Category: Infectious Disease

U.S. Physicians are Awful at Prescribing Antibiotics

…and the Emergency Department is one of the worst offenders.

This is an analysis of the National Hospital Ambulatory Medical Care Survey, a representative sampling of ambulatory settings across the United States.  These authors simply reviewed all the antibiotic prescriptions and diagnosis codes for adult visits to offices, outpatient departments, and Emergency Departments.  10% of visits result in antibiotic prescriptions – and 61% of these prescriptions were broad-spectrum agents (amoxicillin/clavulanate, quinolones, etc.).  The largest category of antibiotic prescribing was for acute respiratory infections – and only 32% of those prescriptions were for diagnosis codes where antibiotics were typically indicated.  88% of respiratory diagnoses for which antibiotics were rarely indicated (e.g., bronchitis) received a broad-spectrum antibiotic.

This is retrospective, and the NHAMCS database has limitations – but this is farcical.  We’re passing out antibiotics without regard to the consequences – and we’re overusing broad-spectrum agents when narrow-spectrum agents are likely appropriate.  We’re far behind Europe in antibiotic stewardship, and the end result is certainly net population harm from over-treatment and induction of microbial resistance.

And, this doesn’t even account for pediatric visits – which are probably even worse.

Tragically, physician reimbursement is tied to patient satisfaction – or is an emphasized part of a healthcare business model in for-profit settings – and the evidence clearly indicates patients are more satisfied when they receive antibiotics.(pubmed, pubmed, archives of pediatrics)

Yet another example of perverted incentives degrading medical practice.

“Antibiotic prescribing for adults in ambulatory care in the USA, 2007 – 09”
www.ncbi.nlm.nih.gov/pubmed/23887867‎

The Overtreatment of Elderly UTIs

Urinalysis is frequently performed in elderly females presenting to the Emergency Department with non-specific symptoms – owing to the general trend of non-focal constitutional complaints failing to localize disease as age increases.  Understandably, then, this population is thoroughly subjected to increased diagnostic testing.

And, of course, if you run enough tests, you’ll find some “answers”.  The question, of course, is whether these “answers” are in fact true positives, accurately reflecting underlying clinical disease.  In this retrospective cohort of 153 elderly patients for whom a urine culture was sent along with a urinalysis, nearly half of urinalyses were false positives.  Adding in the not-insignificant incidence of non-pathogenic asymptomatic bacteriuria, some of these positive culture results were likely false positives as well.  The authors of this article feel this reflects substantial overdiagnosis and overtreatment.

This assertion is almost certainly correct.  However, these authors are short of suggestions regarding the improvement of diagnostic accuracy.  They suggest, perhaps, urine samples ought only be taken by catheter, and treatment be initiated only on positive culture results.  However, more practical and expedient diagnostic methods are lacking.

“Overtreatment of Presumed Urinary Tract Infection in Older Women Presenting to the Emergency Department”
www.ncbi.nlm.nih.gov/pubmed/23590846‎

Bacterial Meningitis in Complex Febrile Seizure

The AAP has guidelines for simple febrile seizure – “There, there, the frightening demonic possession your child just experienced is nothing to worry about.”  Complex febrile seizures, however, are offered far less conclusive guidance.

This little retrospective review from UC San Diego evaluates 193 patients presenting with complex febrile seizure.  Lumbar puncture was performed in 136, and 1 patient ultimately received a diagnosis of bacterial meningitis.  The authors suggest, cognizant of the limitations, that complex febrile seizures need not routinely undergo LP.

This is entirely reasonable and consistent with the prior literature.  The largest retrospective review, from Boston Children’s, identified 3 cases with bacterial meningitis out of 526 children.  A systematic review and meta-analysis identified 41 cases of bacterial meningitis out of 1996 children.  There are additional cases of viral meningitis and encephalitis in these cohorts as well – of uncertain clinical significance – but the general implication is that otherwise well-appearing children ought not need LP absent other signs of CNS infection.

It would, of course, be fabulous if a consensus guidelines would further reinforce this evidence.

“Necessity of Lumbar Puncture in Patients Presenting with New Onset Complex Febrile Seizures”
www.ncbi.nlm.nih.gov/pubmed/23687537

“Yield of lumbar puncture among children who present with their first complex febrile seizure.”
www.ncbi.nlm.nih.gov/pubmed/20566610‎

“Risk of bacterial meningitis in young children with a first seizure in the context of fever: a systematic review and meta-analysis.”
www.ncbi.nlm.nih.gov/pubmed/23383133‎

Simple SBI Prediction – Hopeless

It remains a noble endeavour to attempt to identify the risk of serious bacteria infections in children.  That said, many have tried, and many have failed.

These authors from the Netherlands and the United Kingdom try, yet again.  They note the best performing decision instrument incorporates 26 variables – which they feel is unworkably unwieldy in a clinical setting – and attempt to derive their own, tighter instrument.  Unfortunately, the clinical variables that shake out of their prediction methodology all have odds ratios less than 6 – leading to a prediction model that can be calibrated only either for horrible sensitivity or horrible specificity.  The sensitive model will lead to over-testing of an otherwise well population, and the specific model will essentially pick up only the cases that were clinically obvious.

It’s becoming pretty clear over the years that attempting to reduce the number of discrete clinical variables in the febrile SBI decision-instrument is a dead-end strategy.  Complex clinical problems simply defy dimension reduction.  Furthermore, the true test of a decision instrument also ought not just be statistical evaluation in a vacuum, but comparison with clinical judgement.

“Clinical prediction model to aid emergency doctors managing febrile children at risk of serious bacterial infections: diagnostic study”
www.bmj.com/content/346/bmj.f1706

Falling Short on Pneumonia Prediction

These authors address a real problem: which coughing adults have pneumonia?  Unfortunately, after evaluating 2,820 of them – they still don’t really know.


This is an interesting article because it pulls together a symptom profile along with two of the other non-specific inflammatory markers being touted as important diagnostic tools: CRP and procalcitonin.  Primary care physicians enrolled adults presenting with acute cough, and used plain radiography as their gold standard for diagnosis of pneumonia.


In short:

  • “Symptoms and signs” suggestive of pneumonia (fever, tachycardia, abnormal lung exam) all had positive OR between 2.0 and 5.3, and combined offered an AUC of 0.70.
  • Adding CRP as a continuous variable to symptoms and signs gave an OR of 1.2 and increased the AUC to 0.78.
  • Adding procalcitonin as a continuous variable to symptoms and signs gave an OR of 1.1 and increased the AUC to 0.72.

Using CRP as a dichotomous cut-off at 30 mg/L, in addition to the independent symptom predictors, gave them the discriminating ability to produce a low, intermediate and high risk group: 0.7%, 3.8%, and 18.2% chance of pneumonia.  A high-risk group where fewer than one in five have the disease?  The authors recommend consideration of empiric antibiotic therapy in this group, but I prefer their other recommendation to consider radiography as confirmation in this subset.  The remainder ought to be candidates for observation, as false positives and harms from additional testing are likely to outweigh true positives.


Again, refuting the terrible JAMA distortion, procalcitonin had no useful discriminatory diagnostic value.


“Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study”

Azithromycin & Cardiovascular Risk, Belabored

Last year, I noted a study concerning a report of excess deaths associated with azithromycin use.  This study, a retrospective, observational cohort from Tennessee Medicaid data suggested a death rate double that of other antibiotics.  This led to the FDA issuing a warning regarding azithromycin use.


I thought all this fuss was absurd – the data quality was one step above junk and the absolute magnitude of the proposed harms was trivial.


Now, we have the counterpoint – a retrospective, observational cohort from Denmark, using their national health system database to compare prescriptions for azithromycin to penicillin V over the last 13 years.  In their cohort, there’s an obvious increase in risk of death from cardiovascular causes simply from being prescribed any antibiotics – but no difference between azithromycin and penicillin V.  This seems to indicate either the systemic infectious process contributes to excess cardiovascular risk, or that respiratory symptoms are being misdiagnosed as infectious rather than cardiovascular.  The absolute effect in their propensity matched cohorts is also tiny – a handful of patients or fewer spread across a million prescription events.


The accompanying opinion seems to attempt to justify the FDA review based on the wide confidence intervals in the Danish study – the OR for death from cardiovascular causes vs. penicillin V is 1.06 (0.54 – 2.10) and doesn’t statistically contradict the Tennessee study.  However, yet again, I would point to the reason behind the wide confidence intervals – the nearly trivial absolute magnitude of the harms, which amount to fractions of a patient per 1000 patient-years.

Again, plenty of reasons to responsibly reduce azithromycin prescriptions – but this cardiovascular hullabaloo probably isn’t one of them.


“Use of Azithromycin and Death from Cardiovascular Causes”
http://www.nejm.org/doi/full/10.1056/NEJMoa1300799

Levamisole-Induced Vasculitis

Let the good times roll – unless, of course, those good times are cut with levamisole.

This short case report from my good friends across the street at Baylor showcases a couple lovely pictures of the purpuric and necrotizing skin lesions associated with the anti-helminth levamisole – which, for some reason, is an increasingly popular additive to cocaine.  They are quite distressing and usually present following several courses of failed outpatient antibiotics.

I don’t think I specifically ever saw the exact patient these authors report upon, but it’s not a unique presentation in our county healthcare system.  This article is open-access for all to view without an institutional subscription.

“Levamisole-adulterated Cocaine Induced Vasculitis with Skin Ulcerations”
http://www.escholarship.org/uc/item/4rd630zt



Bonus link nomination for best article title ever:

“Healthcare-Associated” Pneumonia Update

While trying to summarize an evidence-based approach to pneumonia for our residency, I discovered an aimless morass that’s far less helpful than originally envisioned.

“Healthcare-associated” pneumonia is a clinical entity introduced by the 2005 Infectious Disease Society of America pneumonia guidelines.  The problem with these guidelines is immediately apparent in the title – “Hospital-acquired”, “Ventilator-acquired”, and “Healthcare-associated” are clearly distinct in their infectious epidemiology – but this guideline lumps them all together into a single empiric treatment strategy.  They recommend triple antibiotic therapy, including double coverage for multi-drug resistant gram-negatives (pseudomonas, among others) and MRSA coverage.  This is a fine recommendation for a critically ill ventilated patient with a new lower respiratory tract infection, but preposterous overkill for an otherwise healthy patient with a short hospital stay a couple months ago.  The harms include increasing antibiotic resistance and incidence of iatrogenic end-organ damage secondary to antibiotic adverse effects.

Several articles have detailed the fallacies in this guideline and its validity in the Emergency Department setting.  Furthermore, meta-analysis of studies evaluating guideline-concordant and guideline non-concordant therapy have shown no survival advantage – as most non-concordant therapy covered the community-acquired organisms that occur with far greater regularity than the multi-drug resistant organisms in the “Healthcare-associated” cohort.

With consultation from Brian Hayes and Haney Mallemat, along with my brief literature review, this is my ad hoc approach:

1) Assess risks for MDR pathogens: recent antibiotics, recent hospitalization, poor functional status, immunosuppression.

2a) Non-severe illness and community-acquired organisms likely (low MDR risk), consider antipseudomonal fluoroquinolone monotherapy (covers some pseudomonas and atypical CAP organisms) and outpatient management.

2b) If high risk for MDR or severe illness, recommend admission with anti-pseudomonal and MRSA coverage:
 • Cephalosporin (e.g. cefepime) OR carbapenem (e.g. imipenem) OR ß-lactam/ß-lactamase inhibitor (e.g., piperacillin-tazobactam)
If severe illness, recent mechanical ventilation, or prior documented pseudomonas infection, add:
 • Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) OR aminoglycoside (e.g. amikacin)
MRSA coverage:
 • Linezolid or vancomycin

Note these recommendations should be guided by your local antibiogram as well – at my institution, cefepime is ~90% efficatious against pseudomonas, which makes it a fine option for monotherapy.  However, our fluoroquinolones are ~70%, which makes them a less desirable choice for the monotherapy option when admitting patients.

Patients clearly do better when their causative organism is effectively covered – but we also have to be responsible stewards of our strongest antibiotics.  Given the heterogeneity of the patient cohort described in the 2005 IDSA guidelines, it’s reasonable to take a stepwise approach to therapy.

“Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia”
http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/HAP.pdf

“Guideline-Concordant Antimicrobial Therapy for Healthcare- Associated Pneumonia: A Systematic Review and Meta-analysis”
www.ncbi.nlm.nih.gov/pubmed/23572322

“Guidelines for hospital-acquired pneumonia and health-care-associated pneumonia: a vulnerability, a pitfall, and a fatal flaw.”
http://www.ncbi.nlm.nih.gov/pubmed/21371658/

“Healthcare-associated pneumonia is a heterogeneous disease, and all patients do not need the same broad-spectrum antibiotic therapy as complex nosocomial pneumonia.”
http://www.ncbi.nlm.nih.gov/pubmed/19352176/

“Low incidence of multidrug-resistant organisms in patients with healthcare-associated pneumonia requiring hospitalization.”
http://www.ncbi.nlm.nih.gov/pubmed/21463391/

EM Lit of Note on KevinMD.com

Featured today as a guest blog, revisiting the JAMA Clinical Evidence synopsis critiqued last month on this blog, here and here.

It’s rather an experiment in discovering just how influential social media has become – open access, crowdsourced “peer review” – and whether this mechanism for addressing conflict-of-interest in the prominent medical journals is more effective than simply attempting a letter to the editor.

KevinMD.com – “The filtering of medical evidence has clearly failed“

Eritoran, We Hardly Knew Ye

Endotoxin mediated circulatory collapse remains a theoretical target in the treatment of sepsis.

But, eritoran won’t be one of the agents used to ameliorate its effects.

After a phase II trial found sepsis patients randomized to eritoran had 37.5% mortality compared with 56.3% in the placebo group, the manufacturer sponsored a multi-national, multi-center phase III trial enrolling 1,951 patients.  And, in short – no mortality benefit overall, and no individual subgroups of severe sepsis with any indication of benefit.  The authors comments speak wistfully of the early favorable results before finally concluding: “Eritoran joins a long list of other experimental sepsis treatments that do not improve outcomes in clinical trials in these critically ill patients.”

Interestingly, the study concluded in 2010 – meaning it took 2 1/2 years for the results to reach publication.  The reader will have to derive their own interpretation regarding whether this had anything to do with being negative results from a manufacturer-sponsored trial.

“Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis”