
• Major Criteria for assessment were
• Diagnosis two or more blood culture, and/or two
  or more echocardiography
• Appropriate randomization
• Similarity in baseline characteristics
• extent of bias in data collection (allocation
  concealment, observer blinding)
• follow-up gt 80
• At least two weeks of follow-up after completion
  of therapies

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Validated study from initial searches

• 3 articles were obtained through MEDLINE search
• Long-course (gt 2 weeks) monotherapy therapy 1
  study (Fortun 1995)
• Short-course antibiotic therapy 2 (monotherapy
  Ribera 1998, and combination Fortun 2001)
• No more randomized controlled trials were found
  through other sources

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Characteristics of included studies

• Fortun 1995 Short-course (2 weeks, Combination)
  vs. longer-course (4 weeks, Single)
• Study carried in a hospital in Spane, published
  in 1995
• Source of funding Not reported
• Methods
• Interventions intravenous
• Treatment arm (2 weeks)
• Cloxacillin (2 g/4h)
• Gentamicin (1.5 mg/kg body weight/8h)
• Comparison arm (4 weeks)
• Teicoplanin (7 mg/kg/24h)
• Randomization issues
• Method of randomization 1 of group A 1 of group
  B
• Allocation sequence generation not reported
• Allocation concealment No
• Observer blinding No
• Follow-up 2--4 weeks after the end of treatment,
  and when clinically indicated

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Characteristics of included studies

• Ribera 1998 Short-course (2 weeks, Single) vs.
  short-course (2 weeks, Combination)
• Publication Year 1998
• Period of Study March 1988 to Feb 1993
• Study country, setting Spain, single center
  (academic hospital), inpatients
• Source of funding Not reported
• Methods
• Interventions (intravenously)
• Treatment arm (2 weeks)
• Cloxacillin (2 g/4h for 2 weeks)
• Comparison arm (2 weeks)
• Cloxacillin (2 g/4h for 2 weeks)
• Gentamicin (1 mg/kg body weight/8h for first
  week)
• Randomization issues
• Method of randomization 5 of group A 5 of group
  B (in a set of 10)
• Allocation sequence generation Yes (using random
  number table)
• Allocation concealment Not clear (sealed
  envelope opened at the start of treatment)
• Observer blinding No

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Characteristics of included studies

• Fortun 2001
• Publication Year 2001
• Period of Study 30 months
• Study country Spain, single center
• Source of funding Not reported
• Methods
• Interventions (all for 2 weeks except indicated,
  intravenously)
• Treatment arm
• Cloxacillin (2 g/4h)
• Gentamicin (1.5 mg/kg body weight/8h)
• Comparison arm I
• Vancomycin (500 mg/6h)
• Gentamicin (1.5 mg/kg body weight/8h)
• Comparison arm II
• Teicoplanin (12 mg/kg body weight/24 h (first
  day24 mg/kg))
• Gentamicin (1.5 mg/kg body weight/8h)
• Randomization issues

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Meta Analysis

• A total of 140 patients were randomized in three
  studies
• Treatment failure T Cloxacillin Gentamicin
  vs. comparisons
• Fortun 1995 2/9 vs. 5/7
• Ribera 1996 14/45 vs. 11/45
• Fortun 2001 .5/11 vs. 10/23
• Meta-Analysis (Total 16/65 vs. 26/75)
• RR (lower 95 upper)
• Fortun1995 0.31 0.08 1.15
• Ribera1996 1.27 0.65 2.49
• Fortun2001 0.10 0.01 1.63
• RR (Fixed effect) 0.71, 95 CI (0.45, 1.12)
• Test for heterogeneity X2(2) 6.28 (p-value
  0.0434)
• RR (Random effect) 0.51, 95 CI (0.13,1.96)
• Test for heterogeneity X2(2) 5.88 (p-value
  0.0529)
• Estimated random effects variance 0.89

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Forest Plot

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Forest Plot...

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Conclusion of the meta-analysis

• Based on the pooled estimate from the
  meta-analyses using both the fixed and random
  effect models, the short-course combination
  therapy of Cloxacillin and Gentamicin did not
  appear to be effective in the treatment of
  right-sided endocarditis in intravenous drug
  abusers
• However, there are substantial heterogeneity
  between study results (Chi-square test of
  homogeneity, p lt .10)
• This might be due to different treatment duration
  or due to single and combination therapy in
  comparison arms or due to both.
• Funnel plot to assess the publication bias could
  not be produced due to small number of studies.

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Subgroup Analysis

• To address the heterogeneity in the study
  results, we planned to do separate analysis for
  each group of long-course and single, long course
  and combination, short-course and single,
  short-course and combination, therapies used in
  the comparison arms

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Subgroup Analysis Long-course monotherapy

• 1 study (Fortun 1995)
• Cloxacilliin Gentamicin (2 weeks) vs.
  Teicoplanin (4 weeks)
• Treatment failure 2/9 vs. 5/7
• Observed RR RR 0.31 95 CI ( 0.15, 0.66 )
• Conclusion
• large effect size short-course treatment of
  right-sided endocarditis with combination of
  Cloxacillin and Gentamicin may be better regimen
  than longer course therapy of teicoplanin
• However, very small study size, In sufficient
  data and follow-up period was relatively short
• Trial had to be stopped prematurely due to
  adverse events in comparison arms

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Subgroup Analysis Short-course monotherapy

• 1 study (Ribera 1996)
• Cloxacilliin Gentamicin (2 weeks) vs.
  Cloxacillin (2 weeks)
• Treatment failure 14/45 vs. 11/45
• Observed RR 1.27 and 95 CI ( 0.63, 2.57 )
• Conclusion
• Drugs under comparison are had similar efficacy
• Trial was of moderate size (90 randomized),
  follow-up period was adequate

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Subgroup Analysis Short-course Combination
therapy

• Separate
• A Cloxacilliin Gentamicin vs. Vancomycin
  Gentamicin
• 0.5/11 vs. 5/11
• Observed RR RR 0.1 95 CI ( 0.01, 0.79 )
• B Cloxacilliin Gentamicin vs. Teicoplanin
  Gentamicin
• 0.5/11 vs. 5/12
• Observed RR 0.11 95 CI ( 0.01, 0.93 )
• Combined
• Cloxacilliin Gentamicin vs. (Vancomycin or
  Teicoplanin) Gentamicin
• 0.5/11 vs. 10/23
• Observed RR 0.1 95 CI ( 0.01, 0.82 )
• Conclusion
• Cloxacillin Gentamicin may be effective,
  however CI of observed effect size RR is
  relatively wide
• Insufficient data, a size of 34 is small
• Trial had to be stopped prematurely due to
  adverse events in comparison arms

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References of included studies

• Short vs. longer therapy
• Combination vs. Single
• Fortun 1995
• Fortun J, Perez-Molina JA, Anon MT, et al.
  Right-sided endocarditis caused by staphylococcus
  aureus in drug abusers. Antimicrobial Agents and
  Chemotherapy 1995 39(2) 525-8
• Short vs. short therapy
• Single vs. combination
• Ribera 1998
• Ribera E, Gomez-Jimenez J, Cortes E, et al.
  Effectiveness of cloxacillin with and without
  gentamicin in short-term therapy for right-sided
  staphylococcus aereus endocarditis. Ann Intern
  Med 1996 125(12) 969-74
• Combination vs. combination
• Fortun 2001
• Fortun J, Navas E, Martinez-Beltran J, et al.
  Short-course therapy for right-sided endocarditis
  due to staphylococcus aureus in drug abusers
  Cloxacillin versus glycopeptides in combination
  with gentamicin. Clinical Infectious Diseases
  2001 33120-5

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• Thank You!