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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
December 19, 2015

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Depression Prevalence Among Resident Physicians Is "Extraordinarily High"
Melanoma Meets Microbiome
SSRI Use During Pregnancy Associated with Autism Risk in Children
Whether Weather's Wetter and Whither Skin Disease
Are Lower Trimethoprim–Sulfamethoxazole Doses Effective for Pneumocystis Pneumonia?
Continuous vs. Intermittent Infusion of β-Lactam Antibiotics for Severe Sepsis

Depression Prevalence Among Resident Physicians Is "Extraordinarily High"
By Amy Orciari Herman
Over a quarter of resident physicians experience depression or depressive symptoms, according to a meta-analysis in JAMA's theme issue on medical education.
Researchers examined data from over 50 cross-sectional or longitudinal studies in which nearly 18,000 resident physicians (mostly in North America) were assessed for depressive symptoms via structured interviews or validated questionnaires. The overall prevalence of depression or depressive symptoms was 29% (range, 21%–43%). The prevalence increased with each calendar year (from 1972 to 2012).
In a secondary analysis of seven longitudinal studies that reported on depressive symptoms before and during residency, the median absolute increase in depression prevalence after residency began was 16%.
In an editorial, Dr. Thomas Schwenk of NEJM Journal Watch General Medicine calls the reported prevalence of depression among residents "extraordinarily high," noting that the lifetime prevalence in the general population is 16%. He concludes, "The time is long overdue for a national conversation on the fundamental structure and function of the graduate medical education system."
Other studies in this issue of JAMA examine the intended scope of practice among family medicine residents, medical students' presence in the emergency department and patient length of stay, and training physicians to provide high-value care. Links are provided below.
Why We Chose This as Our Top Story:
Andre Sofair, MD, MPH: This important study highlights the prevalence of this significant problem in our trainees. It may encourage program directors to systematically approach this issue in their house staff.
William E. Chavey, MD, MS: We need to be aware of the prevalence of depression among physicians and be aware among ourselves and our patients of the risks that extend even beyond training.
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Science 2015 Nov 27; 350:1084
Melanoma Meets Microbiome
Two groundbreaking studies implicate specific bacterial species in regulating gut immunity and response to immunotherapy in physically distant tumors — an entirely new angle in cancer therapy
The influence of the microbiome on cancer susceptibility and therapy effectiveness has been shown. Furthermore, commensal organisms have critical roles in tuning immunity at epithelial surfaces, suggesting their potential role in regulating immunotherapy response.
Sivan and colleagues compared genetically identical mice obtained from two different mouse facilities that had different gut microbiota. Interestingly, these mice reacted differently to syngeneic implanted mouse melanoma tumors, apparently because of differences in the vigor of their anti-tumor T-cell responses. These differences were eliminated by cohousing and could be reversed by fecal transplantation from the mice with anti-tumor immunity, implicating the gut microbiome. Furthermore, fecal transfer augmented responses to anti–PD-L1 immunotherapy. Following sequencing of the bacteria, they found that Bifidobacterium species were overrepresented in mice with better anti-tumor immunity, and introduction of those species into the other mice produced anti-tumor responses.
Vétizou and colleagues linked anti-CTLA4 therapy to human responses to melanoma therapy. Anti-CTLA4 therapy can produce adverse gastrointestinal (GI) tract reactions with the development of antibodies to gut flora. They found that anti-CTLA4 therapy decreased numbers of Bacteroidales andBurkholderiales species and increased Clostridiales species in feces. Patients treated with ipilimumab for melanoma also showed decreased Bacteroidales species in their stool. When this stool was transplanted into mice, it enhanced responses to anti-CTLA4 therapy, and direct inoculation of the relevantBacteroidales species increased melanoma-specific memory T-cell responses.
COMMENT: These technically difficult and groundbreaking studies implicate specific bacterial species in regulating gut immunity and responses to immunotherapies in physically distant tumors. This approach presents an entirely new angle in cancer therapy. How important the gut microbiome is as a determinant of response to therapy is not yet known, but immunotherapies may be optimized by manipulation of the GI microbiome in the future.
CITATION(S): Sivan A et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science 2015 Nov 27; 350:1084. (http://dx.doi.org/10.1126/science.aac4255)
Vétizou M et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science2015 Nov 27; 350:1079.
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SSRI Use During Pregnancy Associated with Autism Risk in Children
By Jenni Whalen, Edited by David G. Fairchild, MD, MPH, and Jaye Elizabeth Hefner, MD
Using selective serotonin reuptake inhibitors (SSRIs) during the second or third trimester of pregnancy is associated with a heightened risk for autism spectrum disorder (ASD) in children, according to a JAMA Pediatrics study.
Researchers used data from a population-based cohort study of women from Quebec who delivered 145,000 full-term singleton infants. Children were followed until a mean age of 6.2 years.
Of these, 0.72% were diagnosed with an ASD. Use of any SSRIs during the second or third trimester was associated with increased risk for ASD, compared with no exposure (adjusted hazard ratio, 2.17; 1.4% vs. 0.72%). Use of multiple antidepressant classes in mid-to-late pregnancy was also tied to increased risk. The association between ASD and antidepressants persisted in a subanalysis of women with a history of depression.
NEJM Journal Watch Women's Health associate editor Allison Bryant comments: "While a small increase in ASD is noted, untreated depression has its own impressive maternal health risks. Research and policy efforts should focus on the provision of comprehensive mental health treatment of pregnant women."
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Int J Dermatol 2015 Dec; 54:1343
Whether Weather's Wetter and Whither Skin Disease
We can expect changes to the incidence of skin and skin-related disorders associated with El Niño.
El Niño is the warm phase of the El Niño Southern Oscillation. An unusually high temperature at the Pacific Ocean surface affects climate all over the world. It also affects people, animals, parasites, disease prevalence, and infectious agents. In the past 3 decades, global warming has increased the frequency and intensity of El Niño weather patterns. These changes have been associated with changes in the incidence of diseases — for example, diarrhea, cholera, Rift Valley fever, and hantavirus pulmonary syndrome. Does El Niño warming affect the incidences of skin diseases, too?
Investigators used databases to search for articles written on the subject since 1990. El Niño was associated with increases in cases of actinic keratoses, tinea, pityriasis versicolor, malaria, folliculitis, rosacea, and dermatitis from Paederus sabeus and P. irritans. Increases also occurred in certain vector and water-borne diseases, such as dengue fever, leishmaniasis, Chagas disease, Barmah Forest virus infection, and leptospirosis. Decreases in incidence of diseases attributed to El Niño included dermatitis, scabies, psoriasis, and papular urticaria.
COMMENT: Heads up: The incidences of skin diseases are changing. We may see diseases in some geographic areas that are normally seen elsewhere. Climate change will change the geography of skin disease. It's not just about mean daily temperatures. Global warming may also affect rain amounts, duration of hot spells, humidity, the distribution of insect vectors, and other changes of flora and fauna. El Niño and global warming also affect human activities, population density changes, disease communicability, sun exposures, and nutrition.
CITATION(S):Andersen LK and Davis MDP.The effects of the El Niño Southern Oscillation on skin and skin-related diseases: A message from the International Society of Dermatology Climate Change Task Force. Int J Dermatol 2015 Dec; 54:1343. (http://dx.doi.org/10.1111/ijd.12941)

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Infection 2015 Oct 15
Are Lower Trimethoprim–Sulfamethoxazole Doses Effective for Pneumocystis Pneumonia?
Half of the currently recommended dose may be sufficient, and patients who improve rapidly can be switched to a low dose.
Current guidelines recommend treating Pneumocystis jirovecii pneumonia (PCP) with high-dose trimethoprim–sulfamethoxazole (TMP–SMX; TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day in 4 divided doses) for 2 to 3 weeks. Given the high frequency of adverse events associated with this regimen — including renal insufficiency, electrolyte disorders, and liver toxicity — researchers in the Netherlands retrospectively examined the efficacy of a TMP–SMX dose step-down strategy in 104 patients with confirmed PCP.
All patients received TMP–SMX doses lower than previously recommended. Eighty patients (77%) received standard therapy with intermediate-dose TMP–SMX (TMP 10–15 mg/kg/day and SMX 50–75 mg/kg/day) for ≥2 weeks; most patients (91%) were treated for 2 weeks and 9% for ≥3 weeks. Twenty-four patients (23%) were switched to low-dose TMP–SMX (TMP 4–6 mg/kg/day and SMX 20–30 mg/kg/day) after a median of 4.5 days (interquartile range, 2.8–7.0 days), either because of a favorable course, TMP–SMX toxicity, or both. The step-down and intermediate-dose groups did not vary significantly in prevalences of underlying conditions (HIV infection, 21% and 15%, respectively; solid organ transplantation, 25% and 34%; hematologic malignancy, 29% and 31%).
All-cause mortality tended to be lower in the step-down group than in the intermediate-dose group (30-day mortality, 4% and 16%; P=0.13; 100-day mortality, 8% and 25%; P=0.08). The median length of hospitalization was similar between groups (approximately 15 days), and ICU admission tended to be less frequent in the step-down group (P=0.13).
COMMENT: Patients in the step-down group were clearly at lower risk for poor outcomes than those continued on the intermediate dose. The lessons learned from this observational cohort study are that patients with PCP who improve rapidly can be safely switched to a lower TMP–SMX dose, and that an intermediate TMP–SMX dose (half of the currently recommended dose) may be sufficient for treating PCP, thereby avoiding toxicity.
CITATION(S):Creemers-Schild D et al. Treatment of Pneumocystis pneumonia with intermediate-dose and step-down to low-dose trimethoprim–sulfamethoxazole: Lessons from an observational cohort study. Infection 2015 Oct 15; [e-pub].
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Am J Respir Crit Care Med 2015 Dec 1; 192:1298
Continuous vs. Intermittent Infusion of β-Lactam Antibiotics for Severe Sepsis
A multinational randomized trial showed no advantage for continuous infusion.
In patients with sepsis, antibiotics must be administered optimally. For β-lactam antibiotics, maximum killing of susceptible bacteria occurs when the concentration of free drug is three to four times the minimum inhibitory concentration against the microorganism. One potential way to achieve optimal concentration of β-lactam antibiotics is with continuous infusion, but its superiority to intermittent dosing has not always been clear in the medical literature.
At 25 intensive care units (ICUs) in Australia, New Zealand, and Hong Kong, 422 adults with severe sepsis who had started piperacillin–tazobactam, ticarcillin–clavulanate, or meropenem had their prescribed antibiotic administered, in randomized fashion, either continuously or via intermittent infusions that lasted 30 minutes each. A pathogen was isolated in only 19% of cases.
The two groups did not differ significantly in the number of ICU-free survival days within 28 days after randomization (the primary outcome), nor in survival at 90 days. Only one significant difference emerged: The postrandomization ICU stay was one day shorter with intermittent dosing than with continuous infusion.
COMMENT: This large, well-designed study has several limitations that an accompanying editorial delineates clearly. They include the low rate of pathogen identification and the lack of β-lactam pharmacokinetic information for the study participants. As the editorialists suggest, without therapeutic drug monitoring, it is actually possible for continuous infusion to yield suboptimal drug concentrations. Given the noninferiority of either approach, clinicians should continue to use either continuous or intermittent infusion according to their local practice.
CITATION(S): Dulhunty JM et al. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. Am J Respir Crit Care Med 2015 Dec 1; 192:1298.

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