Category: Infectious Disease

The Thermometer Accuracy Round-Up

Every patient gets vital signs.  They’re … vital, after all.  And the presence or absence of fever is one of those vital signs – and may substantially alter the diagnostic approach to a number of patients.

However, I’m guessing few of us universally use central sources of temperature measurement – bladder, rectal, pulmonary artery, or esophageal.  We, instead, rely on peripheral measurements – axillary, temporal artery, tympanic membrane, or oral.  And, these authors are here to tell us – within the bounds of their low-quality studies – we are being randomly misled.

This is a meta-analysis and systematic review of 75 studies comparing various peripheral temperature measurement techniques to central gold standard.  These authors rate ±0.5°C as a reasonable, clinically acceptable limit of agreement – and, frankly, even that seems like enough deviation to be relevant.

In their pooled analysis, however, peripheral thermometers were nowhere close – and the ranges worsened both with fever and hypothermia.  In adults, for fever the 95% limit of agreement ranged from -1.44°C to +1.46°C, and for hypothermia the range was -2.07°C to +1.90°C.  This led to a pooled sensitivity and specificity for fever of 64% and 96%.

The authors acknowledge multiple limitations to their data, mostly related to biases in sampling and measurement.  However, this probably still the best evidence available – and it seems it’s just about a flip of a coin whether a peripheral temperature measurement will miss a true fever.

“Accuracy of Peripheral Thermometers for Estimating Temperature”
http://www.ncbi.nlm.nih.gov/pubmed/26571241

The Old Man and the Tamiflu

Winter is coming, and so is Tamiflu.  And, this year, we saw two meta-analyses regarding Tamiflu – the Roche puppet-sponsored analysis was pro-Tamiflu, and the non-sponsored analysis was anti-Tamiflu.  However, it should be made clear – anti-Tamiflu still agrees there’s still some small magnitude of effect that must be weighed against the side effects and cost.

The CDC has been repeatedly castigated regarding their continued zealotry regarding Tamiflu, despite the controversy surrounding its use.  The official statement contends their stance is based on more than just RCT data, including the whole of the observational data regarding its use.

And, so, they’ve gone and created some more junk observational data.

Through torturing the Influenza Hospital Surveillance Network (FluSurv-NET), these authors gathered three years of elderly patients hospitalized for influenza.  They extracted the date of influenza onset and the date of initiation for antivirals, and then examined these for a surrogate outcome for effectiveness: discharge to an extended-care facility.  They found, of course, that antiviral treatment was significantly associated with independent discharge, with an absolute unadjusted magnitude of effect of 4%.  However, they also found age, ethnicity, weight, chronic medical conditions, cardiovascular disease, neurologic disorders, influenza vaccination status, influenza virus type, time of illness onset to hospitalization, and surveillance site to be associated with outcomes – many with similar or larger absolute effect sizes.

So, the conclusions here are based on: the outputs of the statistical black box.  Given the degree of adjustments, and allocation and selection bias, there’s not much can be said here – except to make it into a HealthDay and ACEP daily news headline.  Unfortunately, the authors use these data to support early care and antiviral intervention.  This may be true, of course.  However, in the context of the current study, the suggestion ought not be to inform clinical practice – but, rather, to generate hypotheses for future trials, or to serve as surveillance safety for current practice.

That said, once the overall costs and potential morbidity of hospitalized influenza patients are taken into account, the additive penalty of Tamiflu administration is likely far less than even any small magnitude of benefit.

“Impact of prompt influenza antiviral treatment on extended care needs after influenza hospitalization among community-dwelling older adults”

The Utility of Urinalysis in Young Infants

When faced with the diagnostic evaluation of the young, febrile infant fewer than three months of age, the definitive tool for sepsis from urinary tract infection has traditionally been urine culture.  This stems from uncertainty over the adequacy of urinalysis sensitivity for serious bacterial infection, i.e., those truly bacteremic from a urinary source.

This is an analysis of a multicenter database of infants with bacteremia and urinary tract infection, as measured by isolation of the same pathologic organism from both blood and urine.  The key numbers:

  • Trace or greater leukocyte esterase: 97.6% (94.5-99.2) sensitive and 93.9% (87.9-97.5) specific.
  • Pyuria, >3 WBC/HPF: 96% (92.5-98.1) sensitive and 91.3% (84.6-95.6) specific.
  • Pyuria or any LE: 99.5% (98.5-100) sensitive and 87.8% (80.4-93.2) specific.

These are pretty impressive statistics, and differ significantly from the prior supposed sensitivity of the UA in young infants.  These authors postulate the problem with prior study has been its over-reliance on urine culture, and the resulting false positives.  If this seems a reasonable interpretation of the evidence, it has substantial ramifications for the diagnostic evaluation of young infants.  Importantly, it has the potential for obviating invasive procedures and unnecessary over-treatment.

I would like to see independent confirmation of these authors’ findings, but, considering this study required 15 years to produce the 276 patients analyzed in this paper, this may be the best evidence we see for awhile.

“Diagnostic Accuracy of the Urinalysis for Urinary Tract Infection in Infants, 3 Months of Age”
http://www.ncbi.nlm.nih.gov/pubmed/26009628

It’s the Flu! It’s Not the Flu!

Every year, influenza season travels the globe, led by the four horsemen of the apocalypse, bringing toys and good cheer to obedient little girls and boys.  Unfortunately, this very same influenza contributes to hundreds of thousands of hospitalizations and tens of thousands of deaths in the U.S. alone.  And, despite such ubiquity, clinicians are utterly inept at rapid, accurate diagnosis.

This small study reviews the diagnostic performance of clinicians at a single hospital during the influenza season of 2012-13.  A convenience sample of 270 patients presenting with any history of respiratory or febrile illness were screened and swabbed for influenza, and the results of eventual PCR testing were compared with the sensitivity of the CDC definition of “influenza-like illness” and accuracy of subsequent clinical diagnosis.

The highlights:

  • 42 of 228 patients were positive for influenza.
  • Only 40 out of the entire cohort of 270 met the CDC definition of ILI, a cough or sore throat coupled with fever.
  • 15 of influenza positive patients were thought to have influenza by the treating clinician, as well as 50 of the influenza-negative.
  • A third of actual influenza patients received an antiviral, while half were treated with antibiotics.

Certainly not a paragon of medical prowess.

The authors, unfortunately, use their data as a platform for wickedness.  In the context of inadequate diagnostic skill, the authors call for improved rapid diagnostic tools – such as those manufactured by the study sponsor.  Furthermore, the entire need for such rapid tools is predicated on the assumption of benefit from antiviral therapy – which is also espoused by the authors, who have undeclared ROI with Roche.

“Clinical diagnosis of influenza in the ED”
http://www.ncbi.nlm.nih.gov/pubmed/25827595

Welcome, Zerbaxa, Let Us Never Speak of It Again

It is time once again to visit the twisted world of pharmaceutical advertorials, this time in the Lancet.  Our subject is ceftolozane-tazobactam, a 5th-generation cephalosporin, approved and marketed as Zerbaxa.  It joins an ever-growing arsenal of antibiotics whose intention is to fight the growing tide of antimicrobial resistance.

And, thus, welcome – and let us never use it.

Of course, this study will be the basis of many mailers, presentations, and lunch visits imploring its use.  This is a phase 3 trial, comparing intravenous ceftolozane-tazobactam versus intravenous levofloxacin for treatment of complicated UTI/pyelonephritis, designed as a non-inferiority trial.  The results, as expected in any such paid advertorial, show “composite cure” favoring ceftolozane-tazobactam – a cure rate of 76.8%, versus 68.4% with levofloxacin.  The authors declare superiority based on confidence intervals, and the accompanying editorial further celebrates its availability and success.

Of course, this is “composite cure”, an endpoint based solely on differences in microbiological eradication of the original pathogens; clinical cure showed a non-significant difference.  And, the cohort for evaluation was only a “microbiological modified intention to treat population”, which ultimately excluded over 300 patients from this 1000 patient trial.  And, even then, the supposed difference in efficacy was based solely on the treatment failures in patients with pathogens with levofloxacin resistance.

So, yes, this is non-inferior to levofloxacin – except in price, where this new agent will likely cost $200-$300 per day per patient.  Superior?  No.  Its only utility will be in those locations where resistance is very high, and, even then, there will likely be other, cheaper alternatives with efficacy.

But, Cubist Pharmaceuticals, the sponsor and co-author of this paper, has no interest in use of such cheaper options.

“Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)”
http://www.ncbi.nlm.nih.gov/pubmed/25931244

No Additive Value for Macrolides?

As we’ve been repeatedly drilled by our quality groups – and in part to pneumonia core measures – appropriate empiric treatment for hospitalized community-acquired pneumonia is: 1) a beta-lactam plus a macrolide, or 2) respiratory fluoroquinolone monotherapy.

Or is it?

This cluster-randomized trial across seven hospitals in the Netherlands questioned the additive value of the macrolide, in the name of antibiotic resistance, and appear to have come out ahead.

Participants admitted to non-ICU settings with a clinical diagnosis of CAP received either beta-lactam monotherapy, beta-lactam plus macrolide, or respiratory fluoroquinolone monotherapy.  With between ~650 and ~890 patients enrolled during the time periods assigned to each arm, the final outcome was: no difference.  In fact, across nearly all intention-to-treat, radiographically-confirmed, and strategy-adherent analyses, beta-lactam monotherapy was solidly on the “better than” side of the confidence intervals versus added macrolide therapy.  There was no detectable trend with regard to the fluoroquinolone group – excepting the notable advantage of oral administration.  Nearly 30% of the fluoroquinolone group received their entire therapy by the oral route alone – an appreciable resource savings, at the least.

The authors do note the low seasonal prevalence of atypical pathogens during the time of the trial.  And, as with nearly all topics in medicine, the ultimate conclusion is not an “always” or “never” proposition.  However, in the patients selected for this trial, it certainly did not appear harmful to withhold a macrolide when treating with a beta-lactam.

“Antibiotic Treatment Strategies for Community-Acquired Pneumonia in Adults”
http://www.nejm.org/doi/full/10.1056/NEJMoa1406330

Cellulitis Done … Strangely

The Infectious Disease Society of America updated their recommendations last year with very reasonable guidelines.  Simple, uncomplicated cellulitis requires nothing more than penicillin or a first-generation cephalosporin.  This recognizes the overwhelming preponderance of susceptible organisms implicated in such infections.  Now, in the era of increasingly endemic methicillin-resistant S. aureus, the current prevailing worry is the rate of treatment failure for such inexpensive and old-fashioned first-line agents.

So, why are these authors testing clindamycin versus trimethoprim/sulfamethoxazole?  Not only that, in addition to uncomplicated cellulitis, these authors are also testing these agents following abscess drainage – yet another uncertain indication for antibiotics.

But, so, yes – with 524 patients in the phase of the trial enrolling those with uncomplicated cellulitis, mixed abscess and cellulitis, and abscesses greater than 5 cm, the comparison was a wash.  Clindamycin and TMP/SMX had small differences favoring the former, but not large enough to reach statistical significance.  Each antibiotic has its own specific constellation of adverse effects and interactions, and with treatment failures at roughly 1 in 5 in the ITT population for each, other considerations are probably more important than any efficacy difference between the two.

Of the 296 patients for which cultures were obtained, 167 (31.9% of the total cohort) grew MRSA.  Oddly, the methods state non-suppurative lesions were not cultured, and they report only 47% of patients had purulent drainage.  Yet, cultures were obtained in 56%.  What sort of culture swab was performed on simple cellulitis?

And, of course, as with every trial, every possible comorbidity was excluded.  Someday, we’ll have the wherewithal to compare failure rates in our typical Emergency Department patient – the diabetic, obese, and renally insufficient!

The other arm of the trial, a “limited abscess” group comparing I&D plus antibiotics versus I&D plus placebo will be published separately.

“Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections”
http://www.nejm.org/doi/full/10.1056/NEJMoa1403789

SIRS – Insensitive, Non-Specific

In what is almost certainly news only to quality improvement administrators, this newly published work out of Australia and New Zealand confirms what most already knew: the Systemic Inflammatory Response Syndrome criteria are only modestly associated with severe sepsis.

This is a retrospective evaluation of 13 years of data from the Australia and New Zealand Intensive Care Society Adult Patient Database, comprising routinely collected quality-assurance data.  Of 1,171,797 patients admitted to adult ICUs, 109,663 were identified as having both an infection and organ failure – the general, clinical definition of severe sepsis.  First, the good news:  over the 13 year study period, mortality dropped substantially – from over 30% down to close to 15%.  Then, the bad news:  12.1% of patients in the severe sepsis cohort manifested 0 or 1 SIRS criteria.  Mortality was lower in SIRS-negative severe sepsis, but hardly trivial at 16.1% during the study period, compared with 24.5% in the SIRS-positive patients.

So, the traditional SIRS-criteria definition of severe sepsis, previously thought to have at least sensitivity at expense of specificity will miss 1 in 8 patients with organ failure and an underlying infection.  Considering only approximately 1/3rd of patients with two or more SIRS criteria in the Emergency Department have an underlying infection, the utility of these criteria is substantially less reliable than previously thought.  Sadly, I’m certain many of you are suffering under SIRS criteria-based alerts in your Electronic Health Record – and, if such alerts are introducing cognitive biases by decreased vigilance and alert fatigue, it ought to be obvious we’re simply harming ourselves and patients.

“Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis”
http://www.nejm.org/doi/full/10.1056/NEJMoa1415236

Early Goal-Directed Waste For Sepsis

First there was ProCESS.  Then there was ARISE.  Now there is ProMISe.

If the prior two trials hadn’t already been celebrated and dissected, there would be much more to write regarding this one.  This, like the others, randomized patients to Early Goal-Directed Therapy for severe sepsis versus “usual care”.  This, like the others, found the basic components of resuscitation – intravenous fluids and early antibiotics – are far more important than the specific targets and protocols enshrined by Rivers et al.

These authors screened 6,192 patients to randomize 1,260.  Half had refractory hypotension, and the mean lactate levels were 7.0 and 6.8 in the EGDT and usual care arms.  Patients were enrolled within 6 hours of presentation and randomized within 2 hours of meeting inclusion criteria, with the EGDT arm receiving catheter insertion capable of SCVO2 monitoring within ~1 hour.   EGDT protocol was adhered to for 6 hours following enrollment.

As expected, randomization produced some divergence in treatment due to the EGDT protocol.  The EGDT cohort received more frequent red cell transfusions during both the protocolized period and subsequent care.  Likewise, dobutamine use in the EGDT arm exceeded usual care.  However, some differences occurred outside of the protocol.  EGDT arm patients were more likely to be admitted to an ICU setting, more likely to receive any sort of central line, more likely to receive invasive blood pressure monitoring, and more likely to be placed on vasopressors.  The remaining treatment – crystalloid resuscitation, colloid resuscitation, and other transfusions were similar.

And, finally, 90-day mortality was similar: 29.5% EGDT vs. 29.2% usual care.

A financial analysis found EGDT was more costly, but the result did not reach statistical significance.  However, the cost analysis was performed using different financial models that may not be generalizable to the billing structure in the United States.  The difference in ICU admission and length-of-stay alone certainly has important ramification both from a cost and a resource utilization standpoint.

So, finally, we have the publication of the last of the triumvirate of EGDT trials.  If there were any lingering doubts (hopes?) regarding the necessity of the most resource-intensive interventions, they ought to be laid to rest.  However, as with each of these negative trials, it is important to acknowledge the role of Rivers’ work in aggressively seeking, recognizing, and treating severe sepsis.  Even as we discard the components of his protocol, the main thrust of his work has saved many, many lives.

“Trial of Early, Goal-Directed Resuscitation for Septic Shock”
http://www.nejm.org/doi/full/10.1056/NEJMoa1500896

Sore Throats More Dangerous than Terrorists

“1 in 5 Sore Throats Tied to Scary Bacteria, Study Finds”

Thanks, HealthDay.

Now, clickbait headlines aside, what on earth are they referring to?  And, if ~50% of acute pharyngitis already receives inappropriate antibiotics – how can this sort of news release help us maintain any sort of reasonable antibiotic stewardship while also cultivating some modicum of Press Ganey approval?

This is a cross-sectional survey of throat swabs performed on a convenience sample of students at the University of Alabama.  PCR for an expanded cohort of bacterial pathogens was performed on 312 patients presenting to the student health center with acute pharyngitis, and compared with 180 asymptomatic volunteers.  Among symptomatic patients, 20.5% of PCR detected Fusobacterium necrophorum, compared with 9.4% of the asymptomatic cohort, leading to such conclusions as: “approximately 11% of cases of pharyngitis in patients coming to this university health clinic were caused by F. necrophorum.”  Group A Streptococcus, by comparison, was detected in only 10.3% of symptomatic patients and 1.1% of asymptomatic.

So, an epidemic of F. necrophorum?  Should we, as these authors suggest, be considering penicillin for all sore throats – based on the feared complication of Lemierre syndrome – regardless of rapid streptococcal antigen testing?

No.

While, we shouldn’t forget about F. necrophorum, particularly in the adolescent/young adult population, it is important to remember the vast majority of pharyngitis – even bacterial – is self-limited, with minimal benefit from antibiotics, either for symptom relief or suppurative complications.  For Group A Streptococcus, it is reasonable to suggest well over 200 cases must be treated with antibiotics to prevent progressive disease, and rheumatic fever is virtually extinct.  However, we have no similarly useful statistics regarding F. necrophorum – mostly because serious downstream complications are so rare they are still literally one-in-a-million case reports.  Assuming F. necrophorum is as prevalent in the general, or at least young adult, population in which pharyngitis is triaged for antibiotics using solely the rapid strep swab – clearly many swab-negative patients are being discharged with F. necrophorum carriage and no antibiotics, and we simply don’t see pervasive complications.

Symptomatic management and judicious treatment for acute pharyngitis remains the most appropriate strategy, despite the prevalence of this “scary bacteria”.

“The Clinical Presentation of Fusobacterium-Positive and Streptococcal-Positive Pharyngitis in a University Health Clinic”
http://www.ncbi.nlm.nih.gov/pubmed/25686164