Category: Infectious Disease

Another Appeal for Prudent Antibiotics

Bronchitis, deadly scourge of man – at least, considering the quantity of antibiotics prescribed, it must be, right?

Or, the cure is worse than the disease, as these authors seem to demonstrate.  This is a parallel, single-blinded, placebo-controlled trial in 9 primary care centers in Catalonia, Spain, enrolling patients with acute bronchitis.  Non-immunosuppressed patients with a productive cough of less than a week’s duration were randomized to amoxicillin-clavulanic acid, ibuprofen, or placebo for a 10 day course.  The primary outcome was time to cure, with treatment failure and safety outcomes as secondary outcomes.

With approximately 140 patients in each group, the only clinically meaningful significant difference between groups was the incidence of adverse events in the amoxicillin-clavulanic acid group.  These were mostly gastrointestinal events, occurring in 12% of the antibiotic group, compared with 5% of the ibuprofen group and 3% of the placebo group.  Days with cough, treatment failure, and time to overall symptom resolution showed no significant differences between groups.  There was some suggestion of a trend towards benefit from the ibuprofen arm, but this would have to be confirmed in a larger trial.

The main limitation of this article is failure to include a macrolide antibiotic as a comparator, considering the expected bacterial epidemiology of ambulatory respiratory infections.  Regardless, this adds to the body of evidence demonstrating the futility of antibiotics in healthy patients with bronchitis – and I’d expect similar findings even if azithromycin were included.

“Efficacy of anti-inflammatory or antibiotic treatment in patients with non-complicated acute bronchitis and discoloured sputum: randomised placebo controlled trial”
www.ncbi.nlm.nih.gov/pubmed/24097128

A Plea For Strep Throat Simplicity

A recent article published in the BMJ delightfully demonstrates that regardless of how we choose to overcomplicate the treatment of acute pharyngitis, our patients will all do just fine. The authors do have to be commended for their ambition as they attempt to supplant the mighty Centor’s claim as the clinical tool to guide antibiotic use. Not as self-aggrandizing as Centor, they named their rule FeverPAIN, an acronym for its five components. Their ambition is even more noteworthy as they endeavored to describe this rule’s derivation, validation, revision, bootstrap validation and clinical implementation all in one paper.
Despite the authors’ attempts to woo us with promises of bootstrapping and stepwise logistic regression, this study was essentially a pragmatic trial examining the effectiveness of three treatment strategies to guide antibiotic utilization in patients with acute pharyngitis. Patients (3 years or older) were randomized into one of three groups, either delayed antibiotics,  antibiotics as determined by the FeverPAIN score, or antibiotics as determined FeverPAIN score and a positive rapid antigen test.
Overall all three groups did well. The average duration of symptoms was 4 days. Both the clinical score group and clinical score + antigen test group had on average one day fewer symptoms than the delayed antibiotic group, all while receiving 10% fewer courses of antibiotics. Initially this finding seems counterintuitive. If more antibiotics were given in the delayed antibiotic group, how then did their symptoms last longer than those in the clinical score groups? Unless of course antibiotics played no role in this difference.
Its important to keep in mind that although this was a randomized trial, it was not blinded. Patients in both the clinical score group and the clinical score + antigen group had an experience in which the doctors spent time medically evaluating them and in some cases even running a “test”. Whereas in the delayed antibiotic group the patients had a less fulfilling experience, instructed to go home and a prescription for antibiotics would be waiting for them if they did not improve. Seemingly the prior two groups had a far stronger meaningful response than those in the delayed antibiotic group, demonstrating it is not antibiotics but rather talking to your patients and explaining the expected course of the disease that makes a difference on symptom burden. Interestingly the rapid antigen test added very little to reduction in antibiotic use and had no effect of length of symptoms.
This trial suffers from what is known as the Pollyanna Effect. If everyone will do well regardless of the intervention they receive, then it is almost impossible to show a clinically relevant superiority of one treatment strategy over another. More importantly with the incidence of rheumatic fever being so low it is considered clinically irrelevant. The question is not which of these strategies is most effective for the treatment of acute pharyngitis but rather is any treatment necessary at all? 
“Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomized controlled trial of PRISM (primary care streptococcal management)”. www.ncbi.nlm.nih.gov/pubmed/24114306

Nihilsm, Emergency Medicine and the art of doing nothing at emnerd.com 

A Plea For Strep Throat Simplicity

A recent article published in the BMJ delightfully demonstrates that regardless of how we choose to overcomplicate the treatment of acute pharyngitis, our patients will all do just fine. The authors do have to be commended for their ambition as they attempt to supplant the mighty Centor’s claim as the clinical tool to guide antibiotic use. Not as self-aggrandizing as Centor, they named their rule FeverPAIN, an acronym for its five components. Their ambition is even more noteworthy as they endeavored to describe this rule’s derivation, validation, revision, bootstrap validation and clinical implementation all in one paper.
Despite the authors’ attempts to woo us with promises of bootstrapping and stepwise logistic regression, this study was essentially a pragmatic trial examining the effectiveness of three treatment strategies to guide antibiotic utilization in patients with acute pharyngitis. Patients (3 years or older) were randomized into one of three groups, either delayed antibiotics,  antibiotics as determined by the FeverPAIN score, or antibiotics as determined FeverPAIN score and a positive rapid antigen test.
Overall all three groups did well. The average duration of symptoms was 4 days. Both the clinical score group and clinical score + antigen test group had on average one day fewer symptoms than the delayed antibiotic group, all while receiving 10% fewer courses of antibiotics. Initially this finding seems counterintuitive. If more antibiotics were given in the delayed antibiotic group, how then did their symptoms last longer than those in the clinical score groups? Unless of course antibiotics played no role in this difference.
Its important to keep in mind that although this was a randomized trial, it was not blinded. Patients in both the clinical score group and the clinical score + antigen group had an experience in which the doctors spent time medically evaluating them and in some cases even running a “test”. Whereas in the delayed antibiotic group the patients had a less fulfilling experience, instructed to go home and a prescription for antibiotics would be waiting for them if they did not improve. Seemingly the prior two groups had a far stronger meaningful response than those in the delayed antibiotic group, demonstrating it is not antibiotics but rather talking to your patients and explaining the expected course of the disease that makes a difference on symptom burden. Interestingly the rapid antigen test added very little to reduction in antibiotic use and had no effect of length of symptoms.
This trial suffers from what is known as the Pollyanna Effect. If everyone will do well regardless of the intervention they receive, then it is almost impossible to show a clinically relevant superiority of one treatment strategy over another. More importantly with the incidence of rheumatic fever being so low it is considered clinically irrelevant. The question is not which of these strategies is most effective for the treatment of acute pharyngitis but rather is any treatment necessary at all? 
“Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomized controlled trial of PRISM (primary care streptococcal management)”. www.ncbi.nlm.nih.gov/pubmed/24114306

Nihilsm, Emergency Medicine and the art of doing nothing at emnerd.com 

Down-Titrating Antibiotics for HCAP

The 2005 IDSA guidelines for healthcare-associated pneumonia are a little bit broad.  If you, a family member, or a pet has e-mailed or read about someone in the hospital, the recommendations are for a full-court press with coverage for multi-drug resistant pathogens.

However, this is clearly inappropriate.  The HCAP population is profoundly heterogenous, where patients receiving home wound care are grouped with patients with recent hospitalization and receipt of IV antibiotics.  It is clear, then, patients will suffer adverse effects and costs from overly-broad spectrum antibiotic coverage.

This group in Japan developed a decision instrument to guide antibiotic therapy, and prospectively evaluated it in 124 CAP and 321 HCAP patients over a two-year period.  Their HCAP stratification is very reasonable: mild disease with 1 additional risk factor for MDR or severe disease with zero risk factors for MDR were treated as CAP.  Everyone else received full HCAP coverage, with MRSA and anti-pseudomonal coverage.

A presumptive causative organism was diagnosed in about 50% of CAP and 60% of HCAP.  Of the 93 patients an organism isolated in the “low-risk” HCAP category, none had MRSA, and 3 had pseudomonas.  In the higher-risk HCAP groups, the low-severity group had 18 of 63 with an MDR pathogen, and the high-severity group had 28 of 56.

It is difficult to conclusively describe the safety of the treating-HCAP-as-CAP strategy, given the lack of a control group and the differences between baseline disease severity.  However, on first glance, it seems unlikely this conservative strategy impacts initial treatment failure and mortality rates in a clinical significant fashion.  This is an approach I’ve advocated for in the past, and plan to continue based on this addition to the body of evidence for individualized antibiotic selection for HCAP.

“A New Strategy for Healthcare-Associated Pneumonia: A 2-Year Prospective Multicenter Cohort Study Using Risk Factors for Multidrug- Resistant Pathogens to Select Initial Empiric Therapy”
http://www.ncbi.nlm.nih.gov/pubmed/23999080

What to Make of Esmolol in Septic Shock?

This is the new hotness in critical care discussions – the co-administration of intravenous esmolol to critically ill folks on high-dose vasopressor support in the ICU.  It’s a fascinating thought – considering the alpha- and beta-stimulation of norepinephrine necessary to maintain central perfusion, co-administration of a sympatholytic seems self-defeating, in a sense.

However, this may not be the case.  There are multiple dose-dependent effects of catecholamines on different tissues, as well as concern the tachycardia resulting from sympathomimetic myocardial stimulation in sepsis results in adverse outcomes.  Based on prior observational evidence, these authors performed a randomized, open-label trial of esmolol co-administration in a cohort of critically ill patients on vasopressor support.

They randomized 154 patients with HR >95 and septic shock to esmolol, titrated to a HR between 80 and 94 bpm, vs. usual care.  The hemodynamic variables showed, despite the use of esmolol, norepinephrine dosage was not significantly increased in order to maintain MAP.  Improvements in stroke volume compensated for a lower heart rate, resulting in non-significantly lower cardiac index.  However, what has everyone fascinated – the control group had 90% in-hospital mortality, compared with 67% for the esmolol group.  I don’t think anyone disagrees this is statistically significant and clinically important.

There were differences in baseline variables between groups.  The etiology of sepsis was substantially tilted towards peritonitis in the esmolol group, with obviously different causative organisms.  Lactic acid, base excess levels, and SAPS II scores favored the esmolol group.  The lead author and one co-author also have financial conflicts of interest with Baxter, the makers of esmolol (Brevibloc).  Financial conflicts, open-label, and the size of the study all make me wary of reproducibility and the magnitude of the effect size.

So, there are problems warranting additional and independent confirmation.  That said, the mortality benefit observed in this study is large enough I wouldn’t contest anyone who wanted to go ahead and start trying this in their highest-predicted mortality subset.  However, I’d also consent patients/families to this therapy as experimental and prospectively collect data for at least retrospective pre-/post- comparisons.

“Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock A Randomized Clinical Trial”
www.ncbi.nlm.nih.gov/pubmed/24108526

Yet More Unnecessary Antibiotics

One would think educational efforts regarding the inefficacy of antibiotics for viruses would at some point take root.  I’m pretty sure it’s explicitly covered in our medical school curriculum that antibiotics are indicated specifically to treat infection caused by bacteria.  Despite this, however, the overwhelming evidence is that clinicians have somehow forgotten these basic fundamentals of medicine.
This is a research letter reviewing the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (NAMCS,NHAMCS) databases for visits to primary care or Emergency Departments for code 1455: “sore throat”.  Considering the prevalence of group A strep infection is about 10%, and a small number of additional cases are pathogenic bacterial infections requiring acute treatment, I suppose you would expect the rate of antibiotic prescribing to be quite low?
Is 60% the number you had in mind?
U.S. physicians have been prescribing antibiotics at a mostly steady rate of 60% of visits for sore throat for over a decade.  Not only are they prescribing antibiotics, almost half of prescriptions are for non-ß-lactam antibiotics – including a huge proportion of azithromycin, as if there weren’t enough macrolide-resistant streptococci out there.  Beyond that, a full 15% were not even close to options on the recommended list for acute sore throat, such as fluoroquinolones.
When smart folks like David Newman are calling for the end of routine treatment of strep throat, certainly we are way off base with a 60% rate of treatment.  Forget about OP-15 – we should have a quality measure based on rates of antibiotic prescription for sore throat and ear pain.
“Antibiotic Prescribing to Adults With Sore Throat in the United States, 1997-2010”

Is Cephalexin Monotherapy Sufficient?

Following-up last week’s publication regarding the efficacy of TMP-SMX monotherapy for skin and soft tissue infections – with specific concern for S. pyogenes resistance – this article takes the opposing approach: cephalexin monotherapy.  Cephalexin and other first-generation cephalosporins have been effectively used for their gram-positive coverage in SSTs for quite some time – right up until they fall flat in the MRSA era.  They have excellent utility against Group A Strep, but lack any activity against MRSA.

This is a prospective, comparative-effectiveness trial of cephalaxin monotherapy vs. cephalexin + TMP-SMX in the treatment of uncomplicated, non-purulent cellulitis.  They enrolled 153 patients, lost 7 to follow-up, and the cure rates were 85% in the dual-therapy group and 82% in the monotherapy group.  Baseline differences between groups were generally small and likely clinically insignificant.  Oddly, almost a quarter of both groups received IV antibiotics at the initial visit.  Regardless, cephalexin monotherapy was non-inferior to cephalexin + TMP-SMX dual-therapy in this small trial.

Of course, as usual, this study excludes all patients with diabetes, immunosuppression, or peripheral vascular disease – which is to say, everyone we realistically see in the Emergency Department.  However, for non-purulent cellulitis in the absence of risk factors for MRSA, it is likely reasonable to continue with first-line cephalexin monotherapy.  It should also be noted these authors used full weight-based dosing schedules for their patients, with adults >80kg receiving 1000mg of cephalexin and TMP-SMX 160/800 each four times daily.

“Clinical Trial: Comparative Effectiveness of Cephalexin Plus Trimethoprim- Sulfamethoxazole Versus Cephalexin Alone for Treatment of Uncomplicated Cellulitis: A Randomized Controlled Trial”
http://www.ncbi.nlm.nih.gov/pubmed/23457080

Is TMP-SMX Monotherapy Sufficient?

Caution has traditionally been advised for the use of trimethoprim-sulfamethoxazole for skin and soft-tissue infections.  A significant portion of these infections are caused by Group A Strep – an organism traditionally thought to be resistant to TMP-SMX.

However, these authors feel, with the rising prevalence of MRSA SSTs – for which TMP-SMX provides useful oral spectrum of activity – it is time to re-examine this dogma.  Specifically, they feel the current opinion is based on inappropriate laboratory culture technique that overcomes the anti-bacterial target of TMP-SMX:  thymidine metabolism.  As part of ongoing clinical trials of TMP-SMX monotherapy for SSTs, they collected S. pyogenes isolates from patients and performed susceptibility testing on a variety of media they feel more appropriately reflects in vivo performance.  Of the 200 isolates tested on a variety of media, only one was evaluated by Etest to be resistant to TMP-SMX.  Therefore, these authors conclude TMP-SMX monotherapy may be entirely reasonable.

So, who is right?  These authors – with their new culture media – or the pre-existing dogma?  Unfortunately, the true answer is not yet clear – we need to look at clinical outcomes, not in vitro activity.  One working theory, at least, is infected hosts seem to supply enough thymidine to enable bacteria to negate the mechanism of action for TMP-SMX in vivo.  Only prospective clinical evaluation will provide better direction.  I would not yet suggest TMP-SMX monotherapy for SSTs where Strep were still a possibility.

“Is Streptococcus pyogenes Resistant or Susceptible to Trimethoprim-Sulfamethoxazole?”
http://www.ncbi.nlm.nih.gov/pubmed/23052313

Nothing Reliably Predicts Infected Stone

…but the obvious predictors are, well, obvious.

Ureterolithiasis sounds miserable.  Luckily, it is typically self-limited, temporary, and results in minimal lasting morbidity.  However, infected ureterolithiasis is a higher-risk clinical syndrome – and, even worse, infected, obstructed ureterolithiasis is a potential urologic emergency.  Thus, suspected infected ureterolithiasis certainly ought to be considered for imaging.

In this review of consecutive patients with suspected ureterolithiasis, 7.8% had concomitant urinary tract infection verified by urine culture.  Female, fever, and history of urinary tract infection were fair predictors of UTI, and increasing levels of pyuria and nitrates on urinalysis were strong predictors.  Overall, the presence of greater than 5 WBCs/hpf on microscopic examination was 86% sensitive and 79% specific for UTI.  No predictive feature was universally present, and specificity could be increased only at significant cost to sensitivity.

So, UTI complicating ureterolithiasis is uncommon and inconclusively diagnosed – but the strongest predictors are the obvious ones we’ve been accounting for already.

Fun tidbit:  Stone size ranged from 1 to 50mm.  50mm!

Somewhat-related plea:  These folks performed CT on ~90% of patients.  Many cases of ureterolithiasis can be diagnosed to reasonable certainty simply on clinical grounds.  Stop the cost/irradiation madness!

Somewhat-related plea #2:  There isn’t any proven pro-expulsion therapy.  All the tamulosin trials are small, manufacturer-sponsored, and non-compelling.  IV fluids also don’t help.  If the benefits aren’t proven, then all you have left are costs & potential harms.

“Association of Pyuria and Clinical Characteristics With the Presence of Urinary Tract Infection Among Patients With Acute Nephrolithiasis”
http://www.ncbi.nlm.nih.gov/pubmed/23850311

Suture Everything Closed

Management of dog bites still exhibits significant variability.  Antibiotics, traditionally generally prescribed, are only selectively necessary.  Another element of mythology, primary closure of wounds for optimal cosmesis, is the subject of this trial.

These Greek authors randomized 182 patients to either primary suturing or non-suturing of traumatic bite lacerations.  Obviously, the lacerations receiving primary closure had much improved cosmetic outcome.  The infection rate of suturing was 9.7% vs. 6.9% without, and this study was underpowered to confirm whether this small difference occurred by chance alone.  The main predictor of subsequent infection was treatment >8 hours after injury.  All patients, unfortunately, received local scrubbing with povidone-iodine and were prescribed amoxicillin/clavulanic acid, neither of which were likely helpful.

I think it’s absolutely reasonable to approximate wound edges for dog bite lacerations after gentle and thorough cleansing.  This study doesn’t provide any truly conclusive guidance for wounds >8 hours old – as they had similarly poor outcomes, regardless – other than to offer information to patients on their sub-optimal prognosis.

“Primary closure versus non-closure of dog bite wounds. A randomised controlled trial”
http://www.ncbi.nlm.nih.gov/pubmed/23916901