Comparative evaluation of 2g single dose versus conventional dose azithromycin in uncomplicated skin and skin structure infections. Indian Journal Of Pharmacology. August 2015;Vol. 47; Issue 4

1. Journal Club
Dr Ketan Asawalle
JR2
Dept. Of Pharmacology
Shri VN GMC Yavatmal

2. Indian Journal Of
Pharmacology
August 2015;Vol. 47; Issue 4
Comparative evaluation of
2g single dose versus
conventional dose
azithromycin in
uncomplicated skin and
skin structure infections.

3. Scope Of Presentation
• Aims and Objectives
• Introduction
• Materials and Methods
• Results
• Discussion
• Criticism

4. Aims and Objectives

5. To Compare the effect of 2g single dose
Azithromycin and conventional dose
Azithromycin in uncomplicated skin and
skin structure infections.
Conventional dose = 500mg OD for 5 days

6. Introduction

7. • The skin surface represents a protective boundary between
the body and the outside world.
• Composed of elastic tissue, collagen fibres, vascular
channels, nerve fibres, and several cell types
• Maintaining structural integrity
• Cutaneous inflammatory and infectious conditions liberate
various cytokines.
• Skin infections have been categorized into two broad types
(1) Uncomplicated skin and skin structure infections (uSSSI)
such as simple abscesses, impetigo, furunculosis, folliculitis,
ecthyma, and erysipelas.
(2) Complicated skin and skin structure infections (cSSSI) like
infection either in deeper soft tissues or requiring significant
surgical interventions.

8. • A skin and skin structure infection is usually bacterial in origin.
• Streptococcus pyogenes and Staphylococcus aureus are the
most common etiologic agents.
• Multiple daily dosing is likely to lead to adherence problems.
• Any drug with similar spectrum but less frequency or duration
of use would be a more preferred antibiotic.
• Azithromycin fits this requirement and is a very commonly
used drug for uSSSI.
• The drug quickly gets sequestrated in the intracellular
compartment and this results in high tissue concentration.
• Half-life as long as 11–14 h.
• Single dose has been used successfully in STDs
• Therefore it was decided to compare single supervised dose
of 2 g azithromycin with conventional 500 mg once daily for 5
days dosing in uSSSI. The latter regimen is already well-
established through clinical trials

9. Materials and
Methods

10. Study Type:
Prospective, parallel group, open-label, randomized,
controlled clinical trial.
Study Permissions:
Conforming to Indian Council of Medical Research
guidelines for ethical clinical research and the
Schedule Y Good Clinical Practice guidelines of the
Government of India
Institutional Ethics Committee approval was obtained
Study Setting:
Outpatient dermatology clinic in a tertiary care
teaching hospital

11. Inclusion criteria:
1. Subjects of either sex aged at least 12 years, with
2. Clinically defined cases of uSSSI
Exclusion Criteria:
1. Pregnancy or breast-feeding,
2. History of hospitalization or systemic antimicrobial
use within past 14 days,
3. Signs and symptoms suggestive of cSSSI,
4. History of immunosuppression, and
5. Recent use of certain medications (e.g. warfarin,
phenytoin, methotrexate, and other
immunosuppressive drugs, systemically
administered

12. The primary outcome measure was clinical
response characterized by cessation of the
spread of redness, edema, and induration around
the lesion or reduction of the size of the lesion at
72 h
Secondary outcome measures were
(a)Clinical cure at 7 days.
(b)Suspected adverse drug reactions in the form
of altered vital signs or treatment emergent
adverse events.

13. Sampling:
Sampling was purposive and occurred once a week in
the concerned outpatient department (OPD).
Maximum three subjects were recruited in a day in order
of their appearance.
Randomisation:
Subjects were randomized in fixed blocks of 30 using
computer generated random number lists in 1:1 ratio.
There was no stratification.
Test Arms:
The test group received azithromycin 2 g in tablet form –
four 500 mg tablets were taken orally under the
supervision of the investigator .
The control group received the first tablet of 500 mg
under supervision and was then asked to use up four
more tablets at home at 24 h intervals.

14. Statistical Design:
• The sample size for the study was determined
conventionally and not considering a non-
inferiority design.
• It was estimated that 127 subjects would be
required per group in order to detect a 10%
difference in primary outcome measure between
the groups with 80% power and 5% probability of
Type I error.
• Assuming a 15% dropout rate, the recruitment
target was set at 149 subjects per group or 298
subjects overall (rounded off to 300 subjects).
nMaster 2.0 (Department of Biostatistics,
Christian Medical College, Vellore; 2012)
software was used for sample size calculation.

15. Statistical Analysis:
• Data have been summarized by routine
descriptive statistics.
• Numerical variables were compared between
groups by Student’s t-test, if normally distributed,
or by Mann–Whitney U-test, if otherwise.
• Fisher’s exact test or Pearson’s Chi-square test
was employed for intergroup comparison of
categorical variables.

16. Statistical Analysis:
• Individual sign-symptoms were coded as
categorical variables and were assessed for
change in frequency over time by Cochran’s test.
• All analyses were 2-tailed.
• Statistical significance implied P < 0.05.
• Statistical version 6 (Tulsa, Oklahoma: StatSoft
Inc., 2001) and GraphPad Prism version 5 (San
Diego, California: GraphPad Software Inc., 2007)
software were used for statistical analysis.

17. Results

18. 525 cases of uSSSI were screened
300 cases were allocated to the two study groups
202 did not fulfil IC and
23 refused to participate
150 Arm 2150 Arm 1
146 Arm 2148 Arm 1
The analysis was on modified intention-to-treat basis

23. • ADRs:
Both dosing regimens were well-tolerated overall.
In both groups 10 adverse events were reported.
• Adherence:
1. Drug administration in the single dose arm was
fully supervised so that there is no issue of lack
of adherence in this arm except for two subjects
who were able to take 3 rather than 4 tablets.
2. In the other arm, excellent, good, and poor
adherence was recorded in 126 (86.30%), 7
(4.79%), and 13 (8.90%) subjects, respectively.

24. Discussions

25. • This is possibly the first randomized controlled
study from India to compare the effectiveness of
single supervised dose of azithromycin with
standard azithromycin dosing in uSSSI.
• This study was conducted mainly to show the
efficacy of single dose regimen but at the same
time adverse events comprised a secondary end
point.
• Majority of adverse effects of azithromycin are
gastrointestinal like nausea, vomiting, and loose
stool.
• The results suggest that the effectiveness and
tolerability of single 2 g azithromycin dose were
comparable to that of standard azithromycin
dosing.

26. • Significantly less adherence was noted in the
conventional dosing arm.
• Clinical efficacy rates with these agents for
uSSSIs range from approximately 78% to 100%.
• The dosing regimens of most other antimicrobial
agents would be less convenient than single
dose azithromycin.
• Study Limitations:
1. Children <12 years of age were not included
2. The open label design introduces possibility of
bias
3. The bacterial nature of the infections was not
confirmed

27. • Acknowledgments:
The authors would like to thank Dr. Anusree
Gangopadhyay and Dr. Sanchita Bala, Residents
in the Department of Dermatology, Institute of
Postgraduate Medical Education and Research,
Kolkata, for assistance with patient evaluation.
• Financial Support and Sponsorship
Nil.
• Conflicts of Interest
There are no conflicts of interest.

28. Criticism and
Appraisal

29. Q. What question did the study ask?
Q. Is the research question relevant?
• Patients – Cases of uncomplicated skin infections
• Intervention - Azithromycin 2g single dose
• Comparison - Conventional Azithromycin therapy.
• Outcome(s) - reduction is size of lesions at day 7.
Q. What is the study design used?
RCT Open labeled
Q. How was sample size calculated?
nMaster Version 2.0 developed at CMC Vellore.
Q. Has the study been done ethically?
Informed Consent =Yes
IRB approval = Yes

30. Q.Is the methodology used for recruitment, diagnostic
criteria and follow up appropriate?
Recruitment = OPD based, but no sample sent for
culture.
Diagnostic criteria = Specialist in dermatology was
given task of diagnosis.
Follow up = Day 3 and 7.
Q. What outcome measures are chosen?
The primary outcome measure was clinical
response at 72 h
Secondary outcome measures were
(a)Clinical cure at 7 days.
(b)Suspected adverse drug reactions.

31. 1a. R- Was the assignment of patients to treatments
randomised?
What is best? Where do I find the
information?
Centralised computer randomisation
is ideal and often used in multi-
centred trials. Smaller trials may
use an independent person (e.g, the
hospital pharmacy) to “police” the
randomization.
The Methods should tell you how
patients were allocated to groups
and whether or not randomisation
was concealed.
This paper: Yes No
Unclear
Comment:

32. 1b. R- Were the groups similar at the start of the trial?
What is best? Where do I find the
information?
If the randomisation process worked (that is,
achieved comparable groups) the groups
should be similar. The more similar the
groups the better it is.
There should be some indication of whether
differences between groups are statistically
significant (ie. p values).
The Results should have a
table of "Baseline
Characteristics" comparing the
randomized groups on a
number of variables that could
affect the outcome (ie. age, risk
factors etc). If not, there may be
a description of group similarity
in the first paragraphs of the
Results section.
This paper: Yes No Unclear
Comment:

34. 2a. A – Aside from the allocated treatment, were
groups treated equally?
What is best? Where do I find the
information?
Apart from the intervention the
patients in the different groups should
be treated the same, eg., additional
treatments or tests.
Look in the Methods section
for the follow-up schedule,
and permitted additional
treatments, etc and in
Results for actual use.
This paper: Yes No
Unclear
Comment:

35. 2b. A – Were all patients who entered the trial accounted
for? – and were they analysed in the groups to which they
were randomised?
What is best? Where do I find the
information?
Losses to follow-up should be
minimal – preferably less than 20%.
However, if few patients have the
outcome of interest, then even small
losses to follow-up can bias the
results. Patients should also be
analysed in the groups to which they
were randomised – ‘intention-to-treat
analysis’.
The Results section should
say how many patients were
randomised (eg., Baseline
Characteristics table) and how
many patients were actually
included in the analysis. You
will need to read the results
section to clarify the number
and reason for losses to
follow-up.
This paper: Yes No Unclear Comment:

36. 3. M - Were measures objective or were the patients and
clinicians kept “blind” to which treatment was being
received?
What is best? Where do I find the
information?
It is ideal if the study is ‘double-
blinded’ – that is, both patients and
investigators are unaware of
treatment allocation. If the
outcome is objective (eg., death)
then blinding is less critical. If the
outcome is subjective (eg.,
symptoms or function) then
blinding of the outcome assessor
is critical.
First, look in the Methods
section to see if there is some
mention of masking of
treatments, eg., placebos with
the same appearance or sham
therapy. Second, the Methods
section should describe how the
outcome was assessed and
whether the assessor/s were
aware of the patients' treatment.
This paper: Yes No Unclear Comment:

37. What were the results?

38. Drug administration in the single dose arm was
fully supervised so that there is no issue of lack
of adherence in this arm except for two subjects
who were able to take 3 rather than 4 tablets. In
the other arm, excellent, good, and poor
adherence was recorded in 126 (86.30%), 7
(4.79%), and 13 (8.90%) subjects, respectively.

39. The questions that you should ask before you
decide to apply the results of the study to your
patient are:
• Is my patient so different to those in the study
that the results cannot apply?
• Is the treatment feasible in my setting?
• Will the potential benefits of treatment outweigh
the potential harms of treatment for my patient?
Will the results help me in caring for my patient?
(ExternalValidity/Applicability)

40. Thank You!!!!