Evaluation of an article in NEJM for Oral Versus Intravenous Antibiotics for Bone and joint Infection in a randomized clinical trial.

1. Oral versus Intravenous
Antibiotics for Bone
and Joint Infection
Abdulrahman Shaaban
Seminar
Spring 2018-2019
Presented to: Mohamed Hendaus
1

2. 2
I- General overview about the disease and drug
II- Article evaluation:
o Journal
o Title
o Authors
o Funding
o Abstract
o Introduction
o Methods
o Statistical analysis
o Results
o Discussion and Conclusion
o References
III- Related clinical trials
Outline

3. 3
Clinical Case

4. 4

5. 5

6. I. General Overview About
The Disease And The Drug
6

7. Osteomyelitis
7
• Infection in a bone Osteonecrosis and septic arthritis.
• Traveling through the bloodstream or spreading from
nearby tissue.
• Leg bones, arm bones and vertebra.
• Staphylococcus bacteria.
See your doctor if you experience
worsening bone pain along with
fever.
Osteomyelitis - Diagnosis and treatment - Mayo Clinic

8. Risk Factors
• Bone fracture.
• Animal bite
• Nail piercing.
• Cancer treatment.
• Poorly controlled diabetes.
• Illegal drugs, nonsterile needles.
• Peripheral artery disease, often related to
smoking.
• Sickle cell disease.
8
Recent injury or orthopedic surgery
Circulation disorders
Conditions that impair the immune system
Illicit drugs
Osteomyelitis - Diagnosis and treatment - Mayo Clinic

9. 9
Fever
Swelling
RednessPain
Fatigue
Symptoms
Osteomyelitis - Diagnosis and treatment - Mayo Clinic

10. 10
Diagnosis
Treatment
Result
Osteomyelitis - Diagnosis and treatment - Mayo Clinic

11. Treatment
Cephalosporins
Glycopeptides
11
Quinolones
• β-lactam antibiotics, but are
less susceptible to β-
lactamases.
• Disrupt the synthesis of the
peptidoglycan layer forming
the bacterial cell wall.
• Inhibits bacterial cell
wall formation.
• Treating multi-resistant
Staphylococcus aureus
(MRSA) infections which
are resistant to beta-
lactams.
• Inhibit DNA gyrase
(topoisomerase II type
enzyme) so the bacteria will
be unable to replicate.
Osteomyelitis - Diagnosis and treatment - Mayo Clinic
Rifampin
• Antimycobacterial.
• Inhibits bacterial RNA
polymerase, the enzyme
responsible for DNA
transcription.

12. 1. Diarrhea.
2. Decreased
hemoglobin.
3. Eosinophilia.
1. Ototoxicity.
2. Skin rash.
3. Diarrhea.
4. Nephrotoxicity.
1. Nausea and
Vomiting.
2. Dizziness.
3. Insomnia.
4. Phototoxicity.
MEDICAL 04
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Side Effects
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Cephalosporins Glycopeptides Quinolones Rifampin
Drugs - Side Effects - WebMd
1. Nausea and
vomiting.
2. Fever.
3. Headache.
4. Dizziness.

13. II. Article Evaluation
13

14. • The New England Journal of Medicine (NEJM)
• NEJM publishes weekly: 52 times per week
• Highest impact factor of all general medical journals: 79
• It is a medical journal
Peer reviewed
Well reputable
14

15. Title
Oral versus Intravenous Antibiotics
for Bone
and Joint Infection
15

16. Title Evaluation
 Enough information to decide whether to read or not.
 Unbiased.
 Non-conclusive.
 Attractive to the reader.
x Study design is not mentioned.
x Population is not mentioned.
x Doesn't provide enough information if its about efficacy or safety
outcome
16

17. Suggested Title
A Randomized, Open Label Study To Compare
The Efficacy And Safety Of Oral And
Intravenous Antibiotics for Bone
and Joint Infection
17

18. Authors
18
M.R.C.P.Ho-Kwong Li
• Specialist Registrar Infectious Diseases.
• Clinical Research Fellow at Imperial College.
• 1 publication.
D.Phil.Ines Rombach
• Senior medical statistician at Nuffield department of orthopedics at
university of Oxford.
• 43 publications.
M.Sc.Rhea Zambellas
• Project manager at Nuffield department of clinical Neurosciences,
university of Oxford.
• 4 publications.

19. Authors Evaluation
Specialized in the topic.
Qualified.
Well reputable.
There was a statistician among the authors.
The authors don’t have affiliations with the pharmaceutical
company.
x Don’t have many publications.
x Didn’t participate in many studies.
19

20. 1. National Institute for Health Research.
2. OVIVA.
20
Funding

21. Funding Evaluation
21
NO BIAS

22. 22
Brief and reflective of the
main ideas.
Provided the reader with
sufficient information to
retrieve the entire article.
Well summarized.
Well structured.
Objective was clearly
identified.

23. Introduction
Rationale
• The preference for intravenous antibiotics reflects a broadly held belief that
parenteral therapy is superior to oral therapy. However, intravenous therapy is
associated with substantial risks, inconvenience, and higher costs than oral
therapy.
Hypothesis
• Intravenous antibiotics are not superior to oral therapy and bone infection can
be managed by oral antibiotics.
Objective
• To compare the efficacy and safety of intravenous versus oral antibiotic therapy
for patients with bone and joint infection.
23

24. Introduction Evaluation
 Brief introduction.
 Provides Background information about the topic.
 Clear objective.
 Included rationale and hypothesis.
24

25. Methods
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• Subjects: 1050 patients underwent randomization.
• Randomly recruited.
• Multicenter(26 sites).
• Approved by the U.K. National Research Ethics Committee South Central.
• All patients signed a written informed consent.

26. Methods Evaluation
The disease was defined clearly and appropriate for inclusion
criteria.
Subjects recruitment does not affect the results: they are randomly
recruited.
Clearly identified why each exclusion criteria was made.
26

27. 27
Inclusion Criteria
1- Life expectancy > 1 year.
2- Willing and able to give informed
consent.
3- Aged 18 years or above.
4- a) Localized pain b) Localized
erythema.
c) Temperature >38.0º d) A
discharging sinus or wound.
5- The patient has received 7 days
or less of intravenous therapy after
an appropriate surgical intervention.
6- Bone and joint infection treated
in one of the following categories: a)
Native osteomyelitis b) Native joint
sepsis c) Prosthetic joint infection d)
Orthopedic device or bone-graft
infection.
Exclusion Criteria
1- Staphylococcus aureus bacteremia
on presentation or within the last 1
month.
2- bacterial endocarditis on
presentation or within the last month.
3- Any other concomitant infection.
4- Mild osteomyelitis.
5- Septic shock or systemic features.
6- There is clinical evidence of
mycobacterial, fungal, parasitic or viral
etiology.
7- An infection for which there are no
suitable antibiotic choices to permit
randomization between the two arms
of the trial .

28. 28
2077 Patients
were assessed
for eligibility
1499 Were
eligible
1054 Underwent
randomization
909 Were included in the
per-protocol analysis

29. Treatment
• Randomized distribution.
• Active control.
29
Cephalosporins
• Dose: ----
• Duration: 6
weeks.
• Route: IV
Glycopeptides
• Dose: ----
• Duration: 6
weeks.
• Route: IV
Rifampin
• Dose: ----
• Duration: 6
weeks.
• Route: Oral
Quinolones
• Dose: ----
• Duration: 6
weeks.
• Route: Oral

30. Treatment Evaluation
Study design is described.
Open label.
Drug therapy is accurately discussed.
Control is appropriate.
30

31. Measurement
31
Primary Endpoint Secondary Endpoint
 Definite failure of infection treatment,
where definite failure is indicated by
one or more of the following;
A. Isolating bacteria from 2 or more
samples of bone/spine/peri-prosthetic
tissue, where the bacteria are similarly
typed.
B. A pathogenic organism (e.g.
Staphylococcus aureus but not
Staphylococcus epidermidis) on a
single, closed, biopsy of native bone or
spine.
C. Diagnostic histology on bone/peri-
prosthetic tissue.
D. Formation of a draining sinus tract
arising from bone.
 Secondary adverse effects, including death
according to treatment allocation.
 The frequency of line complications.
 Adherence to oral medication.
 Oxford Hip and Knee Scores.
 Resource allocation determined by; a)
length of inpatient hospital stay b)
frequency of outpatient visits c) antibiotic
prescribing costs.
 Early termination of the planned 6 week
period of oral or IV antibiotics because of
adverse events, patient preference or any
other reason.

32. Measurement Evaluation
 Duration of the trial was sufficient.
 Uniformity of measurements was assured among all centers.
 Adherence/compliance was assessed(Clinical assessments and
patient-reported outcome measures were recorded at enrollment
and at days 42, 120, and 365. Adherence to treatment was assessed
at days 14 and 42.
32

33. Statistical Analysis
• Categorical data were compared with Fisher’s test.
• All analyses were performed with Stata software.
• European Quality of Life–5 Dimensions was used in safety and
efficacy analysis.
33

34. Statistical Analysis Evaluation
Power analysis is done.
P-value is calculated and consistent with the clinical result.
Statistical tests used are appropriate with the study design.
Intention-to-treat method is used.
Per-protocol method is used.
Worst case sensitivity analysis is used.
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35. Results
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P< 0.05

36. 36
P<0.001
P<0.006

37. 37

38. 38

39. Discussion
• Did not seek to compare specific antibiotic agents or to
stipulate which agents should be used.
• Rifampin, which is considered by many to be an important
agent in the treatment of certain biofilm-associated infections,
was more commonly planned as treatment in early antibiotic
regimens in the oral group than in the intravenous group,
although a subgroup analysis showed no significant effect of
planned use on outcome.
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40. Discussion Evaluation
Summarized the important results.
Discussed the clinical implications.
Stated the limitations of the study.
X Did not raise a question for further studies.
X Compare the results to other published trials.
40

41. Conclusion
• Oral antibiotic therapy was non-inferior to intravenous therapy
when used during the first 6 weeks in the management of bone
and joint infection, as assessed by treatment failure within 1
year.
• Oral antibiotic therapy was associated with a shorter length of
hospital stay and with fewer complications than intravenous
therapy.
41

42. 42

43. References Evaluation
18 references.
4 references are outdated.
Authors did not cite themselves excessively.
All references are related to the topic.
Primary and secondary literature were used.
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44. III. Related Clinical Trials
44

45. To measure the efficacy of antibiotics
in treatment of long bone infection.
Surgery.
Vancomycin.
Levofloxacin.
Long bone osteomyelitis is difficult to
treat and is responsible for significant
morbidities, but it can be managed by
appropriate antibiotic treatment
regimen.
45
Osteomyelitis of the Long Bones
Objective
Treatment
Conclusion

46. Bone and joint infections
Objective
To measure the efficacy of antibiotics in
treatment of bone and joint infection.
Treatment
Vancomycin.
Rifampin.
Ciprofloxacin.
Conclusion
Does not result in sterilization of the infected
site.
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47. 47

48. - THANK YOU -
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