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"

http://www.bmj.com/content/346/bmj.f2450

"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/

JAMA, Integrity, Accessibility, and Social vs. Scientific Peer Review

Yesterday, I posted regarding a JAMA Clinical Evidence series article involving procalcitonin measurement to guide antibiotics stewardship.  This is an article I read, raised concerns regarding other negative trials in the same spectrum, and depressingly noted conflict-of-interest with each of the three authors.

Graham Walker, M del Castillo-Hegyi, Javier Benitez and Chris Nickson picked up the blog post, spread it through social media and Twitter, and suggested I write a formal response to JAMA for peer-reviewed publication.  My response – I could put time into such a response, but what would JAMA's motivation be to publish an admission of embarrassing failure of peer-review?  And, whatever response they published would be sequestered behind a paywall – while BRAHMS/ThermoFisher continued to happily reprint away their evidence review from JAMA.  Therefore, I will write a response – but I will publish it openly here, on the Internet, and the social peer review of my physician colleagues will determine the scope of its dissemination based on its merits.

Again, this JAMA article concerns procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections.  This is written by Drs. Schuetz, Briel, and Mueller.  They each receive funding from  BRAHMS/ThermoFisher for work related to procalcitonin assays (www.procalcitonin.com).  The evidence they present is derived from a 2012 Cochrane Review – authored by Schuetz, Mueller, Christ-Crain, et al.  The Cochrane Review was funded in part by BRAHMS/ThermoFisher, and eight authors of the review declare financial support from BRAHMS/ThermoFisher.

The Cochrane Review includes fourteen publications examining the utility of procalcitonin-based algorithms to initiate or discontinue antibiotics.  Briefly, in alphabetical order, these articles are:

• Boudama 2010 - Authors declare COI with BRAHMS.  This is a generally negative study with regards to the utility of procalcitonin.  Antibiotic use was reduced, but mortality trends favored standard therapy and the study was underpowered for this difference to reach statistical significance (24% mortality in controls, 30% mortality in procalcitonin-guided at 60 days).

• Briel 2008 - Authors declare COI with BRAHMS.  This study is a farce.  These ambulatory patients were treated with antibiotics for such "bacterial" conditions as the "common cold", sinusitis, pharyngitis/tonsilitis, otitis media, and bronchitis.  

• Burkhardt 2010 - Authors declare COI with BRAHMS.  Yet another ambulatory study randomizing patients with clearly non-bacterial infections.

• Christ-Crain 2004 - Authors declare COI with BRAHMS.  Again, most patients received antibiotics unnecessarily via poor clinical judgement, for bronchitis, asthma, and "other".

• Christ-Crain 2006 - Authors declare COI with BRAHMS.  This is a reasonably enrolled study of community-acquired pneumonia patients.

• Hochreiter 2009 - Authors declare COI with BRAHMS.  This is an ICU setting enrolling non-respiratory infections along with respiratory infections.  These authors pulled out the 47 patients with respiratory infections.

• Kristofferson 2009 - No COI declared.  Odd study.  The same percentage received antibiotics in each group, and in 42/103 cases randomized to the procalcitonin group, physicians disregarded the procalcitonin-algorithm treatment guidelines.  A small reduction in antibiotic duration was observed in the procalcitonin group.

• Long 2009 - No COI declared.  Unable to obtain this study from Chinese-language journal.

• Long 2011 - No COI declared.  Most patients were afebrile.  97% of the control group received antibiotics for a symptomatic new infiltrate on CXR compared with 84% of the procalcitonin group.  85% of the procalcitonin group had treatment success, compared with 89% of the control group.  Again, underpowered to detect a difference with only 81 patients in each group.

• Nobre 2008 - Authors declare COI with BRAHMS.  This is, again, an ICU sepsis study – with 30% of the patients included having non-respiratory illness.  Only 52 patients enrolled.

• Schroeder 2009 - Authors declare COI with BRAHMS.  Another ICU sepsis study with only 27 patients, of which these authors pulled only 8!

• Schuetz 2009 - Authors declare COI with BRAHMS.  70% of patients had CAP, most of which was severe.  Criticisms of this study include critique of "usual care" for poor compliance with evidence supporting short-course antibiotic prescriptions, and poor external validity when applied to ambulatory care.

• Stolz 2007 - Authors declare COI with BRAHMS.  208 patients with COPD exacerbations only.

• Stolz 2009 - Authors declare COI with BRAHMS.  ICU study of 101 patient with ventilator-associated pneumonia.

So, we have an industry-funded collation of 14 studies – 11 of which involve relevant industry COI.  Most studies compare procalcitonin-guided judgement with standard care – and, truly, many of these studies are straw-man comparisons against sub-standard care in which antibiotics are being prescribed inappropriately for indications in which antibiotics have no proven efficacy.  We also have three ICU sepsis studies included that discard the diagnoses other than "acute respiratory infection" – resulting in absurdly low sample sizes.  As noted yesterday, larger studies in ICU settings including 1,200 patients and 509 patients suggested harms, no substantial benefits, and poor discriminatory function of procalcitonin assays for active infection.  

Whether the science eventually favors procalcitonin, improved clinical judgement, or another biological marker, it is a failure of the editors of JAMA to publish such deeply conflicted literature.  Furthermore, the traditional publishing system is configured in such a fashion that critiques are muted compared with the original article – to the point where I expect this skeptical essay to reach a far greater audience and have a greater effect on practice patterns via #FOAMed than through the traditional route.

Diverticulitis – The Sinusitis of the Colon?

Antibiotics are wonderful things.  They treat and provide life-saving amelioration of symptoms from the common cold, the flu, bronchitis, sinusitis, and otitis – or, more accurately, they don't.  Rather than generalize the treatment with antibiotics for all these illness, it is rather the avoidance of antibiotics that should be generalized, with specific exceptions made as necessary.

The next "-itis" to go under the microscope is diverticulitis.  These authors from Iceland and Sweden deserve, at the minimum, kudos for innovation in swimming against the tide.  The treatment of acute diverticulitis – a febrile illness with an elevated WBC and left-lower quadrant pain – is generally gram-negative and anaerobic coverage as an inpatient or outpatient, depending on comorbidities.  These authors propose that diverticulitis is most frequently a self-limited process, rather than one that requires antibiotics.

This a non-blinded trial of antibiotics vs. non-treatment for CT-demonstrated acute, uncomplicated diverticulitis.  Over 600 patients were admitted, with half receiving simple observation and symptomatic treatment vs. half with the same plus antibiotics.  1% of patients in the antibiotic group suffered treatment failure – progression to abscess or perforation – compared with 2% of patients in the placebo group.

Unfortunately, we're not quite done with antibiotics based on just this study.  It is unblinded with variable enrollment between centers, leading to several sources of potential bias.  Then, ten patients in the no-antibiotics group crossed over to receive antibiotics for clinical worsening during hospitalization.  However, this is still below the 6.5% complication rate the authors thought might be an acceptable failure rate for conservative therapy.

Many more questions to be answered regarding external validity, so hopefully this inspires other investigators to further explore which subset patients will derive benefit from antibiotics in diverticulitis.

"Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis"
www.ncbi.nlm.nih.gov/pubmed/22290281

Viral Testing in Children With Fever

This study attempts to address the question we've been asking ourselves since the dawn of antibiotics – does this child with a fever have a viral infection, or a bacterial infection?  Of course, in reality, we should be asking a more complicated question – does this child have a viral infection, or a bacterial infection for which the increased likelihood of positive outcome with antibiotics outweighs the harms of the antibiotics?  But, I digress.

One hypothesis that is bandied about in literature and practice is, if rapid viral testing were available in the Emergency Department, perhaps a positive viral test result would reduce the likelihood of antibiotic usage.  These folks from Washington University performed viral PCR for a host of common viruses on 75 children with fever without a source, 15 children with probable bacterial infections, and 115 afebrile children presenting for outpatient surgery.  The authors note the patients with bacterial infections were less likely to test positive for a virus – and suggest prospective trials might describe a strategy in which viral testing decreased antibiotic use.

In their cohort, 55% of children aged 2 to 12 months and 39% of those aged 13 to 24 months with no obvious source for fever received antibiotics.  This is irresponsible lunacy.  However, a much faster, cheaper way to decrease antibiotic use is:  to simply return from the abyss of antibiotic overuse to a land of rational practice.  

After all, 40% of the bacterial infections and 35% of the outpatient surgical patients tested positive for a virus – clearly indicating the presence of a virus has limited association with acute viral illness or absence of an acute bacterial infection.  More tests are not the answer – at least, certainly not this battery of PCR tests.

"Detection of Viruses in Young Children With Fever Without an Apparent Source"
http://www.ncbi.nlm.nih.gov/pubmed/23129086

Azithromycin - Not Guilty of Murder

The FDA has announced it is reviewing the safety of azithromycin in lieu of a recent NEJM article documenting an association between azithromycin and cardiovascular death.  In theory, azithromycin has been implicated in QT-prolongation and pro-arrhythmic effects, leading to torsades de pointes and polymorphic ventricular tachycardia.  The authors of this study therefore hypothesized an association between azithromycin use and cardiovascular death.

This is a retrospective study of computerized data generated from the Tennessee Medicaid program between 1992 and 2006, linking deaths to any concurrent antibiotic prescriptions.  The authors data-mined for a cohort aged 30 to 74 years of age, had no "life threatening non-cardiovascular illness", did not abuse drugs, and did not reside in a nursing home.  They compared azithromycin prescriptions to non-prescription controls, as well as amoxicillin, ciprofloxacin, and levofloxacin cohorts.  And, after a little statistical maneuvering, they report a death rate of 85.2 per 1,000,000 courses of antibiotics with azithromycin, which compares to a death rate of 29.8 with no antibiotic and 31.5 with amoxicillin.

So, for every ~20,000 prescriptions of azithromycin written, there is one additional death from cardiovascular causes.  This is another one of those cases where the severity of the absolute difference doesn't quite match the relative difference - it is likely any efficacy difference between a macrolide and a second-line agent results in greater morbidity than the magnitude of effect found in this study.

Then, azithromycin is frequently prescribed for upper and lower respiratory tract infections - conditions that, in the absence of other specific signs, might be non-infectious cardiovascular disease misdiagnosed as having an infectious etiology.  In their non-propensity matched cohorts, 50% more azithromycin prescriptions were written for respiratory symptoms than amoxicillin.  The propensity matching in their statistical analysis attempts to account for this, but 30% of their azithromycin prescriptions had no documented indication - which I think means there's likely a hidden statistical difference in underlying pathophysiology secondary to unknown indications.

Finally, this runs contrary to a 2005 article "Azithromycin for the Secondary Prevention of Coronary Events" published in NEJM - at one point, it was theorized that azithromycin would be protective for coronary events.  For 4,000 patients who took azithromycin weekly for a year, there was no difference in cardiovascular outcomes as compared to placebo (CI -13% to +13% relative risk reduction).

There are lots of reasons not to prescribe azithromycin, but this study isn't the one that should change your practice.

"Azithromycin and the Risk of Cardiovascular Death"
http://www.nejm.org/doi/full/10.1056/NEJMoa1003833

Over-Prescribing of Antibiotics Happens Everywhere

On Twitter a couple weeks back, in response to my plea to reduce empiric macrolide use for benign clinical syndromes, there was an allusion suggesting Pediatricians were the culprits of a poor antibiotic stewardship.

Of course, that's clearly not the case.  And, while we all envision Urgent Cares and customer-service medicine contributing to the over-prescription of antibiotics, it's happening in our academic medical centers, as this article indicates.  This is a retrospective chart review from San Diego that evaluated 836 patients receiving a diagnosis of "acute bronchitis", a typically self-limited disease that evolves into pneumonia only in a minority of cases in elderly patients or patients with significant pulmonary comorbidities.

The average age was 46, 10% had comorbid COPD noted, 17% asthma, 8% diabetes, and 4% HIV/AIDS.  All told, 74% were prescribed antibiotics - 50% received a macrolide, 15% a tetracycline, 6% a fluoroquinolone, along with a few others.

Unfortunate.

And certainly not just the Pediatricians.

"Antibiotic and bronchodilator prescribing for acute bronchitis in the Emergency Department."
http://www.ncbi.nlm.nih.gov/pubmed/22341759

The Tiniest Three Year Sinusitis Trial

Yet again, another article that saturated the lay press due to its publication in JAMA - this time regarding amoxicillin for acute sinusitis.

The problem is, I agree with the fundamental point the authors are making - according to the introduction, antibiotics for sinusitis account for 1 in 5 antibiotic prescriptions in the United States and they're typically unnecessary, especially in an era where better antibiotic stewardship is needed.  However, I cannot imagine how a multicenter study of ten community clinics in St. Louis over three years only managed to enroll 166 adults into this study over the course of three years.  Their recruitment diagram states only 244 patients were assessed for eligibility - which seems like it ought to be a a couple months worth of URI presentations in an outpatient setting.

If you read the newspaper, you already know the main results - "no difference between 10 days of amoxicillin and placebo."  But 11 of 85 intervention group patients discontinued treatment, as well of 12 of 81 placebo patients.  Due to lost data, 4 of 85 intervention patients were excluded from analysis, as well as 7 of 81 placebo patients.  Then, 32% of patients in the intervention group were non-compliant with the intervention - so, while this is valid in a real-world effectiveness sense, they're increasingly no longer relevant to the actual efficacy of the intervention.  These are big holes in a small study.

And, bizarrely, the baseline characteristics they use to describe the two groups include more social characteristics than clinical characteristics - healthcare insurance, family income, etc.  Children living in the home, children in day care, etc., is an interesting demographic criteria, suggesting unique infectious exposure - 9% more intervention group patients had children at home, but this isn't statistically significant because the sample sizes are so tiny.  Then, the clinical characteristics they chose only seem to partially reflect issues relevant to antibiotic efficacy - "usual health excellent or good" isn't a very useful descriptor of whether they have impaired baseline immune function that places them at increased risk of significant bacterial superinfection.  For what it's worth, the control group was significantly "healthier", but also had significantly more smoking history.

Getting back to the main results - yes, the average SNOT-16 scores were equal at day 0, 3 and 10, but favored the intervention at day 7 - leading to their final conclusion that amoxicillin was of no benefit.  But, at the individual patient level, the control group patients were impaired from their usual activities almost 50% longer - 1.67 days vs. 1.15 days, and there was a 12% absolute difference in satisfaction with treatment favoring the intervention - 53% vs. 41 %.  But, due to the tiny sample size, none of these differences reached statistical significance.

In the end, it's a fair real-world trial and addition to the literature, but it's far too small and flawed a trial to stand on to as evidence.

Oddly, one of the authors receives royalties for the SNOT-16 scale.

"Amoxicillin for Acute Rhinosinusitis: A Randomized Controlled Trial"
http://jama.ama-assn.org/content/307/7/685

Dog Bites and Antibiotics

Nicholas Genes of...well, multiple sites of fame, including recurring columns in several EM publications, SAEM leadership, and the long-standing medical blog "blogborygmi" beat me to this ACEP News item from today:

MedPage Today (12/9, Walsh) reports that a study presented in a poster session at the midyear clinical meeting of the American Society of Health-System Pharmacists (ASHP) found that only 64% of the patients presenting to the emergency department with animal bites "were discharged on the appropriate antibiotic."


I won't attempt to replicate his scathing criticism of ACEP News for publicizing a poster from an interim pharmacy conference, just read it for yourself:
http://blogborygmi.tumblr.com/post/13967004314/among-98-patients-seen-with-bites-over-the-course

Ceftaroline - The New Wonder Drug

Don't use it.

If you're like me, every journal you pick up nowadays has a three page glossy fold-out of some confident-looking fake doctor showing off the new broad-spectrum magic medicine, ceftaroline fosamil (Teflaro).  600mg IV q12, ask your doctor if you should be receiving Teflaro.

So, finally, when I got a booklet mailed to my house, I gave in and looked at the literature.  And, I was almost legitimately defeated by the literature because most of the recent, relevant published literature regarding outcomes in the phase III trials...is written by employees of Forest Laboratories and published in a special "clinical supplement" to an infectious disease journal.  There isn't much data out there that isn't just advertising.

However, my survey of the animal studies, and presuming the human studies aren't blatantly made up, seems to indicate this is a great antibiotic.  It doesn't work against VRE, pseudomonas, ESBL e. coli, ESBL klebsiella, or acinetobacter, but it's active against many strains of MRSA, DNS MRSA, and VISA, along with the other strep and staph we worry about.

Which is exactly why we shouldn't use this antibiotic - it's so good it should be on every hospital's formulary, but locked in a vault with the same key system a nuclear launch requires.  Keep it as third- or fourth-line to prevent additional resistances.  But, don't use it.

Sadly, the article I have for you is just a review of all the manufacturer-supported data - but at least it's not written by them.

"Ceftaroline: a comprehensive update."
http://www.ncbi.nlm.nih.gov/pubmed/21420284

Move Over MRSA - It's VISA and VRSA Time

Is it too late to buy stock in the company that makes linezolid?

This group up in Detroit reviewed 320 patients with MRSA bacteremia and found that 52.5% experienced Vancomycin failure.  Their conclusion states several significant OR for failure, but review of the between-group differences doesn't show a lot of significant differences.  Nursing homes, for example, were the only p < 0.05, and predicted vancomycin success with a p of 0.02.

What is more important than their clinical predictors, however, is their review of the bactericidal activity of vancomycin - and that higher MICs and higher troughs are needed to effectively treat patients.  I've seen our pharmacists recognize this at my hospital as well - the 1g IV Vancomycin standard initial load is transitioning to a weight-based dose.

But, more importantly, what we're probably really observing is the initial stages of the end of vancomycin's utility for MRSA.  And, I hate to see what happens when TMP/SMX stops working, too....

http://www.ncbi.nlm.nih.gov/pubmed/21460309

Pediatric Septic Shock Protocol

Another sort of goal-directed sepsis study, this time in Pediatrics at Primary Children's.  They implemented a protocolized triage system in their ED designed explicitly identify more cases of sepsis - which led to increased percentages getting early fluid resuscitation, early lactate level measurements, and more frequently antibiotics in the first three hours.

But the net effect of all these interventions...the only detectable difference in their 345 patient cohort was improved length-of-stay for survivors, from IQR 103-328 hours pre-intervention to IQR 86-214 post-intervention.  Total hospital costs were not significantly different.  No change in mortality - which was already low at 7%.

So, yet again - adherence to "quality measures" has debatable clinical significance.

http://www.ncbi.nlm.nih.gov/pubmed/21576304

Procalcitonin Misleads Antibiotic Therapy In Sepsis

An important negative study of an inflammatory biomarker that's been getting a fair amount of push.

It is absolutely true that procalcitonin levels may be elevated in an inflammatory states such as sepsis.  This group tried to make a clinically relevant protocol for procalcitonin trends by saying, if the procalcitonin level is not decreasing with current therapy, then antibiotic coverage should be expanded and aggressive testing should be undertaken to evaluate for missed source control.

Unfortunately, in the treatment arm where procalcitonin was used in clinical decision making, there was extensively greater broad-spectrum and multiple-antibiotic utilization without any demonstrated mortality benefit.  In addition, LOS and ventilator-depended days were longer in the procalcitonin arm.

There were very minor differences between the two groups, probably favoring the control, but not nearly enough to suggest that procalcitonin has any value in assessing failure of current therapy.

http://www.ncbi.nlm.nih.gov/pubmed/21572328

Early Antibiotics Show No Benefit in Sepsis

Interesting analysis of the EMSHOCKNET cohort, looking to see if there was any association between time to antibiotic administration and survival benefit in septic shock.

And, no.  Earlier antibiotic administration, as measured by arrival time in the the ED, showed no significant impact.

They do another secondary analysis where they try to say, well, if the patient received antibiotics before they met criteria for septic shock - then they had a 2.59 (1.17 - 5.74) OR for survival.  I'm not sure how to interpret this finding - perhaps because they looked at 10 different cut-off points for antibiotic administration, they found one that favored antibiotics by chance.

Or, perhaps antibiotics really aren't the lynchpin in treating sepsis - if you can give antibiotics ahead of SIRS, perhaps you have a milder case - but once you have end-organ dysfunction, the interventions that target improving the physiologic changes of sepsis are more important.

http://www.ncbi.nlm.nih.gov/pubmed/21572327

Augmentin Is Not Non-Inferior to Appendectomy

A lovely study out of The Lancet that tells us what we already know…is not as right as we thought it was.  We've all seen the pediatric patient, usually female, that went to their pediatrician's office with abdominal pain, had evidence of cystitis on a UA, and was prescribed amoxicillin or cephalexin.  They got a little better, but they're still having some nausea, some pain, and some loose stools.  In your ED, the ultrasound is positive for free-fluid without visualization of the appendix, and a CT scan subsequently shows evidence for appendiceal rupture.

The antibiotic group here actually had a lot more success than we imagine - since all we see/remember are those patients where we discovered the "latent" appendicitis, partially treated and festering after that initial course of antibiotics.  But, only 12% of their CT-proven uncomplicated appendicitis went on to have a appendectomy in the first 30 days, and only 30% within a year.  So, you could almost argue that with an 88% short-term cure rate with antibiotics and a 70% medium-term cure rate, antibiotics should be first-line therapy with observation for clinical worsening..

No, definitive therapy has its advantages - you could almost equate the appendix to the gallbladder, and say that the 30% recurrence is almost certain to rise in subsequent years.  But, is there an advantage to waiting to do an appendectomy on an elective basis?  Are the adhesions that might develop more or less of an issue that the risks associated with emergent surgery?  And, of course, in the female pelvis, any undertreated appendicitis represents a significant fertility risk.  This study raises great questions about whether we should change our practice regarding our approach to appendicitis, and it is not inconceivable that this "not non-inferior" adds to the literature behind potentially being less aggressive with surgery.

http://www.ncbi.nlm.nih.gov/pubmed/21550483

Fluoroquinolone-Resistant E. Coli

Doom and gloom from the Netherlands regarding antibiotic resistance in E. coli.  Although they focus on the resistance rates to fluoroquinolones, the more interesting take-home point from this article is the risk factors described for polypharmacy resistance.

Depending on your local resistance patterns, 88% susceptibility to E. coli for fluoroquinolones either sounds great or it sounds terrible.  What's interesting is that the strains of E. coli in this study that had fluoroquinolone resistance also had 33% resistance to amoxicillin-clavulanate, 65% resistance to TMP-SMX, and 14% had an ESBL gene.  So, you can really extend their findings to more a listing of predictive factors for resistance to multiple antibiotics.  In there study, the main univariate risk factors were indwelling catheter (OR 6.0) and prior fluoroquinolone use within six months (OR 18.6).  Less prominent, but still statistically significant were underlying urinary tract disorder (OR 2.3), recurrent UTI (OR 2.2), or recent hospitalization (OR 2.3).

Their conclusion that the presence of any of these risk factors should result in a urine culture being sent, which is reasonable - although even in the absence of risk factors, there was still an 8.2% chance of fluoroquinolone resistance.

http://www.ncbi.nlm.nih.gov/pubmed/21123286

Antibiotics Are Unnecessary After MRSA Abscess Drainage

Almost a year old now, but it's been dredged up for Journal Club (spoiler alert: the next two days might have something in common with vis-a-vis dredging).

Small study randomizing skin abscess to placebo vs. TMP-SMX after incision and drainage in children.  I think it's a fair article with decent external validity, as I would say this directly addresses the practice pattern of pediatric emergency physicians, let alone community pediatricians.  The real issue is statistical power for their secondary endpoint and some minor differences between their two groups.  Treatment failures comparing placebo and TMP-SMX are identical - which just goes to show you that the I&D really is the most important element of treating abscesses.  They do a lot of packing!  I suppose I'm almost more surprised there isn't more packing, since that's the commonly accepted practice, but I digress.

The only fire remaining in their argument is that antibiotics will decrease recurrent abscesses.  And, I am willing to give them that - although, I really expect, if they had a longer follow-up period, a lot of those abscesses would return after the antibiotics were stopped because the environment requires eradication.  However, there's a significant difference in the number of each group with a history of recurrent abscesses favoring the TMP-SMX group, which might explain the magnitude of their difference in recurrent lesions within 10 days.

Too small a study to change our practice - although, our practice probably should never have changed from not treating abscesses with antibiotics in the first place.

http://www.ncbi.nlm.nih.gov/pubmed/19409657

Carbapenem Resistant Bacteria in India

More public health doom and gloom from the infectious disease world - multiple bacterial found carrying stable and transmissible plasmids for the NDM-1 gene, a form of beta-lactamase that endows bacteria with carbapenem resistance.  In the sewage.  And in the drinking water.

http://www.thelancet.com/journals/lancet/article/PIIS1473-3099(11)70059-7/abstract

...but only South Asia, for the time being.  But, they also note that India is a popular destination for "medical tourism" to save money on surgical procedures, and patients have returned as carriers for bacteria with the NDM-1 gene.

This is not a unique development - there's MDR tuberculosis, inducible clindamycin resistance for MRSA, and, my favorite, macrolide-resistant streptococcus.  Macrolide resistance in streptococcus can be directly linked to the overuse of azithromycin, a patient-friendly drug with terrible pharmacokinetics.  In contrast to the medication it replaces, erythromycin, it has such a long half-life (68 hours when multiple doses are administered) after you take your fifth dose that it spends a long period in the body below its therapeutic concentration, just sitting there as substrate to induce resistance without bacteriostatic properties.

Grim.

Antibiotics for Acute Otitis Media

These are two articles coming to us from January's NEJM - one from Pittsburgh and one from Finland.  For a ridiculously prevalent disease managed daily in the ambulatory setting by thousands of providers across the world, we really don't know what we're doing.  Firstly, we know there are bacteria in the middle ear - plenty of studies have aspirated out a variety of pathogens.  Secondly, undertreated AOM may lead to suppurative complications - the surgical emergency of mastoiditis.  Finally, however, we also know the natural history of AOM is to resolve without intervention and treatment in most cases.

The commentary accompanying these articles seemed to think these two studies tilted the balance in favor of routine antibiotic use for AOM.  And, you can read the articles in that fashion - the Finnish article makes an argument that by their standard of care, the placebo group had 45% treatment failure and required antibiotic rescue 30% of the time.  However, I read the article and their definitions of treatment failure are, for the most part, not clinically relevant.  A red ear that still looks red on day three does not predict much - and, actually, a lot of their primary outcome measures were not statistically significant until they added in the 30% they used rescue treatment on to boost their definition of treatment failure.  So, this study doesn't tell much much - except that Augmentin causes diarrhea 40% of the time.

The Pittsburgh study reads much more straightforward and, partially, justifies my criticism of the Finnish study.  By day 7, 80% of their Augmentin group had symptom improvement compared to 74% of their placebo group.  However, the ears still looked terrible in the placebo group - but, obviously, weren't correlating with symptoms.  So, is it clinically relevant to define treatment failure based on the appearance of the ear?  I would say that improvement in symptoms is the appropriate measure of clinical cure - and in that respect, the 80% vs 74% numbers match up better with previously published literature.

To me, these articles don't help.  I don't necessarily mind the AAP recommendations of treating AOM with antibiotics under a year of age - although, really, after their third set of immunizations, it's not as though this is going to be a nidus for SBI.  Clearly, antibiotics offer some advantage - but not to everyone.  When I have a three year-old I have to hogtie to get a one-second glimpse at a red TM, how do I know whether this is a patient whose AOM will resolve on its own, or whether he falls into the subset of patients who will derive benefit from antibiotics?  And, is that 6% absolute difference in clinical outcome worth giving 40% of children horrible diarrhea (not that anyone uses Augmentin first-line for AOM, anyway).  With the NNT with antibiotics to prevent one case of mastoiditis estimated at 4100 from cohort data from the United Kingdom, that's a lot of useless (and harmful) antibiotic prescriptions.  If we want to reduce the amount of antibiotic resistance in this country, I think these studies support a conservative non-antibiotic strategy initially in appropriately selected patients.

http://www.ncbi.nlm.nih.gov/pubmed/21226577
http://www.ncbi.nlm.nih.gov/pubmed/21226576

Addendum 5/11: Scott Weingart & David Newman did a bit of a rant on this topic on the most recent EM:RAP where they attacked the Pittsburgh article specifically regarding result reporting integrity.  Dr. Newman delved into far more detail regarding the multiple primary outcomes listed and found the original research protocol listed only time to resolution of symptoms as the primary outcome - which was statistically equivalent between the two groups.  He and Dr. Weingart seem to suggest there was not sufficient editorial oversight regarding the publication of this article due to these flaws, and that the author's conclusions are suspect to the point of disingenuous.