SGEM#262: Omadacycline – Is it non-inferior to linezolid for skin and soft tissue infections?

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Date: July10th, 2019

Reference: O’Riordan W et al. Omadacycline for Acute Bacterial Skin and Skin-Structure Infections. NEJM Feb 2019

Guest Skeptic: Dr. Anand Swaminathan is an assistant professor of Emergency Medicine at the St. Joseph’s Regional Medical Center in Patterson, NJ. He is a deputy editor for EM: RAP and, associate editor for REBEL EM.

Case: A 22-year-old woman presents with redness and swelling of her left lower leg from the top of the ankle to about midway up the calf on the medial surface of the leg. Her skin is warm with mild tenderness, no fluctuance and no crepitus. She is well appearing without a fever and she has no prior medical history or allergies. You are about to write her a prescription for cephalexin when you suddenly remember reading about a new antibiotic that recently became available for skin and soft tissue infections called omadacycline

Background: We have covered cellulitis and abscesses a number of times on the SGEM (SGEM 13, 131, 156, 164, 209). Often the guest skeptic on these shows is the amazing Physician Assistant, Chip Lange from TOTAL_EM Podcast and the Practical POCUS course.

The production and release of new antibiotics is rare and should be celebrated by clinicians. As antibiotic resistance continues to mount, our options narrow and, in turn, our patients suffer.

Recently, the NEJM published two articles on a new antibiotic that was recently FDA approved, omadacycline. The articles compared omadacycline to moxifloxacin in the treatment of community acquired pneumonia (CAP) and to linezolid in the treatment of skin and soft tissue infections. Both studies yielded promising results for the new drug which should be cause for excitement.

However, significant biases, methodological flaws and poor selection of comparator treatments should temper our excitement.

Clinical Question: Is omadacycline non-inferior to linezolid in terms of early clinical response in the treatment of skin and soft tissue infections?

Reference: O’Riordan W et al. Omadacycline for Acute Bacterial Skin and Skin-Structure Infections. NEJM Feb 2019

Population: Patients older than 17 years with a skin infection (cellulitis, erysipelas or major abscess)
- Exclusions: Patients with one or more doses of systemic antibiotics prior to presentation, topical antibacterial agent within 72 hours, infections that would require more than 14 days of treatment, chronic skin lesions, ulcers or wounds and patients with any liver or renal insufficiency or immunocompromise
Intervention: Omadacycline 100 mg IV Q12 for two doses then 100 mg Q24 for at least two more days with the option to transition to 300 mg Q24 for 7-14 days total
Comparison: Linezolid 600 mg IV Q12 with the option to transition to 600 mg Q12 orally for 7-14 days after at least three days of IV
Outcome:
- Primary: Early clinical response defined as survival with a reduction in lesion size of at least 20% at 48-72 hours after the first dose
- Secondary: Clinical response post-treatment(at 7-14 days)

Authors’ Conclusions: “Omadacycline was noninferior to linezolid for the treatment of acute bacterial skin and skin-structure infections and had a similar safety profile.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Unsure
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). Unsure
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. No
The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They enrolled 655 patients from 55 sites in the US, Peru, South Africa and multiple countries in Europe. The median age was 47 years old and 2/3 were men. It was about 33% wound infection, 38% cellulitis or erysipelas and 29% major abscess.

Omadacycline was non-inferior to linezolid

Primary Outcome: Early clinical response defined as survival with a reduction in lesion size of at least 20% at 48-72 hours after the first dose
- mITT 84.8% in omadacycline vs 85.5% in linezolid. Diff 0.7% 95% CI -6.3 to 4.9
- Noninferiority of omadacycline

Secondary Outcomes: Clinical response post-treatment (at 7-14 days)
- mITT 86.1% vs 83.6% Diff 2.5% (95% CI -3.2 to 8.2)
- Noninferiority of omadacycline

1. Funding: Our current research paradigm involves funding from pharma. Just because a study is funded by industry does not make the results invalid, but it should make us more skeptical. Here is what they said in the methods section: “Paratek Pharmaceuticals designed and conducted the trial and prepared the statistical analysis plan. Analyses were performed and data interpreted by Paratek Pharmaceuticals in conjunction with the authors. “

They went on to say:“All the authors vouch for the integrity, completeness, and accuracy of the data and analyses and assume responsibility for the fidelity of the trial to the protocol and statistical analysis plan, which are available at NEJM.org.”

However, the next sentence was “A medical writer who was supported by the sponsor assisted with preparation of a first draft of the manuscript.” Where do you think their loyalties lie, to science or their employer?

2. Selection Bias: There may have been selection bias in this and the CAP study. They did not state that patients were enrolled consecutively in either study. It’s unclear how many patients met criteria but were not approached.

This is obvious when you see that in the CAP study, only 774 patients were enrolled over 14 months across 86 sites (< 1 patient/site/month) and only 627 patients enrolled in the SSTI study over 12 months across 55 sites (1.2 patients/site/month).

The average ED sees far more of these presentations per week and, thus, many patients were never approached, i.e. the study group seems to have been cherry-picked. Additionally, in the CAP study, there was a 1% absolute difference in mortality. I would be reluctant to prescribe a drug that was no worse than a standard treatment if it had any increase in mortality.

3. Non-Inferiority Trials: There are a few things we wanted to mention regarding this type of trial design. Most people understand that a superiority trial is attempting to demonstrate some treatment is better than another by some pre-determined margin.

A non-inferiority trial does not mean something is equal or equivalent. It is impossible to show something is equal because there will always be small changes between two groups if sample sizes are large enough. But there are equivalent trial designs to say things are within a pre-specified range.

Non-inferiority trials are designed to show that some treatment is not worse than another treatment. Researchers can choose a non-inferiority trial design for a number of reasons including ethical (unethical to expose patient to a placebo), cost (less expensive due to smaller sample size) and safety.

Pharmaceutical companies have used the non-inferiority trial design to sell their new (usually more expensive drug) not based on efficacy but rather on something like ease of use. Here is what we could find on the cost of antibiotics:

Cephalexin (500mg) is $10 for 40 tabs = $1.60/day
Linezolid (600mg) is $50 for 20 tabs = $5/day
Omadacycline (150mg) is $1,245.65 for 6 tabs (taking 300mg/day) = $415.22/day

One of the key elements of a non-inferiority trial is setting the margin considered “non-inferior”. In this trial looking at omadacycline they set the margin at 10% based on historical data from controlled trials comparing antibacterial drugs with non-antibacterial treatments.

Why not set the margin at antibiotic treatment vs. antibiotic treatment? If they had set their non-inferiority margin at say 5% would that change the results and interpretation?

4) ITT vs. PP Analysis: A quality indicator for most RCTs is to look and see if the authors did an ITT. Remember that an ITT looks at all the patients immediately post randomization regardless of the treatment they received. There can be cross over after randomization, but the patients always get analyzed into their original group allocation. This is a conservative way to view the results of in a superiority trial design.

In contrast, PP analysis looks at the actual treatment the patient got. This analysis can over-estimate the point estimate of any effect and could lead to falsely rejecting the null hypothesis of no difference. Again, this is for superiority trials.

However, it is exactly the opposite in non-inferiority trials. You want to see a PP analysis because it would be the conservative approach. It maximizes the differences while the ITT would move you towards less effect and accepting the null and therefore concluding non-inferiority. This can be a tricky concept to get your head around and there is a great video by SketchyEBM you can watch on YouTube.

In this trial they did twelve kind of analysis of various subgroups using mITT and various PP analyses. Nine out of the twelve analyses showed non-inferiority while three did not. Again, if they changed their non-inferiority margin to 5% it looks like only five out of twelve subgroups would be considered non-inferior.

5) Why Linezolid? This is not my go to drug in skin and soft tissue infections. Why did they go with linezolid? Was it because of cost comparison or availability in all countries? It just seems like a strange choice. Why not cephalexin, Bactrim, Clindamycin or Doxycycline?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: The authors found that omadacycline is non-inferior to linezolid for the treatment of SSTI in terms of early clinical response at 48-72 hours. However, the study’s design has numerous flaws and, omadacycline is not cheaper, easier to use or has less side effects than standard treatment.

SGEM Bottom Line: We don’t recommend the routine use of omadacycline in the treatment of skin and soft tissue infections.

Case Resolution: You decide to go with your first thoughts and prescribe the patient cephalexin 500mg four times a day for seven days and schedule a return visit in three days to check out how the patient is doing.

Clinical Application: The usual first line treatment for skin and soft tissue infections should continue to be cephalexin plus or minus trimethoprim-sulfamethoxazole (TMP-SMX) for patients at risk for methicillin-resistant staphylococcus aureus (MRSA).

EM Swami

What Do I Tell My Patient? There are lots of antibiotics that are effective in the treatment of cellulitis. Cephalexin is a tried and true antibiotic and most patients will improve with this antibiotic. You can expect that there may be some mild expansion of the redness over the next 24-48 hours but after that time, it should recede. Come back here or see your doctor in 3-4 days to check out how it’s progressing. If you develop a fever, have vomiting and can’t take your pills or are worried we are happy to see you any time.

Keener Kontest: Last weeks’ winner was, nobody. The answer was the American College of Emergency Physician’s (ACEP) launched the Geriatric Emergency Department Accreditation Program in May of 2018.

Listen to the podcast to hear this weeks’ trivia question. If you know the answer, send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

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