Category: Antibiotics

Let’s Not Treat the Asymptomatic (Urine)

It’s a fairly common picture: the altered/declining/demented/elderly, with a small leukocytosis, and some positive elements on a urinalysis – but no clear symptoms of urinary tract infection. For lack of a better explanation, perhaps, treatment is begun with antibiotics. The benefit is uncertain, but, at the least it is more likely to benefit than harm?

This retrospective study, within the scope of its limitations, finds no reliable benefit to treatment, and more likely harms. This study performed chart reviews on 2,733 hospitalized patients with “asymptomatic bacteriuria”, as defined as a positive urine culture in the absence of documented Infectious Diseases Society of America criteria for UTI. Constitutional or non-specific symptoms in those unable to specifically report (e.g, dementia, AMS) were not considered as consistent with UTI unless multiple systemic signs of infection were also present.

Not only did nearly 80% of patients identified as ASB receive antibiotics, these authors were unable to shed light on any value of treatment. Treatment of ASB was more common in the scenario above, but was also widespread in patients capable of reporting symptoms yet having none documented. The dependence on retrospective chart abstraction limits the accuracy of their observations, but they have face validity.

Patient-oriented outcomes associated with either antibiotic treatment or non-treatment were 30-day mortality, 30-day readmission, 30-day post-discharge Emergency Department visit, C. diff infection, and duration of hospitalization. Most adjusted and unadjusted odds ratios for poorer outcomes were associated with treating ASB, but these differences were generally not statistically significant. Duration of hospitalization, however, was statistically associated with antibiotic treatment. This may be a spurious finding relating to contextual clinical confounders, but it may also represent an element of diagnostic inertia distracting from the true underlying etiology relating to hospitalization.

Regardless, consistent with this journal’s series feature “Less is More”, yet another instance in which common practice does not easily lend itself to confirmation of value.

“Risk Factors and Outcomes Associated With Treatment of Asymptomatic Bacteriuria in Hospitalized Patients”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2748454

CRP for COPD

If you follow this blog, you’ve probably read various critiques of the use of procalcitonin to guide antibiotic prescribing. Procalcitonin, a non-specific inflammatory marker, provides a small amount of informational value regarding the underlying etiology of infection, but my underlying criticism of its envisioned use is:

  • The baseline rate of antibiotic prescribing is so poor, and the likelihood of poor outcomes so low, a safe reduction in prescribing is guaranteed.
  • It provides about the same area-under-the-curve for predicting bacterial etiologies as C-reactive protein.
  • The pro-procalcitonin studies and contributions are effectively covered in the fingerprints of the manufacturers of the assay.

So, then, replace the above complaints with – well, mostly just the top one, because here we are with CRP doing the same things for which procalcitonin is advertised, and the apparent conflict-of-interest is turned down a few notches.

In this study, 86 primary care clinics in England and Wales randomized patients with a diagnosis of COPD and a clinical diagnosis of an acute exacerbation to use of point-of-care CRP testing versus usual care. Similar to those studies seen with procalcitonin, prescribers were provided guidance with respect to various CRP levels and recommendations for either prescribing, possible prescribing, or do not prescribe. The primary outcome and secondary outcomes were associated with receipt of any antibiotics, quality of life, and adverse health outcomes.

Over the course of two years, 649 patients were randomized to the two arms, with a handful of each failing to properly undergo initial study procedures. The prescribing rate at the index visit in the “usual care” group: 69.7%. The prescribing rate with CRP: 47.7%. A winner is CRP!

Except that 76% of patients had CRP less than the threshold at which antibiotics were recommended. Another 12% were in the “antibiotics maybe” group. Thus, nearly 90% of the entire cohort were suspected of having no or limited benefit to antibiotics – so, of course any safety margin to deprescribing would be satisfied. And, considering the baseline rate of prescribing was 70%, again, there is basically no possible way a stewardship intervention could fail.

The editorial accompanying this article is darkly amusing, stating “the findings from this study are compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD”. However, it also goes on to note these data hardly identify “which patients (if any) truly benefit from antibiotic therapy”(emphasis mine). Some trials testing 100% antibiotic prescribing vs. zero prescribing (e.g., placebo) have found minimal, or no, benefit. As with procalcitonin, our problem is a pervasive culture of over-prescribing, and ultimate answer is the same for CRP: we don’t need to introduce a marginally informative test into this low-stakes patient population, we simply need to snap out of our collective insanity.

“C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations”
https://www.nejm.org/doi/10.1056/NEJMoa1803185

Antibiotics & Hospitalization for Asthma

Reactive airway disease and asthma exacerbations. The mainstays of treatment are beta-agonist bronchodilators, systemic corticosteroids, and other adjunctive therapies as indicated. Conspicuously absent from treatment guidelines is any role for antibiotics – but that’s not stopping folks from using them.

In this retrospective data on inpatient hospitalizations comprised of 19,811 patients with acute asthma, 8,788 (44%) received antibiotics within the first two days of hospitalization. Patients receiving early antibiotics were mildly more ill than those who did not, and in their unadjusted analysis “treatment failure” was more common and length-of-stay was longer, as were antibiotic-associated adverse effects. The authors then performed a more evenly-matched propensity score analysis, featuring comparing 6,833 patients in each cohort – and find roughly the same associations, again favoring those who were not treated with antibiotics.

As usual, the limitations are the retrospective nature of a data-dredging exercise such as this, and potential for unmeasured confounders. I wouldn’t make much of the association between no-antibiotics and decreased length-of-stay, as it’s reasonable to expect confounding from selection bias at play for those receiving antibiotics and those who do not. Regardless, antibiotics were frequently used – and rather than wait for proof they are unhelpful, it seems more prudent to wait for proof they are.

There’s also been a fair bit of talk about the so-called anti-inflammatory effect of macrolides, specifically azithromycin. These represented about half the antibiotics used in these patients, and, obviously, there weren’t any further hypothesis-generating signals of benefit along that line of physiologic plausibility.

“Association of Antibiotic Treatment With Outcomes in Patients Hospitalized for an Asthma Exacerbation Treated With Systemic Corticosteroids”

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2721036

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