Category: Antibiotics

Just Stand There! Bacterial Vaginosis Edition

There has long been considered to be a causative association between bacterial vaginosis and preterm delivery – with increasing risk of delivery when BV is identified earlier in pregnancy. Clearly, of course, early antibiotic treatment would eradicate the pathology and improve pregnancy outcomes. It just makes sense.

But, no.

In this large, multicenter trial performed in France, 84,530 pregnant women were screened before 14 weeks gestation, resulting in 5,630 diagnoses of BV. Patients deemed “low-risk” for preterm delivery were treated with one of regimens of clindamycin or placebo, while those few deemed “high-risk” were excluded from placebo randomization. The primary outcome was late miscarriage or early preterm birth, a range of preterm delivery spanning 16-32 weeks gestation.

Approximately 2/5ths of those approached for enrollment declined to participate, leaving 2,869 for randomization into one of the three low-risk arms. There were no important baseline differences between the three cohorts. The results: no difference. About 1% of each group met the primary outcome, and there were no signals of even a small magnitude of benefit to treatment with clindamycin in the low-risk cohorts. Adverse events, of course, clearly favored placebo – as befitting clindamycin’s known propensity for gastrointestinal effects, but no effects on fetal outcomes were apparent.

This is not specifically relevant to Emergency Medicine other than to demonstrate the need to rigorously test even what seems obvious. Widespread screening and aggressive, proactive treatment – even when all signs point to an expected positive result – represented low-value, and potentially harmful care.

“Early clindamycin for bacterial vaginosis in pregnancy (PREMEVA): a multicentre, double-blind, randomised controlled trial”

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31617-9/fulltext

Five-Stars is Bad Medicine

In modern medicine, the patient is the customer. Medical services are customer services. Measures of patient – nay, customer – satisfaction are tied to reimbursement and, by association, contracts and employment. We’ve often remarked this perceived or overt emphasis on satisfaction is an incentive for bad medicine – specifically the “Where’s my Z-pack variety?”, and this is one of the few studies to actually show such an effect.

These authors reviewed three years of data from their direct-to-consumer telemedicine program and assessed the correlation between receiving a 5-star patient rating and various physician-related features. There were 85 physicians included across 8,437 patient visits for respiratory tract complaints, mostly sinusitis, but also pharyngitis, bronchitis, and “other” categories. While adjusted ORs showed a variety of small associations with 5-star service just barely clearing statistical significance, there were clear ORs favoring those who gave out candy. Antibiotics were provided in 66% of all visits, and the aOR for a 5-star rating was 3.23 (2.67-3.91) as compared to no antibiotic, and a non-antibiotic prescription bestowed an aOR of 2.21 (1.80-2.71). No other aOR exceeded 1.30, except the “free coupon” visits at 1.58 (1.31-1.90). They also noted it was not possible to be in the 90th percentile for patient satisfaction unless you were basically in the top half of antibiotic prescribing.

There were a couple physicians who were above the 50th percentile for patient satisfaction while maintaining some semblance of antibiotic stewardship. The authors do not provide any qualitative evaluation of those physicians but – thank you good sirs, please share your wisdom with us all.

“Association Between Antibiotic Prescribing for Respiratory Tract Infections and Patient Satisfaction in Direct-to-Consumer Telemedicine”
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2705078

The Appendix Strikes Back

The classic, time-honored treatments for appendicitis are various forms of shamanism – swallowing lead balls, drinking pounds of quicksilver in hot water, or the application of slain young animals to the abdomen. The disease course of the classic patient, then, was obviously poor. In modern times, appendectomy. Ultra-modern, you might say, is antibiotics. Unfortunately, while the recurrence rate after appendectomy is quite low, short-term recurrence after antibiotics is disquietingly high – leading to additional questions regarding the durability of cure.

So, here are the 5-year outcomes of those patients initially entered into the APPAC randomized clinical trial. There were 530 patients randomized between 2009 and 2012 to either appendectomy or antibiotic therapy. Of the initial 257 randomized to antibiotics, 256 completed 1 year follow-up, 70 (27.3%) with recurrent appendicitis. Now, at 5 years, 246 were contacted for follow-up, with an additional 30 having undergone appendectomy. All told, this brings the total to a failure rate of 39.1% of antibiotic therapy in the original cohort. These authors also report quality-of-life and complication outcomes, but, as with the original trial, these are skewed because the initial cohort routinely underwent open appendectomy rather than laproscopic.

So, it seems as though the appendix, once identified as misbehaving, is prone to do it again. This does not disqualify antibiotics-first as a viable strategy for the treatment of uncomplicated acute appendicitis, but it would seem the long-term durability is more a coin flip rather than a roll of the dice.  That said, as long-term data grows more robust, it continues to push us in the direction of at least offering the option to our patients.

“Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial”

https://jamanetwork.com/journals/jama/fullarticle/2703354

The Fluoroquinolone/Aortic Dissection Association

We’ve been hearing about elevated incidence of connective-tissue disorders in patients having been prescribed fluoroquinolones for quite some time, primarily in the context of tendonopathies. Now, with aortic dissection.

The differences are quite small, but probably real. This retrospective case-crossover from Taiwan included 1,213 patients hospitalized with aortic pathology, and compared their fluoroquinolone exposure with those who did not experience aortic dissection despite similar disease risk scores from a national database. Using their time-period referent design, patients were about twice as likely to have been exposed to a fluoroquinolone in the aortic pathology group.

This isn’t the only recent look at the association between fluoroquinolone exposure and aortic pathology. Combine this with the profound impact on gastrointestinal flora these broad-spectrum antibiotics have, and the reasons are just piling up to avoid fluoroquinolones whenever clinically reasonable.

“Oral Fluoroquinolone and the Risk of Aortic Dissection”
https://www.ncbi.nlm.nih.gov/pubmed/30213330

Urgent Cares (and Emergency Departments and Medical Offices) Are the Worst!

This small research article has been making the rounds in the news over the last couple days. In theory, these findings supposedly surprising and enlightening – although to anyone in medicine, or who follows this blog, they are hardly profound.

This is a simple retrospective, cohort analysis of the Truven Health MarketScan Commercial Claims and Encounters Database, which pools de-identified data from patients with employed-sponsored health insurance. In this study, they simply chopped up claims for office, urgent care, retail clinics, and emergency department visits. They publish rates of antibiotic use for various coded discharge diagnoses, again, chopped into categories of “antibiotic almost always indicated” (e.g., urinary tract infection), to “antibiotic may be indicated”, to “Antibiotic-inappropriate” (e.g., influenza, bronchitis).

The numbers get ugly in this latter category, and reflect least favorably on urgent care clinics. Rates of antibiotic prescribing for viral upper respiratory infection and bronchitis, for example, were 41.6% and 75.8%, respectively. This is obviously pathetic, and urgent care centers are rightfully taking heat for this, but neither the ED nor the medical offices deserve much credit, either. The ED was at 18.7% and 56.6%, and offices were at 29.9% and 73.1%, for viral URI and bronchitis, respectively. Retail clinics were not great, but certainly better, at 10.5% and 31.1%.

Of course, these are coded diagnoses and do not always fairly reflect the underlying clinical presentation or diagnosis. And then there’s this:

“We used facility codes but could not validate whether facilities were actually urgent care centers, retail clinics, EDs, or medical offices.”

When the crux of the study pits these different types of facilities against each other, that’s probably somewhat important.

“Comparison of Antibiotic Prescribing in Retail Clinics, Urgent Care Centers, Emergency Departments, and Traditional Ambulatory Care Settings in the United States”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2687524

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

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