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March 2016
Journal Club
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases.

Peer Comparison and Accountable Justification to Reduce Inappropriate Antibiotic Prescribing in Primary Care
Reviewed by Sheila Mitsuma, MD

Acute respiratory tract infection (ARTI) is the most common reason for acute outpatient physician office visits and antibiotic prescription in adults in the United States. A portion of these prescriptions, estimated at up to 50 percent, are inappropriate. To address this issue, authors from the Centers for Disease Control and Prevention and the American College of Physicians recently offered guidance on appropriate antibiotic use for ARTI in an article in Annals of Internal Medicine.

Changing behavior in practice, however, is often challenging. To help determine what strategies may be effective, investigators in Boston and Los Angeles performed a cluster randomized trial evaluating the effects of three different behavioral interventions on antibiotic prescribing in the primary care setting and published their results in the Journal of the American Medical Association. The trial included 249 physicians from 49 primary care practices within three health systems randomized to zero, one, two, or three behavioral interventions for an 18-month period. Three interventions were implemented either alone or in combination:

  1. Suggested alternatives (electronic order sets presented non-antibiotic alternatives)
  2. Accountable justification (electronic health records prompted entry of free-text justification for antibiotic use)
  3. Peer comparison (emails sent to providers comparing their prescription rates with “top performers,” i.e., those with the lowest prescription rates)

The primary outcome measured was the antibiotic prescription rate for antibiotic-inappropriate diagnoses, defined as care not concordant with guidelines. These diagnoses included upper respiratory tract infection, acute bronchitis, and influenza, as defined by ICD-9 code. A total of 31,712 visits (14,753 in the baseline period and 16,959 in the intervention period) met criteria for outcome evaluation.

Mean antibiotic prescribing rates decreased from 24.1 percent at intervention start to 13.1 percent 18 months later, for an absolute difference of -11.0 percent for control (no intervention) practices. Compared to control practices, a statistically significant difference was found between the control group and the accountable justification and peer comparison groups, with an absolute difference of -18.1 percent in the accountable justification group and a -16.3 percent difference in the peer comparison group (p < 0.001). While a -16 percent difference was measured in the suggested alternatives group, this did not reach statistical significance. No significant differences in the proportion of ARTI diagnoses were seen between baseline and intervention periods.  

Although this study has limitations, particularly sample size and generalizability, it highlights that strategies derived from behavioral science and change management may aid in antimicrobial stewardship efforts.

(Harris et al. Ann Intern Med. 2016 Jan. 19.)

(Meeker et al. J Am Med. 2016;315(6):562-570.)


Difficulties in Dosing Colistin
Reviewed by Christopher J. Graber, MD, MPH, FIDSA

In its first few decades of use after its introduction in the 1950s, dosing of colistin (polymyxin E), available as its prodrug colistimethate, was based on very limited pharmacologic data. With its re-emergence over the past decade, more data has become available that has informed dosing guidelines established by the U.S. Food and Drug Administration (FDA) in 2013 and the European Medicines Agency (EMA) in 2014. However, a recent report published in Clinical Infectious Diseases notes that dosing according to these guidelines (particularly FDA’s) may result in low rates of attainment of clinically relevant serum concentrations at differing levels of renal function.

The authors obtained pharmacokinetic data from 162 critically ill patients with a wide range of renal function who were receiving colistin in order to determine average steady-state concentrations that would be achieved if they received EMA- or FDA-recommended doses specific to their level of renal function. They then calculated the probability of achieving clinically relevant serum concentrations based on these dosing recommendations, most notably 2 mg/L (corresponding to the current susceptibility breakpoint of ≤ 2 mg/L established by the Clinical and Laboratory Standards Institute for Pseudomonas and Acinetobacter species). While EMA dosing recommendations were associated with a relatively high probability of achieving a steady-state concentration of 2 mg/L at lower levels of renal function (approximately 90 percent for creatinine clearance (CrCl) < 80 mL/min), FDA dosing recommendations were associated with much lower probabilities (less than 10 percent for CrCl < 30 mL/min and approximately 50-60 percent for CrCl 30-80 mL/min). Neither was associated with high probability of target attainment of 2 mg/L at CrCl ≥ 80 mL/min (EMA: 33 percent; FDA: less than 25 percent). 

While nephrotoxicity was not specifically addressed in this study, prior studies indicate that nephrotoxicity may be more prevalent at serum concentrations ≥ 2.5 mg/L and in patients with CrCl ≥ 80 mL/min. Thus, colistin likely has an exceedingly narrow therapeutic window, making appropriate dosing difficult, particularly at higher levels of renal function. This study adds to a growing list of concerns regarding the utility of colistin, including batch-to-batch variability of active drug, poor data to support breakpoint determination, poorly available therapeutic monitoring, and recently described plasmid-mediated resistance. While polymyxin B may offer more favorable pharmacokinetics, its efficacy data is even more limited.  Better drugs are clearly needed to treat infections caused by resistant Gram-negative bacteria.

(Nation et al. Clin Infect Dis. 2016;62(5):552-558.)

Strong Evidence Against Adjunctive Corticosteroids in HIV-Associated Cryptococcal Meningitis
Reviewed by Brian R. Wood, MD

Cryptococcal meningitis remains one of the most common opportunistic infections in HIV-infected persons, causing significant mortality and morbidity, even with optimal antifungal therapy. Thus, there exists substantial need to investigate strategies that might improve outcomes. A previous study that examined optimal timing of antiretroviral therapy (ART) initiation in cryptococcal meningitis was stopped early due to worse outcomes with early ART. Now, a trial reported in the New England Journal of Medicine provides strong evidence that adjunctive corticosteroids provide no survival benefit and in fact confer harm.
Researchers enrolled adults with advanced HIV and confirmed cryptococcal meningitis at multiple sites in Asia and sub-Saharan Africa (about 60 percent on ART at enrollment) and randomized participants in double-blind fashion to dexamethasone (intravenous, weight-based dosing for two weeks, followed by tapering oral dosing for four weeks) or placebo. Induction antifungal therapy included amphotericin and high-dose fluconazole.
Investigators halted the trial after enrolling 451 patients due to evidence of harm in the dexamethasone arm. While this arm did experience greater reductions in  intracranial pressure in the first two weeks, data showed significantly higher disability at 10 weeks and adverse events at six months (including grade 3 or 4 infections) plus slower cerebrospinal fluid fungal clearance. There was a trend towards lower survival with dexamethasone compared to placebo (47 percent versus 41 percent at 10 weeks and 57 percent versus 49 percent at six months). The findings were consistent across all study sites and subgroups.
The authors conclude that adjunctive corticosteroids, at least at the dose and duration used, elicit harm. Several questions linger. Would a shorter course of dexamethasone change outcomes? There was some suggestion of benefit from dexamethasone in the first three weeks. What role do corticosteroids play in cryptococcal immune reconstitution inflammatory syndrome (IRIS)? The trial found no suggestion of benefit for suspected IRIS cases, but was not powered to answer that question. As the authors note, this is strong evidence against routine adjunctive corticosteroids in cryptococcal meningitis, and improving access to first-line antifungal agents like flucytosine must be a priority.

Antibiotics May Not Always be Necessary for Treatment of Uncomplicated UTIs
Reviewed by Manie Beheshti, MD

The recent paradigm shift in the approach to urinary tract infections (UTIs) has led to a better understanding of the most common bacterial infection in women. The appropriate clinical approach to UTIs and the need to treat uncomplicated UTIs has been recently questioned by some intriguing studies. 
With the concerning rise in bacterial resistance to antimicrobials and the critical need for limiting antimicrobial use, a recent study in The BMJ was designed to assess a novel strategy for reducing antibiotics for the treatment of uncomplicated UTIs. Investigators sought to determine if symptomatic versus antimicrobial treatment of uncomplicated UTIs would lead to fewer courses of antibiotics during the 28-day study period. Building on their smaller pilot study, this multi-center controlled trial in Germany randomized nearly 500 women aged 18-65 with symptoms of UTI to two blinded groups: fosfomycin 3-gram single dose versus ibuprofen 400 milligrams twice daily for three days. The primary endpoints were total antibiotic use in the 28-day study period and symptom burden as scored by reported daily symptoms.
Although the ibuprofen group had greater symptom burden during the 28-day study period, they used 64.7 percent fewer courses of antibiotics compared to the fosfomycin group (85 women in the ibuprofen group received antibiotics versus 243 women in the fosfomycin group). In a subgroup analysis of those with negative urine cultures, this reduction was even more pronounced at greater than 90 percent. Most notably, two-thirds of women in the ibuprofen group recovered without antibiotics.
While this study cannot support the use of ibuprofen, it does lend potentially critical data to the question of whether all UTIs warrant therapy. In the right setting, the authors noted, “lower antibiotic consumption [could be] ‘bought’ at the expense of a higher burden of symptoms … .” 

A Change Two Decades in the Making: Redefining Sepsis and Septic Shock
Reviewed by Nirav Patel, MD

Sepsis has always presented a clinical management challenge due to a lack of a diagnostic gold standard. Historically, clinicians have depended on the Systemic Inflammatory Response Syndrome criteria to provide clinical parameters. However, in bedside care, these non-specific markers did not provide the necessary accuracy to meet clinical demands. In the Feb. 23 issue of the Journal of the American Medical Association, a series of articles by a multidisciplinary taskforce describes the result of a paradigm-shifting effort to redefine sepsis and septic shock.
Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” Organ dysfunction is ascertained by a change in the Sequential Organ Failure Assessment (SOFA) by greater than or equal to two points, which reflects an approximate 10 percent risk of mortality. A new measure, qSOFA, requires two of the following three elements to be considered: respiratory rate greater than or equal to 22/min, altered mental status, and systolic blood pressure of less than or equal to 100 mm Hg. While not as robust as SOFA, the new measure requires no specialized testing, and can be performed serially and rapidly at bedside.  The predicative validity for hospital mortality in intensive care unit (ICU) patients for SOFA had an area under the receiver operating characteristic curve (AUROC) of 0.74, while qSOFA was 0.66. Furthermore, in non-ICU patients the AUROC for SOFA was 0.79 and qSOFA was 0.81, suggesting high utility in this setting.
Septic shock was more loosely defined than in the previous definitions: “a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.” Clinically, this was defined as persistent hypotension requiring vasopressors to maintain mean arterial pressure greater than or equal to 65 mm Hg and a serum lactate greater than 2 mmol/L despite volume resuscitation. In the derivation study, risk-adjusted mortality of greater than 40 percent was noted in patients who met both criteria, 30.1 percent in those who only required vasopressors, and 25.7 percent in those with hyperlactatemia alone.
The task force utilized large data sets, all including patients from 2005 or more recent years, to derive these parameters. Sepsis was assessed using 1.3 million patient records in the University of Pittsburgh Medical Center (UPMC) system, including 148,907 patients with suspected infection, and four other data sets comprised of 706,399 encounters at 165 U.S. and non-U.S. hospitals. Septic shock was assessed in the UPMC data set, the Surviving Sepsis campaign database of 28,150 patients from 18 countries, and 1.9 million patients from Kaiser Permanente Northern California. 
The future challenge will be the prospective validation of the new definitions and the qSOFA score, as well as evaluation in more resource-limited settings. An accompanying editorial noted that sepsis is a “syndrome and not a specific disease.”  Further work will be needed to clarify the unique biochemical signature of individual disease states that are currently grossly defined as “sepsis”. Nonetheless, the definitional changes help clarify the epidemiological understanding of this complex disease process and pave the way for continued research efforts.

Back to Top

For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases:

March 15
  • Staphylococcus aureus Bacteremia: Risk of Hematogenous Infection of Joint Prostheses
  • Mucormycosis and Fusariosis in Allogenic Hematopoietic Stem Cell Recipients
March 1
  • Miltefosine May Be Losing Efficacy in the Treatment of Leishmaniasis
  • Fifteen Years of Remarkable Progress in Preventing Malaria in Africa, With Much Left to Do
  • Zika in the Western Hemisphere
February 15
  • Plague—Older Than We Knew
  • Trypanosoma cruzi Infection and Nonischemic Cardiomyopathy in California
  • Case Vignette: Staphylococcus aureus: It’s MSSA—No, It’s MRSA
February 1
  • Improving Attitudes Toward Vaccination: Accentuate the Consequences of Failing to Vaccinate Children
  • “Hey, You, Get Off of My Cloud”
  • The Skin Microbiome May Play a Role in Resistance to Infection
  • Case Vignette: Autoantibodies and Disseminated Mycobacterium haemophilum Infection
  • Case Vignette: High-Level Vancomycin Resistance in Methicillin-Susceptible Staphylococcus aureus

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