Category: Antibiotics

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

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

Ceftriaxone: It’s Not For Stroke

Negative trials are just as important – if not moreso – than positive trials.  Without negative trials, well-meaning clinicians continue with unproven and unverified treatments, incurring unnecessary costs and exposing patients to unneeded potential adverse effects.

This prospective trial of 2,550 patients randomized patients post-stroke to four days of prophylactic ceftriaxone versus no treatment, using an open-label, masked endpoint design.  The theory – some of the mortality and disability post-stroke may be in excess as result of infectious (primarily respiratory) complications.  The fact – no.  There was no difference in functional outcome at any modified Rankin Score ordinal cut-off, nor mortality.  There were actually not fewer cases of pneumonia in the ceftriaxone group, but urinary tract infections were significantly suppressed.  Clostridium difficile infection occurred only in two cases, both in the ceftriaxone group.

As a random aside, the median NIHSS in this trial was 5 – and 37% of patients achieved mRS 0-1.  This is rather surprisingly low, considering the SITS-MOST cohort and pooled placebo groups from RCTs with median NIHSS’ ~12 had achieved mRS 0-1 in 38% and 33% of the time, respectively.  A window into the lack of generalizability of the thrombolysis RCTs?  Perhaps – or just a curiosity.

Oh, but, back to the point – it does not appear to have clinical utility to routine use ceftriaxone as antibiotic prophylaxis after acute ischemic stroke.

“The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial”
http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)62456-9.pdf

Preposterous Inpatient Antibiotic Overuse

It is one matter entirely to give antibiotics for self-limited bacterial or viral conditions.  It is another matter to regularly, simultaneously prescribe multiple, redundant antibiotics with overlapping coverage, excepting a few particular situations.

And, we are clearly using overlapping coverage far more than just a few particular exceptions.

This review of proprietary data from inpatient antibiotic use in 505 U.S. hospitals between 2008 and 2011 looked at three types of antibiotic overlap – that for MRSA, for anaerobic bacteria, and for ß-lactam therapy.  These authors noted 32,507 cases in which patients received at least two consecutive days of redundant, simultaneous antibiotics.  The largest offender, by far:  82,018 days in which patients received both intravenous metronidazole and intravenous piperacillin-tazobactam.  The majority of the remainder were also anerobic overlap, and the authors also cited over a thousand cases each of dual-MRSA therapy or dual-ß-lactam therapy.

Now, there are certain tissues in which vancomycin has poor penetration, and vancomycin-intermediate strains are increasing – so it’s unreasonable to say all dual-MRSA therapy is inappropriate.  The same applies to the dual-ß-lactam therapy, as double-coverage for pseudomonas and other MDR pathogens frequently requires at least initial redundant therapy.  However, I think this data still reasonably reflects an abundance of opportunity to curtail inappropriate antibiotics use.

The authors, mostly employed by a health services consulting company, also try to do a cost-analysis to quantify the scope of the redundant use.  Unfortunately, in each case, they assume the more expensive antibiotic is the redundant one – which inflates and exaggerates their estimates.  Presumably, this comes out of the need to subsequently promote their company’s services, and these numbers are best ignored.

But, we can, at least, do much better than our present state of affairs.

“Economic Impact of Redundant Antimicrobial Therapy in US Hospitals”
http://www.ncbi.nlm.nih.gov/pubmed/25203175

Updated IDSA Soft Tissue Infection Guidelines

Our infectious disease experts have bestowed upon us an update in the management of skin and soft tissue infection.  This is particularly relevant in our new Age of MRSA, where over-reaction and antibiotic overuse has become the norm – and almost certain to usher in a new, more dire, era of resistant pathogens.

But, this update provides a lovely pathway describing the treatment options for SSTIs that, happily, includes many narrow spectrum antibiotics.  Non-abscess SSTIs may be managed with simple penicillins or first-generation beta-lactams.  Purulent pathology is managed simply by incision and drainage – and antibiotics added only in the setting of moderate or severe disease.  They also, importantly, note most impetigo should be treated solely with topical antibiotic ointment.

There are a handful of odd statements, however.  Cultures are still recommended, but the authors acknowledge treatment is reasonable without.  Considering avoidance of cultures in uncomplicated SSTI is part of ACEP’s Choosing Wisely Recommendations, I’d prefer to see revised phrasing from the authors in the associated passages.  Recommendations for antibiotic prophylaxis after dog and cat bites appropriately require specific risk-factors for superinfection, but may yet still be overly broad.  At least, however, the level of evidence supporting their recommendation is appropriately cited as “low”.

And, of course, it’s always nice to be reminded of the appropriate treatment of glanders.

Finally, the recommendations do not overtly appear to reflect the influence of financial conflicts, despite many authors declaring substantial COI.

“Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America”

Abscess Management in the Era of MRSA

Every so often, it’s good to circle back from the esoteric to the basics, and remind ourselves how to provide the best, evidence-based treatment for some of the most common diseases – in this case, abscesses.

This review in the New England Journal is a reasonable, concise overview of the evidence behind management of cutaneous abscesses, updated for the increasing prevalence of methicillin-resistant Staphylococcus aureus.  And, quite simply, there’s no evidence for any reason yet to panic.  The authors of this article summarize the literature thusly:

  • Incision & drainage is definitive treatment.  Non-complicated disease does not require additional antibiotic treatment, and the incremental benefit – if any – would be single-digit differences in clinical failure.
  • Packing of abscesses is a matter of tradition, and evidence is neither sufficient to conclusively confirm nor refute this practice.
  • Primary closure of abscesses after I&D is reasonable, particularly for larger, exposed, and cosmetically important areas.
  • Antibiotic coverage for primarily cellulitic soft-tissue infections ideally includes both MRSA and streptococcal coverage, but recent evidence showed no advantage to double-coverage.  Clinical trials regarding antibiotic use are ongoing:  NCT00729937 NCT00730028  NCT00729937
  • Wound cultures are not necessary.

One could argue covering such basics in infection and wound management is a sundry affair for a blog frequently covering the cutting edge.  However, current management of such a common condition is so highly variable and frequently low-value, ACEP even made a point to include abscess management in their Choosing Wisely campaign list.

Now, go and do as little harm as possible.

“Management of Skin Abscesses in the Era of Methicillin-Resistant Staphylococcus aureus”
http://www.ncbi.nlm.nih.gov/pubmed/24620867

Conclusively Settling Azithromycin’s Cardiac Toxicity Forever

We’ve been obsessed with azithromycin’s cardiovascular effects for quite some time – with some studies showing an increase in events, and other studies using azithromycin as the active agent to decrease coronary events.  Why is it such an issue?  Mostly because azithromycin has become the nonsensical cure-all of eager-to-please primary care physicians for self-limited or viral conditions, let alone the mainstay of treatment for pneumonia.

This latest study comes from a retrospective cohort of Veterans Affairs patients admitted and receiving IDSA guideline-compliant treatment for community-acquired pneumonia.  These authors compared a cohort of patients receiving ß-lactam + azithromycin with any other guideline-compliant therapy, typically fluoroquinolone monotherapy.  They created two propensity-matched cohorts based on known confounders, resulting in comparison groups of 31,863 patients each, with a treatment period spanning 2001 to 2012.

Of these, 1,948 patients exposed to azithromycin had a myocardial infarction recorded within 90 days, compared with 1,523 in the non-azithromycin cohort, for an OR of 1.11 (95% CI 1.03-1.20).  No other cardiovascular disease was increased, and no specific subgroup conferred a higher or lower risk of MI after azithromycin use.  Most of the difference in MI occurred within 30 days of exposure.

However, interestingly, the overall 90-day mortality was 6,582 in the azithromycin cohort, compared with 8,152 in the non-azithromycin cohort, for an OR of 0.73 (95% CI 0.70-0.76).  And, the authors happily run with this mortality advantage – concluding “azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality (number needed to treat of 21)”.  But, how does a short course of a macrolide antibiotic generate such a profound survival curve that progressively widens months after exposure?  The authors do not provide data on causes of death, nor do they provide much explanation for the observed survival advantage.  Either short-course azithromycin provides a powerful, anti-inflammatory effect with long-term advantage – as implied by the authors – or there’s a problem with the data and the matching.

My vote is for problems with the data.  Propensity matching is only as good as the prognostic importance of variables included in the algorithm, and suffers tremendously when performed on retrospective data not gathered specifically to support such analyses.  Sadly, this study is probably best served to be assigned to the scrap heap of unreliable retrospective observations.

“Association of Azithromycin With Mortality and Cardiovascular Events Among Older Patients Hospitalized With Pneumonia”

Let’s Make MRSA Stronger

Yesterday, the NEJM published two new trials regarding new lipoglycopeptide antibiotics targeting MRSA.  And, it remains to be seen whether their use represents the beginning of the end.

Oritavancin and dalbavancin differ from vancomycin – and this is their primary advertised advantage – in terms of substantially lengthened terminal half-life.  This means oritavancin may be used as a one-time dose, and dalbavancin as a two-dose regimen a week apart.  Both trials involved severe soft-tissue infection, and were non-inferiority trials comparing each against either intravenous vancomycin alone or intravenous vancomycin transitioning to oral linezolid.  Exclusion criteria were extensive for each, but the ultimate non-inferiority results for treatment failure are reasonably generalizable.  Adverse events, as well, were similar between study populations.  At face validity – if you trust trials that are designed, conducted, and analyzed by pharmaceutical companies – these treatments are safe and effective.

The accompanying editorial enthusiastically supports these new options, saving patients unnecessary costs and risks associated with hospitalization or indwelling intravenous catheters.  This is likely true, although it remains to be see whether single-dose infusion pricing will ultimately prove less expensive than a transition to oral linezolid.  Then, single-dose antibiotic strategies may have a horrible downside: induced resistance.  With terminal half-lives up to two weeks in the case of oritavancin, the active metabolite will be present in the body for a prolonged period of time below the minimum inhibitory concentration.  As we’ve seen with azithromycin, another antibiotic with a long half-life, increased use was associated with a rapid rise in macrolide resistant streptococcus.  It’s hardly a stretch to project similar effects here.

Widespread use of these “convenient” antibiotics may eventually result in significant unintended harms, and possibly the loss of an entire class of effective treatment for MRSA.

“Once-Weekly Dalbavancin versus Daily Conventional Therapy for Skin Infection”
http://www.nejm.org/doi/full/10.1056/NEJMoa1310480

“Single-Dose Oritavancin in the Treatment of Acute Bacterial Skin Infections”
http://www.nejm.org/doi/full/10.1056/NEJMoa1310422

More of the Same Inappropriate Antibiotic Prescribing

There is no debate regarding the correct treatment of acute bronchitis in patients without underlying immunodeficiency or pulmonary structural disease.  The correct antibiotic treatment is: none.  This is not a controversial subject.  Indeed, as this research letter in JAMA notes, since 2005 the National Committee of Quality Assurance has published a measure in the Healthcare Effectiveness Data and Information Set stating the correct rate of antibiotic prescribing in acute bronchitis is: zero.

If you’re hoping this next part is where I excitedly share a successful reduction in inappropriate antibiotic use, you’ll be more than a little disappointed.

Using The National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, these authors found, unfortunately, that 71% of patients with acute bronchitis are receiving a prescription for antibiotics in outpatient settings.  There was essentially no difference in prescribing rates over any of the NAMCS samples – we were just as irresponsible in the 2008-2010 survey period as we were in the 1996-1998 period.  There was no difference in rate between Emergency Department and primary care settings, nor in race, age, insurance status, nor care location.  41% of patients received an extended macrolide – azithromycin – followed most commonly by fluroquinolones, aminopenicillins, and cephalosporins.

Yes, Virginia, a self-limited condition for which antibiotics confer no benefit frequently receives fluoroquinolone therapy.

Words fail me.  I will simply quote the authors’ conclusion:

“Avoidance of antibiotic overuse for acute bronchitis should be a cornerstone of quality health care. Antibiotic overuse for acute bronchitis is straightforward to measure. Physicians, health systems, payers, and patients should collaborate to create more accountability and decrease antibiotic overuse.”

“Antibiotic Prescribing for Adults With Acute Bronchitis in the United States, 1996-2010”
http://jama.jamanetwork.com/article.aspx?articleid=1872806

VUR, Renal Scarring and other Fictitious Maladies

A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.

As Emergency Physicians, one of the more vexing tasks asked of us is to identify the otherwise well appearing patient who has an occult illness that, if not identified, will lead to poor outcomes. With this in mind, we now turn our attention to the well appearing febrile infant and our unfounded obsession with urine. The fear that these children are quietly infarcting their nephrons is one of the more far fetched tales in emergency medicine.



In a recent NEJM article published by the RIVUR Trial Investigators, the authors examined whether prophylactic antibiotics for children with voiding cystourethrogram (VCUG) confirmed vesicoureteral reflux(VUR) were effective in preventing recurrent infections and more importantly, decreasing the extent of renal scarring (as per DMSA scan). Patients were randomized to either daily trimethoprim-sulfamethoxazole (TMP-SMX) suspension or placebo for one year. Authors found that children treated with prophylactic antibiotics had an absolute decrease in the recurrence of urinary tract infections by 12%. Meaning, you would have to treat 8 children for 12 months to prevent one case of recurrent UTI. More importantly the rate of renal scaring at follow up was identical.

  Among the children who experienced their first recurrent UTI, the rates of E. coli resistance to to TMP-SMX was 63% in the active group vs 19% in the controls.

Though this trial fails to address the futility of our quixotic attempts to diagnose and treat every UTI, clearly the utility of searching for and diagnosing VUR in febrile children in the hopes of preventing future renal scarring is a flawed concept. Furthermore it is unclear whether the surrogate endpoint of renal scarring, as seen on DMSA, is clinically relevant.  Not only are we most likely treating a fictitious disease process, but as the RIVUR authors demonstrated we are doing so ineffectively.

“Antimicrobial Prophylaxis for Children with Vesicoureteral Reflux.” http://www.ncbi.nlm.nih.gov/pubmed/24795142