Month: September 2019

It’s Lefamulin Time

New antimicrobials – particularly those with novel mechanism of action – are rare. Lefamulin, a pleuromutilin class antibiotic, is not new, but it’s new to humans – or, even more specifically, new to oral and intravenous availability in humans.

This article in JAMA details LEAP-2, the sequel (of course) to LEAP-1. This clinical trial demonstrates the non-inferiority of oral lefamulin to oral moxifloxacin for the treatment of generally mild community-acquired pneumonia. LEAP-1, as I’m certain you recall, demonstrated its non-inferiority as an intravenous-to-oral regimen for slightly-less-mild CAP in whom hospitalization was reasonable. Without belaboring the results too greatly, “early clinical response in the intention to treat population” and “test of cure in modified intention to treat populations” were generally similar, with response rates of about 90% for each arm. However, lefamulin is certainly less well-tolerated – diarrhea, nausea, and vomiting far exceeded the frequency observed in the moxifloxacin cohort.

These are likely valid results with respect to efficacy and a 10% non-inferiority margin, considering pleuromutilin antibiotics have been used effectively in animals for decades. This was, however, a tightly-controlled trial, narrowly targeted at meeting the threshold for approval in Europe and the United States (i.e., 50% of patients required to be PORT Class II, so 50.4% of them were). All authors, study procedures, and analyses were overseen by the sponsor, and trial sites were scattered across the (somewhat) developing world. Irregularities regarding efficacy differences and assessments were seen at several sites and addressed in the supplementary appendix, noting mostly the exclusion of results from these sites would not have affected the overall trial outcome. All these signals, however, do raise concerns regarding underreporting of adverse events and systematic minimization of any efficacy differences.

It’s splendid to have a new option for cases of multidrug resistance. For $200 to $300 a day, however, no need to indulge unnecessarily – or be the first on your block to drive the new hotness.

“Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia”
https://jamanetwork.com/journals/jama/fullarticle/2752331

Saving Lives with Lifesaving Devices

Automated electronic defibrillators are quite useful in many cases of out-of-hospital cardiac arrest – specifically, those so-called “shockable rhythms” in which defibrillation is indicated. Ventricular fibrillation, if treated with only bystander conventional cardiopulmonary resuscitation, has dismal survival. However, when no AED is available, the issue is mooted.

This is an interesting simulation exercise looking to improve access to AEDs such that availability might be improved in cases of cardiac arrest. These authors pulled every AED location in Denmark, along with the locations of all OHCAs between 2007 and 2016. Then, they used all OHCA from 1994 until 2007 as their “training set” to help derive an optimal location for AED placement with which to simulate. Optimal AED placements were dichotomized into “intervention #1” and “intervention #2” based on whether their building location provided business-hours access, or 24/7 access.

In the “real world” of 2007 to 2016, AED coverage of OHCA was 22.0%, leading to 14.6% bystander defibrillation. Based on their simulations and optimization, these authors propose potential 33.4% and 43.1% coverage, depending on business hours, leading to increases in bystander defibrillation of 22.5% and 26.9%. This improved coverage and bystander defibrillation would give an absolute increase in survival, based on the observed rate, of 3.4% and 4.1% over the study period.

This is obviously a simulation, meaning all these projected numbers are ficticious and subject to the imprecision of the inputs, along with extrapolated outcomes. However, the underlying principle of trying to intelligently match AED access to OHCA volume is certainly reasonable. It is hard to argue against distributing a limited resource in some data-driven fashion.

“In Silico Trial of Optimized Versus Actual Public Defibrillator Locations”
https://www.sciencedirect.com/science/article/pii/S0735109719361649

Counterpoint: Topical Anesthetics for Corneal Abrasions

We’ve seen a few articles recently discussing the potential utility of topical anesthetics for analgesia for corneal abrasions. The general point: there’s no consistent, modern evidence of harm, so why should we cling to older ways?

Counterpoint from the corneal specialist community: cling to old ways.

In this long correspondence, the authors detail the physiologic basis for their opposition to topical anesthetics as it relates to stimulation of endothelial growth. They follow this up with a three question survey regarding the practice, distributed to “an international community of cornea trained specialists”.

The clear winner in each of their three questions: “strongly disagree” with provision of topical anesthetics for acute corneal abrasions.

Interestingly, they also conflate these results with lack of justification for a clinical trial to further explore the safety and efficacy of such use:

“Often when there is a difference in clinical practice or clinical equipoise, there is an opportunity for a clinical trial. However, it is our hypothesis that within the ophthalmology community, there is not equipoise with respect to our practice of not prescribing topical anesthetics after traumatic corneal abrasions.”

I think it’s clear these specialists are making valid points regarding the potential for topical anesthetic abuse, but their citations hardly support their practice stance. I do agree, at least, regarding the lack of utility of clinical trials – but not because their use is so dangerous it cannot be tested. Rather, any clinical trial simply would be of low value as adverse events would be so rare it would be unlikely to reliably detect a difference between management strategies. It is clear topical anesthetic use will not be safe in all clinical situations, but it is rather more appropriate to provide guidance on the proper use of topic anesthetics than to simply ban them completely while continuing to cite the same anachronistic, limited evidence.

“Cornea Specialists Do Not Recommend Routine Usage of Topical Anesthetics for Corneal Abrasions”
https://www.ncbi.nlm.nih.gov/pubmed/31445551

The Antibiotic Penalty on Blood Cultures

As the administrative team likes to remind us: blood cultures before antibiotics.

Blood cultures before antibiotics.

Blood cultures? Before antibiotics.

What’s the point, we say – aren’t the antibiotics the actual life-saving intervention? And the answer, when relevant, ties into identifying the specific susceptibility of the infective agent, such that antibiotics may ultimately be narrowed to the minimum necessary for cure. It’s a noble premise, at least.

But, so, what does happen when you give antibiotics first?

At least one recent retrospective study has pulled data from their health system showing a clear decrease in blood culture positivity following administration of antibiotics, but these results may be limited by potential differences between groups. In contrast, this clever little study looks at it prospectively: the same 325 Emergency Department patients with “severe manifestation of” sepsis – hypotensive or lactate >4 mmol/L – received blood culture draws both prior to, and just following, antibiotic administration.

Before antibiotics: 31.4% positive blood cultures.

After antibiotics: 19.4% positive blood cultures.

It is not a perfect study by any means, but a long story short: if you’re going to go to the trouble of drawing and processing blood cultures, draw them before you start antimicrobial treatment. But, clearly, the antimicrobials are doing their job – do it expeditiously such that your patient does not suffer from unwanted delay.

“Blood Culture Results Before and After Antimicrobial Administration in
Patients With Severe Manifestations of Sepsis”
https://annals.org/aim/fullarticle/2751453/blood-culture-results-before-after-antimicrobial-administration-patients-severe-manifestations