Category: Infectious Disease

More Bad News for Influenza Antivirals

Deep in the throes of influenza season, I’m sure the oseltamivir is flying off the shelves around the country. In Japan, however, it’s baloxavir that’s flying off the shelves. Unfortunately, as was presaged by the data from their definitive clinical trial, resistance to baloxavir is rapidly increasing.

And, now, tucked into this retrospective look at “early” versus “late” oseltamivir treatment in the critically ill – additional data regarding its general futility. In this 1,330 patient ICU cohort of patients who received osteltamivir within 48 hours of symptom onset (“early”) or later (“late”), overall mortality was 46.8% – and no different between the two groups. There are obvious issues here with regards to confounding and baseline differences, but it should be apparent a beneficial treatment … provides some benefit.

The authors did observe an absolute 10% survival advantage associated with “early” treatment in those infected with A/H3N2 – but as this accounted for a minority of their cases, overall, the entire cohort was a wash. This is consistent with another review specific to data from the 2009A/H1N1 pandemic. Mortality in included studies was only 8%, but no survival advantage was seen in those treated with oseltamivir. While universal and indiscriminate treatment with neuraminidase inhibitors is engrained in the conflict-of-interest-infested IDSA guidelines, one can only hope these data points encourage additional prospective evaluation into the true narrow value of our tools for the treatment of influenza.

“Effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study”

https://www.ncbi.nlm.nih.gov/pubmed/30753349

IDSA Influenza – Class A, Level III

The last time the IDSA updated their influenza practice guidelines, it was the time of the 2009 H1N1 influenza pandemic. Fittingly, we are entering another season of H1N1 – and we have new guidelines, incorporating all the new evidence gathered in the meantime.

And, unfortunately, that is to say: we don’t really have any new, high-quality evidence.

The grading system for their recommendations includes two categories. Strength of recommendation:

  • A: Good evidence to support a recommendation for or against use
  • B: Moderate evidence to support a recommendation for or against use
  • C: Poor evidence to support a recommendation

Quality of evidence:

  • I: Evidence from 1 or more properly randomized controlled trials
  • II: Evidence from 1 or more well-designed clinical trials, without randomization; from cohort or case-controlled analytic studies (preferably from >1 center); from multiple time-series; or from dramatic results from uncontrolled experiments
  • III: Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees

It would follow, then, for an “A” strength recommendation, this ought to reflect I or II quality of evidence – but a bizarrely staggering number of their recommendations are A-III, effectively self-contradicting. Most of their “Which Patients Should Be Tested for Influenza?” recommendations are A-III. The critical “Which Patients With Suspected or Confirmed Influenza Should Be Treated With Antivirals?” section features another batch of A-III recommendations, followed by several C-I and C-IIIs.

A long story short, this is simply paradoxical, making level A recommendations from class III evidence in the form of manufacturer sponsored trials, indirectly-sponsored meta-analyses, and observational data. Many authors of this piece are neck deep in reported financial and professional conflicts of interest with industry, which almost certainly eases any pain felt by distributing such internally invalid recommendations. After decades of controversy and hundreds of millions of dollars in profit for Genetech/Roche, we’re still bumbling along with our original momentum lacking a full understanding of the effectiveness and value of these medications.

“Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza”
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciy866/5251935

Rochester v. Philadelphia, Pediatric Edition

It’s a little tough for Rochester to go head-to-head against Philadelphia – with apologies to the Americans, Red Wings, Rhinos, Knighthawks, and Razorsharks. The playing field of … the playing field … is just on another level in Philadelphia. The playing field of febrile infants, however, is another matter.

This small study re-analyzed prospective data from 135 febrile children ≤60 days of age with documented invasive bacterial illness, and applied the Rochester and modified Philadelphia criteria for risk-stratification. IBI was defined as having a positive blood or CSF culture, if obtained. In this small sample, both Rochester and Philadelphia were 100% sensitive for all cases of meningitis in infants greater than 28 days of age, but each missed similar numbers of those with bacteremia. A comparison for those below 28 days is frankly irrelevant, as the modified Philadelphia criteria specifically applies only to those >28 days of life – so, yes, it is comically 100% sensitive and 0% specific in neonates. The Rochester criteria, which does not mandate CSF, if applied to those ≤28 days, would have missed two cases of meningitis, and is therefore not suitable for use.

The takeaway here is not so much which criteria is superior to the other – the elements of each are virtually identical. Moreso, it is the recognition that each is about 83% sensitive, and all children in this age range evaluated in the ED and discharged will require close follow-up for re-evaluation of clinical status.

“Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture”
https://www.ncbi.nlm.nih.gov/pubmed/30425130

New Anti-Flu, Just Like the Old Anti-Flu

Mitigating the harm of influenza pandemic is certainly an important endeavor. Despite the clinical importance, however, we’ve simply been kicking the oseltamivir can down the road for over a decade. Given the ongoing controversy over its usefulness, this is suboptimal – and winter, of course, is coming.

The newest agent to the scene is baloxavir marboxil, being developed in Japan. Baloxavir is a selective inhibitor of influenza endonuclease, rather than a neuraminidase inhibitor like oseltamivir. This recent article details the phase 2 dose-ranging study and subsequent phase 3 placebo and oseltamivir-controlled trial, CAPSTONE-1.

There were 1,436 patients enrolled in CAPSTONE-1, 1,064 of whom were ultimately confirmed to have influenza A or B. Most of the patients (~85%) had influenza A. The results are – well, “favorable”, by which I mean most likely “profitable”. Symptom duration in the infected population was attenuated by the the same length of time as oseltamivir, which in turn was about a day shorter than placebo. Various measures of viral expression were improved by baloxavir, which seemed to virtually eliminate detectable infective activity within the first 24 hours. There were a small number of extra treatment-related adverse events in the baloxavir cohort, but there were only a handful in each cohort overall, and it remains to be seen in further surveillance the true incidence.

As anyone who has been afflicted by influenza can tell you, a day’s shorter illness is no small feat.  of course, this is just a single, sponsored trial, with all the advantages to the “home team”, as it were.  Whether treatment with baloxavir can be demonstrated to decrease clinically important deterioration remains to be seen – as has been a persistent struggle for other antivirals, given the low rate of complications, overall.  Then, even with rigorous screening, a third of those treated did not have influenza.  Real-world use would almost certainly include a greater proportion of patients without influenza.  Lastly, baloxavir-treated patients were observed to develop resistance mutations in substantial numbers, leading to questions whether this medication will provide durable efficacy in widespread use.

“Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents”
https://www.nejm.org/doi/full/10.1056/NEJMoa1716197

More Snapshots of Awful Antibiotic Use

Is there ever any good news these days? Geopolitical disasters, unwarranted pharmaceutical price increases – and physicians can’t even manage to get the evaluation for group A strep right.

This is a “successful” quality improvement paper wrapped around depressing and embarrassing data from a typical primary care pediatrics practice. These authors, primarily pediatric infectious disease specialists, were dismayed by the rate of guideline-non-compliant group A streptococcal testing and treatment in their group.

How bad?

The base rate of unnecessary GAS testing was 64% of all rapid strep tests performed. The base rate of inappropriate antibiotic prescribing – driven primarily by treating positive results in those who should never have been tested (e.g., likely non-pathogenic colonization) – was 49%.

After their multifaceted year-long intervention, they were able to achieve the amazing results of: 40% unnecessary testing … and the same, inappropriate 49% for antibiotic prescribing. When restricted to selection of antibiotic, at least, first-line antibiotics used 87% of the time.

Is this really the best we can possibly do, even after intent focus on practice improvement? And for a disease entitiy with such limited benefit for antibiotic in most modern settings?

“Improving Guideline-Based Streptococcal Pharyngitis Testing: A Quality Improvement Initiative”
http://pediatrics.aappublications.org/content/early/2018/06/18/peds.2017-2033

Treating Influenza with Antibiotics & Other Stories

Every time I review an article espousing the benefits of a protocol based on the use of procalcitonin to improve antibiotic stewardship, I usually say something along the lines of: “We don’t need this test, it only looks like we need it because our baseline antibiotic prescribing is hysterically shameful.”

Well, here’s another piece of evidence describing the basis for that statement.

This is a secondary analysis of observational data collected from the Influenza Vaccine Effectiveness Network. All patients were eligible for inclusion in the study if they presented with an acute cough of duration fewer than 7 days. Patients all received influenza testing as part of disease surveillance, as well as any other testing indicated.

Of 14,987 patient visits analyzed, 6,136 (41%) were associated with an antibiotic prescription. Of these, 2,494 patients (52%) received diagnoses for “potentially indicated” antibiotics – pharyngitis, sinusitis, and otitis media – while 2,522 (41%) fell into a category of “antibiotics not indicated” – viral upper respiratory infection, bronchitis, allergy or asthma, clinical influenza, or “other”. So, as far as the coded diagnosis is reliable, it is likely half of prescribed antibiotics are simply unnecessary.

Then, of the 14,987 analyzed, 3,381 had laboratory-confirmed influenza. Excluding those receiving a diagnosis of pneumonia, there were 945 who received a prescription for antibiotics. Finally, there were an estimated 860 patients with a diagnosis of pharyngitis and a negative test for Group A Strep, 327 (38%) of whom received antibiotics.

And, let’s not even get into whether patients received an appropriate narrow-spectrum antibiotic (44%).

There are limitations to the precision and clinical context of using diagnosis codes to classify antibiotic prescribing as appropriate or not, but these results are broadly consistent with the prior literature.  Before we start deferring our prescribing decisions to something like a PCT assay, there’s a huge opportunity to simply Do The Right Thing, first. Once the low-hanging fruit has been resolved, then we can worry about tweezing out the uncertain cases in a narrow cohort with potential limited application of PCT or other infectious disease differentiation engine.

“Outpatient Antibiotic Prescribing for Acute Respiratory Infections
During Influenza Seasons”
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2683951

Predicting Cellulitis Treatment Failure

To (mostly) no one’s surprise, in descending order:

  • Tachypnea at triage
  • Chronic skin ulcers
  • History of MRSA
  • Recurrent cellulitis
  • Chronic kidney disease
  • Diabetes mellitus

Adjusted ORs for failure topped out at ~6.3, and descend into statistical noise from there.

However, reliably unpacking and generalizing these data is far more challenging, considering the variety of permutations for treatment and treatment failure. Of the initial 500 consecutive non-purulent skin-and-soft-tissue infections enrolled, patients were managed with all manner of combinations of inpatient and outpatient oral and intravenous antibiotics (including 6 patients with both). Treatment failure in the 288 managed primarily as outpatient, as evaluated from 48 hours to 14 days after the initial ED visit, could result in a change of oral agent, change to outpatient intravenous antibiotics, or hospitalization. While the validity of the predictive features of treatment failure is probably not affected by the specifics of their clinical setting, the rate of failure of oral antibiotics – almost 30% – is likely unique to their population and practice pathway.

At least, in contrast to my last cellulitis article, only 3 patients were subsequently judged by an infectious disease specialist to have a misdiagnosis of cellulitis.

“Predictors of Oral Antibiotic Treatment Failure for Non-Purulent Skin and Soft Tissue Infections in the Emergency Department”
https://www.ncbi.nlm.nih.gov/pubmed/29869364

That Time Dermatology Saved the Day!

Thanks to the insightful teaching of Seinfeld, we know dermatology’s scope exceeds that of “Pimple Popper, MD“. However, when an article published reviewed the rate of misdiagnosis of cellulitis in the hospital, pegged the costs half a billion dollars per year, and suggested a dermatologist be involved in every case where the skin ain’t look right – I was skeptical.

This publication details the results of a trial in which patients admitted with a diagnosis of cellulitis were randomized to either consultation of with a dermatologist within 24-hour of admission or to routine medical care. And, by consultation with a dermatologist – actually just one dermatologist, the senior author on the paper. Over the five year-study period, this dermatologist screened 1,300 patients for potential inclusion, yielding 175 for randomization. The primary outcome, a little unclear from the clinicaltrials.gov registration, is either antibiotic usage or inpatient length-of-stay.

Regardless, the dermatology consultation appeared to improve medical care, although the magnitude of the benefit is more difficult to pin down. The dermatologist identified approximately an excess of one-quarter of the cases to be “pseudocellulitis” – venous stasis dermatitis, erythema migrans, contact dermatitis, or some such ilk – leading to changes in therapy based on misdiagnosis.  Both length-of-stay and antibiotic-free days displayed modest absolute gains in those evaluated by dermatology. The author further tabulated her other recommendations for treatment, including wound care, steroid treatment, and additional testing, and suggests there are many peripheral benefits to specialist involvement.

This is all fairly reasonable at face validity, although it is nearly impossible to generalize this single-institution, single-dermatologist, low-enrollment study to general practice. Given the scarcity of dermatology specialists in many settings, it would take some substantial innovation to find a cost-effective and high-value protocol for utilization.

“Effect of Dermatology Consultation on Outcomes for Patients With Presumed Cellulitis”
https://jamanetwork.com/journals/jamadermatology/fullarticle/2672582

Anti-Calcitonin

The use of procalcitonin to guide antibiotic therapy has been gradually increasing over the past several years – driven, in no small part, by increased recognition of the harms of antibiotic overuse. However, what evidence we have regarding its utility is primarily derived from manufacturer-sponsored trials – including virtual carpet-bombing of the literature by their sponsored representatives.

So, what happens when the manufacturer isn’t part of the trial?

No benefit.

This is the ProACT trial, an individual-randomized comparison between a procalcitonin-guided arm and “usual care” in patients with suspected lower respiratory tract infection for whom the indication for antibiotics is unclear. Physicians caring for patients randomized to the procalcitonin arm were provided results tied to antibiotic use recommendations – “strongly discouraged”, “discouraged”, “encouraged”, “strongly encouraged” – on initial presentation in the Emergency Department, and then in serial fashion for those admitted to the hospital. In those in the “usual care” arm, procalcitonin results were obtained, but not provided to the treating clinicians.

Then: Across 14 hospitals and 1,656 patients, there were no statistically significant differences between antibiotic-free days or adverse outcomes between the two arms. Done? Done.

Except, as skeptical as I might be regarding procalcitonin-guided therapy, there are big holes in these data as the definitive word on its disutility. Unlike other trials, these centers provided only passive guidance to clinicians regarding the procalcitonin algorithm. This resulted in only 72.9% of physicians adhering to protocol, with the greatest numbers of violations being antibiotic use in patients for whom it were discouraged, including 30% of those for whom antibiotic use was “strongly discouraged”:

Even though the “per-guideline” analysis also shows no difference, this is mostly because the bulk of the procalcitonin “per-guideline” population were those who appropriately received antibiotics – effectively eliminating the possibility of showing a difference in antibiotic use.

There are a few signals within these data reflecting the potential advantages of a procalcitonin-guided algorithm, should the protocol actually be followed. There were small differences in prescribing favoring the procalcitonin arm for almost every final clinical diagnosis – excepting about 15% absolute advantages for “acute bronchitis” and for those with non-specific diagnoses. It is likely these represented the cases for which the appropriateness of antibiotics was lowest, and probably also represent the majority of protocol violations. That said, one could easily make the argument this advantage only exists as a result of culturally-ingrained poor antibiotic prescribing habits for these sorts of borderline cases.

In short, these data clearly show there is no advantage to introducing procalcitonin into practice specifically in the fashion demonstrated here – but these cannot be generalized to say a different implementation or application of procalcitonin has no value.  On the flip side, however, places that have implemented procalcitonin-driven stewardship programs also struggle with inappropriate and high-volume test ordering.  There is work yet to be done for both proponents and skeptics of its value.

“Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection”
https://www.nejm.org/doi/full/10.1056/NEJMoa1802670

Whoa! Fosfomycin in Prime Time!

For many years, I’ve tossed out the idea of using fosfomycin for uncomplicated urinary tract infections to various trainees – the vast majority of whom looked at me as though I had three heads. Even now, it’s easy to find folks who’ve never heard of fosfomycin, despite its mention in the most recent guidelines for UTIs. In the United States, the land of low-value health care, fosfomycin is preposterously expensive for a single dose – and rarely used.

The story, however, is a little different outside the U.S. Thus, the question – which is a better options, fosfomycin or nitrofurantoin? The answer: in Israel, Switzerland, and Poland, nitrofurantoin, probably.

This is an open-label trial with 513 patients randomized either to five days of nitrofurantoin or a single 3g dose of fosfomycin. Outcomes included clinical and microbiologic cure, and both favored nitrofurantoin by an absolute margin of ~10%. Oddly enough, their primary outcome was a 28-day clinical cure – which starts to stretch the measurement window into the range of subsequent, unrelated infection, rather than response to the initial therapy. This is apparent when looking at the 14-day and 28-day microbiologic response, in which bacterial counts were clearly creeping back up after an initial nadir.

Regardless, both agents are options – and fine options, depending on local resistance patterns, suspected pathogens, and other contextual clinical features. That said, in the U.S., most of the current appropriate prescribing is for trimethoprim-sulfamethoxazole – so, a similar trial comparing this with these alternative agents would need to be performed to better inform practice here.

“Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women”
https://jamanetwork.com/journals/jama/article-abstract/2679131