Double Coverage, Cellulitis Edition

The Infectious Disease Society Guidelines are fairly reasonable when it comes to cellulitis. Non-suppurative cellulitis – that is to say, without associated abscess or purulent drainage – is much less likely to be methicillin-resistant s. aureus. The guidelines, therefore, recommend monotherapy with a ß-lactam, typically cephalexin. Conversely, with a suppurative focus, trimethoprim-sulfamethoxazole monotherapy is an appropriate option. However, it’s reasonable to estimate current practice involves prescribing both agents somewhere between one fifth and a quarter of cases – presumably both wasteful and potentially harmful. This trial, therefore, examines this practice by randomizing patients to either double coverage or cephalexin plus placebo.

The short answer: no difference. The rate of clinical cure was a little over 80% of both cohorts in the per-protocol population. Of those with follow-up and treatment failure, over half progressed to abscess or purulent drainage on re-evaluation – and about two-thirds were cultured out as s. aureus. There was no reliable evidence, however, co-administration of TMP-SMX prevented this progression.

The really fun part of this article, however ties into the second line of their abstract conclusion:

“However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed.”

This hedging stems from the fact 17.8% were excluded from the enrolled cohort for inclusion in the per-protocol analysis – and, depending on the modified intention-to-treat analysis definition, there was actually up to a 7.3% difference in failure rate favoring double coverage (76.2% vs 69.0%). This resulted from almost twice as many patients in the cephalexin monotherapy cohort taking <75% of antimicrobial therapy, missing follow-up visits, or other protocol deviations.

The best Bayesian interpretation of this finding is probably – and this is where frequentism falls apart – simply to ignore it. The pre-study odds of dramatic superiority of double coverage are low enough, and the outcome definition for the modified intention to treat cohort in question is broad enough, this finding should not influence the knowledge translation of this evidence. Stick with the IDSA soft-tissue guidelines – and one antibiotic at a time, please.  It is important to recognize – and educate patients – that about 1 in 6 may fail initial therapy, and these failures to not necessarily reflect inappropriately narrow antibiotic coverage nor therapeutic mismanagement.

“Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis”
http://jamanetwork.com/journals/jama/article-abstract/2627970

Making Urine Cultures Great Again

As this blog covered earlier this month, the diagnosis of urinary tract infection – as common and pervasive as it might be – is still fraught with diagnostic uncertainty and inconclusive likelihood ratios. In practice, clinicians combine pretest likelihood, subjective symptoms, and the urinalysis to make a decision regarding treatment – and invariably err on the side of over-treatment.

This is an interesting study taking place in the Nationwide Children’s Hospital network regarding their use of urine cultures. In retrospect, these authors noted only half of patients initially diagnosed with UTI had the diagnosis ultimately confirmed by contemporaneous urine culture. Their intervention, then, in order to reduce harm from adverse effects of antibiotics, was to contact patients following a negative urine culture result and request antibiotics be stopped.

This tied into an entire quality-improvement procedure simply to use the electronic health record to accurately follow-up the urine cultures, but over the course of the intervention, 910 patients met inclusion criteria. These patients were prescribed a total of 8,648 days of antibiotics, and the intervention obviated 3,429 (40%) of those days. Owing to increasing uptake of the study intervention by clinicians, the rate of antibiotic obviation had reached 61% by the end of the study period.

There are some obvious flaws in this sort of retrospective reporting on a QI intervention, as there was no reliable follow-up of patients included. The authors report no patients were subsequently diagnosed with a UTI within 14 days of being contacted, but this is based on only 46 patients who subsequently sought care within their healthcare system within 14 days, and not any comprehensive follow-up contact. There is no verification or antibiotics actually being discontinued following contact. Then, finally, antibiotic-free days are only a surrogate for a reduction the suspected adverse events associated with their administration.

All that said, this probably represents reasonable practice. Considering the immense frequency with which urine cultures are sent and antibiotics prescribed for dysuria, the magnitude of effect witnessed here suggests a potentially huge decrease in exposure to unnecessary antibiotics.

“Urine Culture Follow-up and Antimicrobial Stewardship in a Pediatric Urgent Care Network”
http://pediatrics.aappublications.org/content/early/2017/03/14/peds.2016-2103

Another Step in Antibiotics for Appendicitis

Antibiotics are unnecessary! No, antibiotics are great! No, we give too many antibiotics! It’s getting hard to keep track of which conditions we’re giving and withholding antibiotics for these days.

This article is a teaser for more evidence to come regarding strategies for managing appendicitis without surgical intervention. We’ve seen a few trials already, with essentially unconvincing results in either direction. A large trial regarding an antibiotics-first strategy in an adult population was criticized for using open surgical technique rather than laproscopic – and the one-year failure rate was still rather high. However, a pilot report in a pediatric population probably demonstrates an antibiotic-first strategy is still a reasonable option to present in shared decision-making.

This is a pilot project describing the initial results and feasibility outlook for an antibiotics-first protocol for appendicitis. In this protocol, patients randomized to an antibiotics-first strategy received an intravenous dose of ertapenem in the Emergency Department, were eligible for discharge directly from the Emergency Department, returned for a second dose of ertapenem the next day, and then completed an 8-day course of oral cefdinir and metronidazole.

In their pilot, 42 patients were screened and 30 patients consented for randomization. Of these, 15 were adults and 1 was a pediatric patient. Of the 15 adults, 14 felt well enough for discharge after initial Emergency Department observation. The pediatric protocol called for in-hospital observation regardless of symptoms at presentation.

The results are generally of lesser consequence than the effectiveness of this pilot demonstrating the feasibility of the protocol, and the yield at which patients could be enrolled for a larger trial. There were a couple instances of recurrent appendicitis in the antibiotics-first cohort, one of which was successfully treated with antibiotics a second time. There were a couple surgical complications in the surgery cohort. Costs and overall quality of life scores favored the antibiotics-only group, obviously – but, again, this sample is small enough none of these outcomes have been measured with reliable accuracy or precision.

I think it is reasonable to expect an antibiotics-first strategy to eventually take root as part of acceptable medical practice. However, I suspect this transition will be slow in coming – and more data would be quite helpful in determining any specific risks for antibiotic strategy failures.

“Antibiotics-First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management”

https://www.ncbi.nlm.nih.gov/pubmed/27974169

Insight Is Insufficient

In this depressing trial, we witness a disheartening truth – physicians won’t necessarily do better, even if they know they’re not doing well.

This study tested a mixed educational and peer comparison intervention on primary care physicians in Switzerland, with an end goal of improving antibiotic stewardship for common ambulatory complaints. The “worst-performing” 2,900 physicians with respect to antibiotic prescribing rates were enrolled and randomized to the study intervention or none. The study intervention consisted of materials regarding appropriate prescribing, along with personalized feedback regarding where their prescribing rate ranked compared to the entire national cohort. The core of their hypothesis involved whether just this passive knowledge regarding their peer performance would exert normalizing influence over their practice.

Unfortunately, despite providing these physicians with this insight, as well as tools for improvement, the net effect of their intervention was effectively zero. There were some observations regarding changes in prescribing rates for certain age groups, and for certain types of antibiotics, but dredging through these secondary outcomes leads to only unreliable conclusions.

This is not particularly surprising data. These sorts of passive feedback mechanisms unhitched from material consequences have never previously been shown to be effective. There are other, more effective mechanisms – focused education, decision-support interventions, and shared decision-making – but, for a fragmented, national health system, this represented a relatively inexpensive model to test.

Try again!

“Personalized Prescription Feedback Using Routinely Collected Data to Reduce Antibiotic Use in Primary Care”

https://www.ncbi.nlm.nih.gov/pubmed/28027333

No, All Bacteria Do Not Require Antibiotics

The natural world is replete with bacteria.

Humans have existed on this planet for millennia.

In the ages before antibiotics, many humans succumbed to bacterial infections – while, of course, the vast majority survived.

This is not a profoundly reliable observational study, but it does help reinforce this basic concept. This report is a secondary analysis of the GRACE-10 study, which involved primary care patients recruited with a diagnosis of acute cough. The original study was a randomized, placebo-controlled trial for non-specific lower respiratory tract infection, as part of a genomics analysis for evaluation of antibiotic resistance.

This analysis, however, looks solely at the placebo arm, and examines the symptom course and resolution of those who were ultimately diagnosed with a bacterial cause of their LRTI and compares the with those who were not. Of the 834 patients included in their analysis (those with complete symptom diaries), 162 were thought to have a bacteria pathogen based on respiratory culture, nasal swab, or whole blood antibody titers.

S pneumoniae and H influenzae were the most common bacterial pathogens, with most of the remainder the “atypicals” for community-acquired pneumonia. And, at the end of the day: virtually everyone did fine. Patients with a confirmed bacterial pathogen in the setting of their LRTI improved slightly more slowly than those without, had more re-visits in follow-up due to worsening or new symptoms, and a greater percentage were placed on antibiotics in follow-up (12% vs. 6%). The remainder eradicated their bacterial pathogens without antibiotics – you know, the way humans and other contemporary mammals survived for eons.

Now, some of these cases positive for LRTI may be colonization and not pathogenic infection, while some of the negative cases were not diagnosed due to lack of sensitivity. But, regardless, the overall point of this article is probably valid – some bacterial infections will worsen, but in the generally healthy population, a delayed-antibiotic strategy might be valid as an attempt to improve antibiotic stewardship.

“Disease Course of Lower Respiratory Tract Infection With a Bacterial Cause”

http://www.annfammed.org/content/14/6/534.full

More Coverage of Inappropriate Antibiotic Prescribing

If this feels like déjà vu, it might be because it is.

This short research letter in JAMA Internal Medicine describes patterns of antibiotic prescribing for three common conditions: otitis media, sinusitis, and pharyngitis. In all of these cases – in the infrequent occasion antibiotics are necessary – the appropriate first-line antibiotic is amoxicillin/penicillin. These authors estimate, based on treatment failures, allergies, and complicated disease, approximately 80% of antibiotic prescriptions for these conditions should be the first-line agents.

How did we do? Well, better in pediatrics than adults, but first-line prescribing ranged from a low of 37% to a high of 67%. The most commonly used inappropriate antibiotics were macrolides (invariably azithromycin) and fluoroquinolones. Macrolides are usually inappropriate due to high levels of resistance among common pathogens, and fluroquinolones are simply too broad-spectrum to be appropriate.

The catch, unfortunately, is the data source: the National Ambulatory Medical Care Survey, warts and all, from 2010 to 2011. The authors state they expect practice patterns have not changed much in the last five years, but it’s still a little challenging to generalize this to current practice.

Finally, as a nice corollary, this Medical Letter article was featured in JAMA regarding fluoroquinolones and their increasingly detected serious adverse effects. When antibiotics are truly necessary, physicians should try and choose one of the many alternatives presented in the article.

“Frequency of First-line Antibiotic Selection Among US Ambulatory Care Visits for Otitis Media, Sinusitis, and Pharyngitis”
http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2571613

Antibiotics for Diverticulitis, the End Must Be Near

I’ve talked about the inflammatory vs. infectious theory for diverticulitis in a couple of my national and international presentations, and I’ve talked about the evidence supporting an observation-only strategy. Until now, that evidence was mostly a single-center randomized trial from Finland, followed by an observational report from the same.

Now, this non-treatment paradigm has migrated across the little river between Scandanavia and Europe, and has been taken up by the Dutch in this latest randomized trial. In this trial, 22 clinical sites randomized 570 patients with uncomplicated diverticulitis to either admission for antibiotic treatment, or observation and disposition per clinical stability. The antibiotic chosen was amoxicillin-clavulanic acid, with ciprofloxacin/metronidazole in the case of allergy. The primary outcome was time to recovery, with secondary outcomes relating to complications and recurrence.

Of the 570 randomized, ultimately, only 528 were analyzed. A handful were lost to follow-up, and then 35 patients withdrew from the study after allocation – 22 in the observation cohort and 13 in the antibiotics cohort. There were minor, potentially confounding differences between the two cohorts analyzed – about 8% more of the antibiotics cohort suffered from mild or severe comorbid disease.

Most patients selected for observation were admitted – with only 13% managed as outpatients. With respect to the primary outcome, there was no difference between cohorts in time to recovery. There were also few statistically significant differences in secondary outcomes, although the numbers suggest a small magnitude of harm relating to observation. Complications – ongoing diverticulitis within 6 months, need for sigmoid resection, and hospital readmission – all favored the antibiotic cohort by small, non-significant amounts. Conversely, morbidity numbers generally favored the observation cohort – relating mostly to antibiotic-related adverse effects.

Regardless, the sum of benefits and harms – in the context of the other evidence – supports antibiotic-free strategies for uncomplicated diverticulitis.

“Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis”
http://onlinelibrary.wiley.com/doi/10.1002/bjs.10309/abstract

The Downside of Antibiotic Stewardship

There are many advantages to curtailing antibiotic prescribing. Costs are reduced, fewer antibiotic-resistant bacteria are induced, and treatment-associated adverse events are eliminated.

This retrospective, population-based study, however, illuminates the potential drawbacks. Using electronic record review spanning 10 years of general practice encounters, these authors compared infectious complication rates between practices with low and high antibiotic prescribing rates. Spanning 45.5 million person-years of follow-up after office visits for respiratory tract infections, there is both reason for reassurance and reason for further concern.

On the “pro” side, cases of mastoiditis, empyema, bacterial meningitis, intracranial abscess and Lemierre’s syndrome were no different between those who prescribed high rates (>58%) and those with low rates (<44%). However, there is a reasonably clear linear relationship with excess follow-up encounters for both pneumonia and peritonsilar abscess. Incidence rate ratios were 0.70 compared with reference for pneumonia and 0.78 compared with reference for peritonsillar abscess. However, the absolute differences can best be described as “large handful” and “small handful” of extra cases per 100,000 encounters

There are many rough edges and flaws relating to these data, some of which are probably adequately defeated by the massive cohort size. I think it is reasonable to interpret this article as accurately reflecting true harms from antibiotic stewardship. More work should absolutely be pursued in terms of strategies to mitigate these potential downstream complications, but I believe the balance of benefits and harms still falls on the side of continued efforts in stewardship.

“Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records”

http://www.bmj.com/content/354/bmj.i3410

The “IV Antibiotics” Sham

Among the many overused tropes in medicine is the myth of the supremacy of intravenous antibiotics.  In the appropriate clinical context, it’s just a waste.

This is a retrospective analysis of 36,405 patients hospitalized for community-acquired pneumonia, and for whom a fluoroquinolone was selected as therapy.  The vast majority – 94% – received an intravenous dose, while the remaining 2,205 (6%) were treated orally.  Unadjusted mortality favored the oral dose – unsurprisingly, as those patients also generally has fewer comorbid conditions.  In their multivariate, propensity-matched analysis, there was no difference in mortality, intensive care unit escalation, or mechanical ventilation.

These results are wholly unsurprising, and the key feature is the class of antibiotic involved.  Commonly used antibiotics in the fluoroquinolone class, trimethoprim-sulfamethoxazole, metronidazole, and clindamycin, among others, have excellent oral absorption.  I have seen many a referral to the Emergency Department for “intravenous antibiotics” prior to an anticipated discharge to home therapy when any one of these choices could have obviated the entire encounter.

“Association Between Initial Route of Fluoroquinolone Administration and Outcomes in Patients Hospitalized for Community-acquired Pneumonia”
http://www.ncbi.nlm.nih.gov/pubmed/27048748

The Magic Bacterial Divining Rod

Antibiotic overuse is a real issue.  In modern countries, despite obsessing over antibiotic stewardship, we are still suckers for the excessive use of both narrow-spectrum antibiotics for ambulatory patients and broad-spectrum antibiotics for the critically ill.  In less resource-capable areas, the tests used to stratify patients as potentially bacterial or viral exceed the cost of the antibiotics – also leading down the path to overuse.

This breathless coverage, featured in Time, the AFP, and proudly advertised by Stanford Medicine, profiles a new panel of tests that is destined to bring clarity.  Rather than relying simply on a single biomarker, “our test can detect an infection anywhere in the body by ‘reading the immune system’”.

They used retrospective genetic expression cohorts from children and adults with supposedly confirmed non-infectious or infectious etiologies to derive and validate a scoring system to differentiate the underlying cause of sepsis.  They then further trim their model by eliminating infants and predominately healthy patients from outpatient cohorts.  Ultimately, they then test their model on a previously uncharacterized whole blood sample from 96 pediatric sepsis patients and report an AUC for viral vs. bacterial sepsis of 0.84, with a -LR of 0.15 and +LR of 3.0 for bacterial infections.  At face value, translated to a presumed clinical setting with a generally low prevalence of bacterial infection complicating SIRS, this is an uninspiring result.

However, these authors rather focus their discussion and press releases around the -LR of 0.10 and +LR of 2.34 produced as part of their ideal validation cohort, trumpeting its superiority over the -LR for procalcitonin of 0.29 as “three-fold improvement”.  This is, of course, nonsense, as the AUC from that same procalcitonin meta-analysis was 0.85, and these authors are simply cherry-picking one threshold and performance characteristic for their comparison.

Now, that’s hardly to say this is not novel work, and their confusion matrices showing clustering of non-infected SIRS vs. bacterial sepsis vs. viral sepsis are quite lovely.  Their approach is interesting, and very well could ultimately outperform existing strategies.  However, their current performance clearly does not match the hype, and they are miles away from a meaningful validation.  Furthermore, the sort of nano-array assay required is neither fast enough to be clinically useful nor likely to be produced cheaply enough to be used in some of the resource-poor settings they claim to be addressing.

It makes for a nice headline, but it’s better consigned to the “Fantasy/Science Fiction” shelf of your local bookstore for now.

“Robust classification of bacterial and viral infections via integrated host gene expression diagnostics”
http://stm.sciencemag.org/content/8/346/346ra91