Category: Antibiotics

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/

JAMA, Integrity, Accessibility, and Social vs. Scientific Peer Review

Yesterday, I posted regarding a JAMA Clinical Evidence series article involving procalcitonin measurement to guide antibiotics stewardship.  This is an article I read, raised concerns regarding other negative trials in the same spectrum, and depressingly noted conflict-of-interest with each of the three authors.


Graham Walker, M del Castillo-Hegyi, Javier Benitez and Chris Nickson picked up the blog post, spread it through social media and Twitter, and suggested I write a formal response to JAMA for peer-reviewed publication.  My response – I could put time into such a response, but what would JAMA’s motivation be to publish an admission of embarrassing failure of peer-review?  And, whatever response they published would be sequestered behind a paywall – while BRAHMS/ThermoFisher continued to happily reprint away their evidence review from JAMA.  Therefore, I will write a response – but I will publish it openly here, on the Internet, and the social peer review of my physician colleagues will determine the scope of its dissemination based on its merits.


Again, this JAMA article concerns procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections.  This is written by Drs. Schuetz, Briel, and Mueller.  They each receive funding from  BRAHMS/ThermoFisher for work related to procalcitonin assays (www.procalcitonin.com).  The evidence they present is derived from a 2012 Cochrane Review – authored by Schuetz, Mueller, Christ-Crain, et al.  The Cochrane Review was funded in part by BRAHMS/ThermoFisher, and eight authors of the review declare financial support from BRAHMS/ThermoFisher.


The Cochrane Review includes fourteen publications examining the utility of procalcitonin-based algorithms to initiate or discontinue antibiotics.  Briefly, in alphabetical order, these articles are:

  • Boudama 2010 – Authors declare COI with BRAHMS.  This is a generally negative study with regards to the utility of procalcitonin.  Antibiotic use was reduced, but mortality trends favored standard therapy and the study was underpowered for this difference to reach statistical significance (24% mortality in controls, 30% mortality in procalcitonin-guided at 60 days).
  • Briel 2008 – Authors declare COI with BRAHMS.  This study is a farce.  These ambulatory patients were treated with antibiotics for such “bacterial” conditions as the “common cold”, sinusitis, pharyngitis/tonsilitis, otitis media, and bronchitis.  
  • Burkhardt 2010 – Authors declare COI with BRAHMS.  Yet another ambulatory study randomizing patients with clearly non-bacterial infections.
  • Christ-Crain 2004 – Authors declare COI with BRAHMS.  Again, most patients received antibiotics unnecessarily via poor clinical judgement, for bronchitis, asthma, and “other”.
  • Christ-Crain 2006 – Authors declare COI with BRAHMS.  This is a reasonably enrolled study of community-acquired pneumonia patients.
  • Hochreiter 2009 – Authors declare COI with BRAHMS.  This is an ICU setting enrolling non-respiratory infections along with respiratory infections.  These authors pulled out the 47 patients with respiratory infections.
  • Kristofferson 2009 – No COI declared.  Odd study.  The same percentage received antibiotics in each group, and in 42/103 cases randomized to the procalcitonin group, physicians disregarded the procalcitonin-algorithm treatment guidelines.  A small reduction in antibiotic duration was observed in the procalcitonin group.
  • Long 2009 – No COI declared.  Unable to obtain this study from Chinese-language journal.
  • Long 2011 – No COI declared.  Most patients were afebrile.  97% of the control group received antibiotics for a symptomatic new infiltrate on CXR compared with 84% of the procalcitonin group.  85% of the procalcitonin group had treatment success, compared with 89% of the control group.  Again, underpowered to detect a difference with only 81 patients in each group.
  • Nobre 2008 – Authors declare COI with BRAHMS.  This is, again, an ICU sepsis study – with 30% of the patients included having non-respiratory illness.  Only 52 patients enrolled.
  • Schroeder 2009 – Authors declare COI with BRAHMS.  Another ICU sepsis study with only 27 patients, of which these authors pulled only 8!
  • Schuetz 2009 – Authors declare COI with BRAHMS.  70% of patients had CAP, most of which was severe.  Criticisms of this study include critique of “usual care” for poor compliance with evidence supporting short-course antibiotic prescriptions, and poor external validity when applied to ambulatory care.
  • Stolz 2007 – Authors declare COI with BRAHMS.  208 patients with COPD exacerbations only.
  • Stolz 2009 – Authors declare COI with BRAHMS.  ICU study of 101 patient with ventilator-associated pneumonia.

So, we have an industry-funded collation of 14 studies – 11 of which involve relevant industry COI.  Most studies compare procalcitonin-guided judgement with standard care – and, truly, many of these studies are straw-man comparisons against sub-standard care in which antibiotics are being prescribed inappropriately for indications in which antibiotics have no proven efficacy.  We also have three ICU sepsis studies included that discard the diagnoses other than “acute respiratory infection” – resulting in absurdly low sample sizes.  As noted yesterday, larger studies in ICU settings including 1,200 patients and 509 patients suggested harms, no substantial benefits, and poor discriminatory function of procalcitonin assays for active infection.  

Whether the science eventually favors procalcitonin, improved clinical judgement, or another biological marker, it is a failure of the editors of JAMA to publish such deeply conflicted literature.  Furthermore, the traditional publishing system is configured in such a fashion that critiques are muted compared with the original article – to the point where I expect this skeptical essay to reach a far greater audience and have a greater effect on practice patterns via #FOAMed than through the traditional route.

Diverticulitis – The Sinusitis of the Colon?

Antibiotics are wonderful things.  They treat and provide life-saving amelioration of symptoms from the common cold, the flu, bronchitis, sinusitis, and otitis – or, more accurately, they don’t.  Rather than generalize the treatment with antibiotics for all these illness, it is rather the avoidance of antibiotics that should be generalized, with specific exceptions made as necessary.

The next “-itis” to go under the microscope is diverticulitis.  These authors from Iceland and Sweden deserve, at the minimum, kudos for innovation in swimming against the tide.  The treatment of acute diverticulitis – a febrile illness with an elevated WBC and left-lower quadrant pain – is generally gram-negative and anaerobic coverage as an inpatient or outpatient, depending on comorbidities.  These authors propose that diverticulitis is most frequently a self-limited process, rather than one that requires antibiotics.

This a non-blinded trial of antibiotics vs. non-treatment for CT-demonstrated acute, uncomplicated diverticulitis.  Over 600 patients were admitted, with half receiving simple observation and symptomatic treatment vs. half with the same plus antibiotics.  1% of patients in the antibiotic group suffered treatment failure – progression to abscess or perforation – compared with 2% of patients in the placebo group.

Unfortunately, we’re not quite done with antibiotics based on just this study.  It is unblinded with variable enrollment between centers, leading to several sources of potential bias.  Then, ten patients in the no-antibiotics group crossed over to receive antibiotics for clinical worsening during hospitalization.  However, this is still below the 6.5% complication rate the authors thought might be an acceptable failure rate for conservative therapy.

Many more questions to be answered regarding external validity, so hopefully this inspires other investigators to further explore which subset patients will derive benefit from antibiotics in diverticulitis.

“Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis”
www.ncbi.nlm.nih.gov/pubmed/22290281

Viral Testing in Children With Fever

This study attempts to address the question we’ve been asking ourselves since the dawn of antibiotics – does this child with a fever have a viral infection, or a bacterial infection?  Of course, in reality, we should be asking a more complicated question – does this child have a viral infection, or a bacterial infection for which the increased likelihood of positive outcome with antibiotics outweighs the harms of the antibiotics?  But, I digress.

One hypothesis that is bandied about in literature and practice is, if rapid viral testing were available in the Emergency Department, perhaps a positive viral test result would reduce the likelihood of antibiotic usage.  These folks from Washington University performed viral PCR for a host of common viruses on 75 children with fever without a source, 15 children with probable bacterial infections, and 115 afebrile children presenting for outpatient surgery.  The authors note the patients with bacterial infections were less likely to test positive for a virus – and suggest prospective trials might describe a strategy in which viral testing decreased antibiotic use.

In their cohort, 55% of children aged 2 to 12 months and 39% of those aged 13 to 24 months with no obvious source for fever received antibiotics.  This is irresponsible lunacy.  However, a much faster, cheaper way to decrease antibiotic use is:  to simply return from the abyss of antibiotic overuse to a land of rational practice.  

After all, 40% of the bacterial infections and 35% of the outpatient surgical patients tested positive for a virus – clearly indicating the presence of a virus has limited association with acute viral illness or absence of an acute bacterial infection.  More tests are not the answer – at least, certainly not this battery of PCR tests.

“Detection of Viruses in Young Children With Fever Without an Apparent Source”
http://www.ncbi.nlm.nih.gov/pubmed/23129086