journal club indian journal of pharmacology

Journal ClubDr Ketan Asawalle

JR2Dept. Of PharmacologyShri VN GMC Yavatmal

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.

Scope Of Presentation

• Aims and Objectives• Introduction• Materials and Methods• Results• Discussion• Criticism

Aims and Objectives

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

Introduction

• 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.

• 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

Materials and Methods

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 IndiaInstitutional Ethics Committee approval was obtainedStudy Setting:Outpatient dermatology clinic in a tertiary care teaching hospital

Inclusion criteria:1. Subjects of either sex aged at least 12 years,

with2. Clinically defined cases of uSSSIExclusion Criteria:3. Pregnancy or breast-feeding,4. History of hospitalization or systemic

antimicrobial use within past 14 days,5. Signs and symptoms suggestive of cSSSI,6. History of immunosuppression, and7. Recent use of certain medications (e.g.

warfarin, phenytoin, methotrexate, and other immunosuppressive drugs, systemically administered

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 hSecondary 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.

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.

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.

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.

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.

Results

525 cases of uSSSI were screened

300 cases were allocated to the two study groups

202 did not fulfil IC and23 refused to participate

150 Arm 2150 Arm 1

146 Arm 2148 Arm 1

The analysis was on modified intention-to-treat basis

• 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.

Discussions

• 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.

• 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

included2. The open label design introduces

possibility of bias3. The bacterial nature of the infections was

not confirmed

• 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.

Criticism and Appraisal

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 =YesIRB approval = Yes

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 hSecondary outcome measures were(a)Clinical cure at 7 days.(b)Suspected adverse drug reactions.

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:

1b. R- Were the groups similar at the start of the trial?


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:

2a. A – Aside from the allocated treatment, were groups treated equally?


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.


2b. A – Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?


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.


3. M - Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received?


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.


What were the results?

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.

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)

Thank You!!!!

journal club indian journal of pharmacology

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