You are likely referring to our primary clinical end point, which was resolution of all signs of infection at 14-21 days. That has been a standard outcome measure for antibiotic studies of skin infections for many years, but you correctly point out the limitation of that endpoint, which is that most skin infections have resolved well before that time, almost regardless of which antibiotic they get. After we had started our study, the FDA came out with new guidance on clinical trials for skin infections. The recommended primary endpoint now is clinical response at 2-3 days, which is probably a better measure of comparative efficacy of antibiotics. We added this as a secondary endpoint, and found no difference between the 1 or 2 antibiotic regimens. While only 27% in each group met the clinical cure criteria at 2-3 days, most continued therapy to eventual cure. We did not get daily checks to allow us to give a specific resolution time with each antibiotic regimen, but they were comparable at each follow up time point, so I doubt there would be any difference in resolution time between the two treatments.
For the 1 in 7 failure : What is the next step of management ? Are ther predictors of failure Eg Diabetis Peripheral vascular disease Immunological Competence problems Obesity Smoking Psychiatric Problems ?
In order to protect the blinding, the study protocol specified that treatment failures would receive either doxycycline or clindamycin. Those antibiotics were chosen because they were not part of the study treatment, and would cover expected pathogens, including MRSA. Note also that about 1/3 of the treatment failures were found to have an abscess at the time of failure, so drainage is the more important part of the treatment for those. We did not do a secondary analysis to look at predictors of failure overall, but did not find a difference between the two treatment groups when we did sub-analyses stratified by fever, diabetes, or larger area of cellulitis.
The study you cite was comparing parenteral to oral treatment. While they found no difference, the study was probably too small (<50 patients total) to have convincing results. Nonetheless, I believe it is likely that we are over-admitting patients for IV treatment of skin infections that would do fine with oral antibiotics. We used the common dosing of cephalexin 500mg qid in our study, which should achieve levels above the MIC for skin pathogens Strep and Staph. Note that for the added Trimethoprim-Sulfa that we compared to placebo, we used the higher dose of 2 double strength tablets bid. We did that to avoid the critique that we might have found a difference if we had used a higher dose. My own practice when using TMP-SMX for skin infections is to give one double strength tablet bid, which should also achieve levels above the MIC for Staph. I will sometimes go up to 2 DS bid for patients with BMI above 30 or so.
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Marlene G. - October 17, 2017 9:20 AM
3 weeks seems like a dreadfully long time for resolution of cellulitis. Any information on resolution time with 1 vs 2 antibiotics?
Greg M., MD FAAEM - October 18, 2017 10:29 AM
You are likely referring to our primary clinical end point, which was resolution of all signs of infection at 14-21 days. That has been a standard outcome measure for antibiotic studies of skin infections for many years, but you correctly point out the limitation of that endpoint, which is that most skin infections have resolved well before that time, almost regardless of which antibiotic they get. After we had started our study, the FDA came out with new guidance on clinical trials for skin infections. The recommended primary endpoint now is clinical response at 2-3 days, which is probably a better measure of comparative efficacy of antibiotics. We added this as a secondary endpoint, and found no difference between the 1 or 2 antibiotic regimens. While only 27% in each group met the clinical cure criteria at 2-3 days, most continued therapy to eventual cure. We did not get daily checks to allow us to give a specific resolution time with each antibiotic regimen, but they were comparable at each follow up time point, so I doubt there would be any difference in resolution time between the two treatments.
Marlene G. - October 18, 2017 10:37 AM
Thanks!
Ian L. - October 18, 2017 11:08 PM
For the 1 in 7 failure :
What is the next step of management ?
Are ther predictors of failure Eg Diabetis Peripheral vascular disease Immunological Competence problems Obesity Smoking Psychiatric Problems ?
Greg M., MD FAAEM - October 19, 2017 8:35 AM
In order to protect the blinding, the study protocol specified that treatment failures would receive either doxycycline or clindamycin. Those antibiotics were chosen because they were not part of the study treatment, and would cover expected pathogens, including MRSA. Note also that about 1/3 of the treatment failures were found to have an abscess at the time of failure, so drainage is the more important part of the treatment for those.
We did not do a secondary analysis to look at predictors of failure overall, but did not find a difference between the two treatment groups when we did sub-analyses stratified by fever, diabetes, or larger area of cellulitis.
Shu-Haur O. - October 29, 2017 8:21 PM
what about just using bigger doses? although i'm not sure how this Australian study would generalise to the US population
https://www.ncbi.nlm.nih.gov/pubmed/25336165
pre study our typical oral regimen was 500 mg qid of fluclox/ cephlexin; post study it was more often 1g qid fluclox/ cephlexin.
Greg M., MD FAAEM - November 22, 2017 10:02 AM
The study you cite was comparing parenteral to oral treatment. While they found no difference, the study was probably too small (<50 patients total) to have convincing results. Nonetheless, I believe it is likely that we are over-admitting patients for IV treatment of skin infections that would do fine with oral antibiotics. We used the common dosing of cephalexin 500mg qid in our study, which should achieve levels above the MIC for skin pathogens Strep and Staph. Note that for the added Trimethoprim-Sulfa that we compared to placebo, we used the higher dose of 2 double strength tablets bid. We did that to avoid the critique that we might have found a difference if we had used a higher dose. My own practice when using TMP-SMX for skin infections is to give one double strength tablet bid, which should also achieve levels above the MIC for Staph. I will sometimes go up to 2 DS bid for patients with BMI above 30 or so.