Category: Antibiotics

The “IV Antibiotics” Sham

Among the many overused tropes in medicine is the myth of the supremacy of intravenous antibiotics.  In the appropriate clinical context, it’s just a waste.

This is a retrospective analysis of 36,405 patients hospitalized for community-acquired pneumonia, and for whom a fluoroquinolone was selected as therapy.  The vast majority – 94% – received an intravenous dose, while the remaining 2,205 (6%) were treated orally.  Unadjusted mortality favored the oral dose – unsurprisingly, as those patients also generally has fewer comorbid conditions.  In their multivariate, propensity-matched analysis, there was no difference in mortality, intensive care unit escalation, or mechanical ventilation.

These results are wholly unsurprising, and the key feature is the class of antibiotic involved.  Commonly used antibiotics in the fluoroquinolone class, trimethoprim-sulfamethoxazole, metronidazole, and clindamycin, among others, have excellent oral absorption.  I have seen many a referral to the Emergency Department for “intravenous antibiotics” prior to an anticipated discharge to home therapy when any one of these choices could have obviated the entire encounter.

“Association Between Initial Route of Fluoroquinolone Administration and Outcomes in Patients Hospitalized for Community-acquired Pneumonia”
http://www.ncbi.nlm.nih.gov/pubmed/27048748

The Magic Bacterial Divining Rod

Antibiotic overuse is a real issue.  In modern countries, despite obsessing over antibiotic stewardship, we are still suckers for the excessive use of both narrow-spectrum antibiotics for ambulatory patients and broad-spectrum antibiotics for the critically ill.  In less resource-capable areas, the tests used to stratify patients as potentially bacterial or viral exceed the cost of the antibiotics – also leading down the path to overuse.

This breathless coverage, featured in Time, the AFP, and proudly advertised by Stanford Medicine, profiles a new panel of tests that is destined to bring clarity.  Rather than relying simply on a single biomarker, “our test can detect an infection anywhere in the body by ‘reading the immune system’”.

They used retrospective genetic expression cohorts from children and adults with supposedly confirmed non-infectious or infectious etiologies to derive and validate a scoring system to differentiate the underlying cause of sepsis.  They then further trim their model by eliminating infants and predominately healthy patients from outpatient cohorts.  Ultimately, they then test their model on a previously uncharacterized whole blood sample from 96 pediatric sepsis patients and report an AUC for viral vs. bacterial sepsis of 0.84, with a -LR of 0.15 and +LR of 3.0 for bacterial infections.  At face value, translated to a presumed clinical setting with a generally low prevalence of bacterial infection complicating SIRS, this is an uninspiring result.

However, these authors rather focus their discussion and press releases around the -LR of 0.10 and +LR of 2.34 produced as part of their ideal validation cohort, trumpeting its superiority over the -LR for procalcitonin of 0.29 as “three-fold improvement”.  This is, of course, nonsense, as the AUC from that same procalcitonin meta-analysis was 0.85, and these authors are simply cherry-picking one threshold and performance characteristic for their comparison.

Now, that’s hardly to say this is not novel work, and their confusion matrices showing clustering of non-infected SIRS vs. bacterial sepsis vs. viral sepsis are quite lovely.  Their approach is interesting, and very well could ultimately outperform existing strategies.  However, their current performance clearly does not match the hype, and they are miles away from a meaningful validation.  Furthermore, the sort of nano-array assay required is neither fast enough to be clinically useful nor likely to be produced cheaply enough to be used in some of the resource-poor settings they claim to be addressing.

It makes for a nice headline, but it’s better consigned to the “Fantasy/Science Fiction” shelf of your local bookstore for now.

“Robust classification of bacterial and viral infections via integrated host gene expression diagnostics”
http://stm.sciencemag.org/content/8/346/346ra91

Changing Clinician Behavior For Low-Value Care

I’ve reported in general terms several times regarding, essentially, the shameful rate of inappropriate antibiotic prescribing for upper respiratory infections.  Choosing Wisely says: stop!  However, aggregated data seems to indicate the effect of Choosing Wisely has been minimal.

This study, from JAMA, is a prospective, cluster-randomized trial of multiple interventions in primary care practices aimed at decreasing inappropriate antibiotic use.  All clinicians received education on inappropriate antibiotic prescribing.  Then, practices and participating clinicians were randomized either to electronic health record interventions of “alternative suggestion” or “accountable justification”, to peer comparisons, or combinations of all three.

The short answer: it all works.  The complicated answer: so did the control intervention.  The baseline rate of inappropriate antibiotic prescribing in the control practices was estimated at 37.1%.  This dropped to 24.0% in the post-intervention period, and reflected a roughly linear constant downward trend throughout the study period.  However, each different intervention, singly and in combination, resulted in a much more pronounced drop in inappropriate prescribing.  While inappropriate prescribing in the control practices had reached mid-teens by the end of the study period, each intervention group was approaching a floor-level in the single digits.  Regarding safety interventions, only one of the seven intervention practice clusters had a significantly higher 30-day revisit rate than control.

While this study describes an intervention for antibiotic prescribing, the basic principles are sound regarding all manner of change management.  Education, as a foundation, paired with decision-support and performance feedback, as shown here, is an effective strategy to influence behavioral change.  These findings are of critical importance as our new healthcare economy continues to mature from a fee-for-service free-for-all to a value-based care collaboration.

“Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices”
http://www.ncbi.nlm.nih.gov/pubmed/26864410

Again With No Antibiotics, This Time for UTI

Frequent readers of this blog may have noticed a bit of an anti-antibiotic tendency.  Diverticulitis!  Strep throat!  All manner of upper respiratory symptoms!

How about urinary tract infections?

This German study randomized ambulatory women with urinary tract infection symptoms and positive findings on urine dipstick to either fosfomycin plus placebo tablets for three days, or simply ibuprofen for three days.  Patients were then reassessed after three days, and those with treatment failure were provided an additional course of antibiotics.  “Co-primary” endpoints were antibiotics utilization and the AUC of sums of daily symptom scores.

The results are, like last week’s URI trial, a little mixed.  The authors included 484 patients in their intention-to-treat analysis, and 77% of them ultimately had culture-positive UTIs.  A lot – 69% – of patients randomized to ibuprofen had spontaneous resolution of their symptoms and avoided antibiotic use for their UTI.  However, obviously, those who did not improve spontaneously, and ultimately were given antibiotics, did worse than their fosfomycin counterparts – and the symptom scores clearly favored the antibiotic cohort.  Furthermore, 5 of 241 of patients randomized to ibuprofen advanced to pyelonephritis, and one more patient suffered ulcer-related bleeding due to ibuprofen.

I’m not sure how many women would opt for the trial of ibuprofen as part of a shared decision-making conversation, were practice to be based on this specific trial.  That said, it does raise a bit of an interesting question regarding potential strategies to reduce antibiotic use.  Would a 24- or 48-hour “waiting period” help?  If routine urine cultures weren’t already grossly low-value care, could waiting for those results help triage appropriate use of antibiotics?  Could a different symptom adjunct, such as pyridium, help reduce the difference in symptom scores while awaiting spontaneous resolution?

Regardless, it is is yet again an insight into the general effectiveness of the human body’s natural antibacterial defense mechanisms.  How much of modern medicine is critically important – and how much is simply are mildly harmful minor ameliorations of mostly self-limited disease processes?

“Ibuprofen versus fosfomycin for uncomplicated urinary tract infection in women: randomised controlled trial”
http://www.bmj.com/content/351/bmj.h6544

The Antibiotic Mandatory Waiting Period?

It has become generally accepted within the medical community the vast majority of cases of pediatric otitis media will resolve without antibiotics.  However, the tradition of treating OM with antibiotics is slow to wane, fueled by momentum and parental expectations.  Some success has been achieved with delayed-prescription strategies, where parents are provided with antibiotics, but encouraged to wait a few days and observe for spontaneous improvement.

These authors applied the same school of thought to benign upper respiratory tract infections – sinusitis, pharyngitis, and bronchitis.  They randomized 398 patients with common URTI-spectrum symptoms to one of four treatment strategies:  immediate antibiotic initiation; antibiotics provided immediately, but patient encouraged to wait-and-see a few days for spontaneous improvement; antibiotics available for pick-up three days later, if desired; and no antibiotics.  The primary outcome was duration and severity of symptoms, with various secondary outcomes of absenteeism, satisfaction, and antibiotic utilization.

The results of this study are a little bit mixed.  The patients initiating antibiotics immediately had shorter symptoms duration than any other strategy.  The sample sizes are small, and the standard deviation of symptoms in each cohort is huge, but it’s probably reasonable to estimate antibiotic use truncated moderate or severe symptoms by about a day or a day and a half from a 5-6 day illness duration.  Twelve of 98 randomized to no prescription ultimately crossed over to antibiotics.

But the remainder, despite their randomization to benign neglect, improved regardless, without any detectable difference in safety outcomes.  After all, the majority of these infections are either viral, or self-limited bacterial infections handled by the body’s natural immune system without complications.

The interesting outcomes, however, were the two delayed-antibiotic strategies.  Compared to the 91% antibiotic usage rate of the immediate antibiotic group, the patient-initiated and delayed-collection strategies resulted in 33% and 23% antibiotic usage rates, respectively.  Symptom duration, as to be expected, was mildly attenuated, falling between immediate antibiotic use and no antibiotics.

Is this the happy medium strategy needed to finally divorce ourselves from our addiction to unnecessary care for URTI disease?  “Choosing Wisely” as a general philosophy doesn’t seem to have had the desired effect – how about an executive action to mandate the same waiting period for antibiotics as we have for guns?

“Prescription Strategies in Acute Uncomplicated Respiratory Infections: A Randomized Clinical Trial”
http://www.ncbi.nlm.nih.gov/pubmed/26719947

The New “Standard of Care” for Appendicitis

Effectively, that is the question raised by this study – regarding antibiotics vs. surgery for acute, uncomplicated appendicitis.

This is a pragmatic, prospective study conducted in the pediatrics population at Nationwide Children’s Hospital.  The intervention and comparison were simple: qualifying patients with objectively mild appendicitis were offered a choice between hospitalization and intravenous antibiotics alone, or appendectomy with 12 hours.

And, as generally expected, not every patient choosing antibiotics successfully completed follow-up without crossover.  Of the 37 patients and families choosing antibiotics, 2 failed initial hospitalization, another 2 failed within 30 days, and 5 more failed within a year.  Median follow-up was 21 months at the time of article submission, and no further patients had undergone appendectomy.  Of 65 children undergoing surgery, 5 had post-operative complications, two of which were major (re-hospitalization, re-operation).

However, as I stated above, the question raised regarding antibiotics and appendicitis – is it now necessary it be discussed?  Have we reached a critical mass in the literature where all patients with suspected uncomplicated disease be offered antibiotics-only?  It is certainly unreasonable foundation for a complaint if an informed consent for surgical treatment of appendicitis did not include an antibiotics-only strategy as a legitimate alternative.  It was, in this cohort, much less disabling, in general, and substantially cheaper.

If not now – the not-to-distant future.

“Effectiveness of Patient Choice in Nonoperative vs Surgical Management of Pediatric Uncomplicated Acute Appendicitis”
http://archsurg.jamanetwork.com/article.aspx?articleid=2475977

The Slow Demise of Antibiotics for Diverticulitis

We have been prescribing antibiotics for diverticulitis for an eternity.  Some patients, after all, do quite poorly without – and progress to perforation, sepsis, and death.  Very few clamor for such an outcome.  The question with diverticulitis has never been “antibiotics?”, only “inpatient or outpatient”?

Now, this dogmatic practice seems ripe to change.

This latest bit of published literature is an observational series from Sweden.  These authors followed up their previously-published randomized trial with an initial foray into practice change, considering the consistent harms of antibiotic overuse.  They prospectively enrolled 155 patients with CT-verified, uncomplicated diverticulitis and simply followed them after discharge without antibiotics.  Management consisted solely of pain control, typically paracetamol (acetaminophen), an initial liquid diet, and then gradual progression to full diet as tolerated.  Patients were followed daily by phone, at 1 week in clinic, and at 3 months again in clinic.

Of these 155 patients, there were a mere 4 treatment failures requiring admission.  This treatment failure rate is similar to the ~2.5% rate expected with antibiotics.  Two progressed to perforation and a third developed abscess – the last of which was apparent on re-review of the initial CT.  Each patient with progression was treated with antibiotics as an inpatient and recovered.

This is, however, an observational trial, and there were another 66 patients diagnosed with uncomplicated diverticulitis in the same time period but missed for enrollment.  This leads to concerns regarding selection bias, although the few presented clinical characteristics of the missed patients were similar to those included in the trial.  Patients were also excluded on the basis of many comorbidities thought to increase the risk of treatment failure, and those treated as inpatients.

But, at the least, in this trial and those prior, there is clearly a cohort of uncomplicated diverticulitis that derives little benefit from antibiotics.  And, furthermore, these few trials have not gone unnoticed: new guidelines in several countries, including the American Gastroenterological Association, have updates reflecting the validity of selective antibiotic use.

The evidence quality to date is still cumulatively low – but this is probably a treatment change paradigm just about ready for prime-time.

“Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: a prospective study”
http://www.ncbi.nlm.nih.gov/pubmed/25989930

“American Gastroenterological Association Institute Guideline on the Management of Acute Diverticulitis”
http://www.ncbi.nlm.nih.gov/pubmed/26453777

The Macrolide Scourge, Updated

We’ve had a couple prior alerts regarding the potential cardiovascular risks of macrolides.  These have been taken with quite the grain of salt, particularly considering macrolides were, at one point, prescribed in a trial thought to be cardioprotective.

This meta-analysis is probably the most reasonable data to date on the subject.  These authors (of which there are 17) gather 33 studies comprising 20,779,963 participants.  These studies show, reasonably consistently, small increases in ventricular arrhythmias and sudden cardiac death.  The relative risks reported are 2.52 for VT and 1.31 for SCD, and there was not much reliable variation between different macrolide antibiotics.
However, these relative risks translate into just a handful of additional cases per million prescriptions.  The number needed to harm with cardiovascular death is about 25,000.  On the flip side, across the included studies, the all-cause mortality was unchanged.  So, yes, perhaps macrolides are not entirely benign – but neither is the underlying condition for which they are prescribed.
Overall, this study doesn’t add much to our insight into appropriate macrolide usage.  There may be particular subgroups for whom they may be best avoided, but, the alternative agent must be equally effective against the existing pathology – and not have its own particular undesired interaction.

Of course, if macrolides are used in context where their benefit is minimal or zero – then there is only harm.

“The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk”

Goodness Gracious We’re &*@ing Up Sinusitis

The American Academy of Allergy, Asthma, and Immunology has a lovely Choosing Wisely statement on sinusitis, featuring the following highlights:

  • Antibiotics usually do not help sinus problems.
  • Antibiotics cost money.
  • Antibiotics have risks.

So, how does one of the United States largest organized health systems fare for the treatment of such a simple, basic, commonplace condition?  A system, perhaps, that prides itself on internal quality initiatives and guideline adherence?  Well, based on this sample of 152,774 Primary Care, Urgent Care, and Emergency Department patients in Kaiser Southern California, they are: still awful.

  • ED patients received antibiotics 72.8% of the time.
  • UC patients received antibiotics 89.3% of the time.
  • PC patients received antibiotics 89.8% of the time.

And, not only that, antibiotic usage was all over the map, with large cohorts receiving prescriptions for less-appropriate options such as azithromycin and trimethoprim-sulfamethoxazole.

Why are we so terrible at this?

“Low-Value Care for Acute Sinusitis Encounters: Who’s Choosing Wisely?”
http://www.ajmc.com/journals/issue/2015/2015-vol21-n7/Low-Value-Care-for-Acute-Sinusitis-Encounters-Choosing-Wisely

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