Category: Antibiotics

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

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

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

U.S. Physicians are Awful at Prescribing Antibiotics

…and the Emergency Department is one of the worst offenders.

This is an analysis of the National Hospital Ambulatory Medical Care Survey, a representative sampling of ambulatory settings across the United States.  These authors simply reviewed all the antibiotic prescriptions and diagnosis codes for adult visits to offices, outpatient departments, and Emergency Departments.  10% of visits result in antibiotic prescriptions – and 61% of these prescriptions were broad-spectrum agents (amoxicillin/clavulanate, quinolones, etc.).  The largest category of antibiotic prescribing was for acute respiratory infections – and only 32% of those prescriptions were for diagnosis codes where antibiotics were typically indicated.  88% of respiratory diagnoses for which antibiotics were rarely indicated (e.g., bronchitis) received a broad-spectrum antibiotic.

This is retrospective, and the NHAMCS database has limitations – but this is farcical.  We’re passing out antibiotics without regard to the consequences – and we’re overusing broad-spectrum agents when narrow-spectrum agents are likely appropriate.  We’re far behind Europe in antibiotic stewardship, and the end result is certainly net population harm from over-treatment and induction of microbial resistance.

And, this doesn’t even account for pediatric visits – which are probably even worse.

Tragically, physician reimbursement is tied to patient satisfaction – or is an emphasized part of a healthcare business model in for-profit settings – and the evidence clearly indicates patients are more satisfied when they receive antibiotics.(pubmed, pubmed, archives of pediatrics)

Yet another example of perverted incentives degrading medical practice.

“Antibiotic prescribing for adults in ambulatory care in the USA, 2007 – 09”
www.ncbi.nlm.nih.gov/pubmed/23887867‎

The War on Blood Cultures

There are two problems with blood cultures.  The first question is with regard to the likelihood you’ll get a true positive result.  That question is covered by this JAMA Rational Clinical Examination.

The second question regards whether the true positive result is clinically meaningful.  This retrospective review of 639 cellulitis patients – 325 without medical comorbidities and 314 with – evaluated for changes in therapy as a result of positive cultures.  46 cultures returned positive – with half being judged due to contaminants.    Of the 23 true positives, 5 resulted in a change of antibiotic therapy – only 2 of which expanded the initial antibiotic choice to include coverage for a new pathogen.  Both changes in therapy occurred in the immunosuppressed group.

Yet another example of the incredibly low yield of an expensive test.  We’re clearly simply asking a question for which we already have the answer.

“Blood culture results do not affect treatment in complicated cellulitis”
www.ncbi.nlm.nih.gov/pubmed/23588078

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”

“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/