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Journal Club

July 18, 2018


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.

A. Krishna Rao, MD, MS

Antibiotic Exposure Increases the Risk of Subsequent Sepsis

Reviewed by A. Krishna Rao, MD, MS

Sepsis affects 1 million people each year in the U.S. and is associated with significant morbidity and mortality. Thus, prevention of sepsis could save many lives. Prior literature has shown that alterations in the microbiome by antibiotics can predispose to invasive infection, but the overall risk and possible causal connection to sepsis epidemiologically has not been well established.

In the April 1 issue of Clinical Infectious Diseases, researchers assessed the risk of subsequent sepsis in the 90 days following a hospital stay with antibiotic exposure. This study used the Truven Health MarketScan Hospital Drug Database, which has granular drug utilization data from approximately 500 hospitals. They used several metrics to quantify antibiotic exposure: 1) low, medium, and high level of microbiome disruption, based on prior data on the association of the antibiotic with Clostridium difficile infection; 2) the number of antibiotic classes to which the patient was exposed; and 3) the duration of antibiotic therapy. The primary and secondary outcomes were severe sepsis and sepsis, respectively. 

Of 5.4 million included patients, 57.2 percent had some antibiotic exposure during the admission. The overall absolute risk of severe sepsis after exposure to high-risk antibiotics compared to no/low-risk/medium-risk antibiotics rose to 0.3 percent from 0.1 percent. In the study, this represented an excess 705 cases per year on average. The increased risk remained after adjusting for baseline patient/hospital characteristics. Findings were similar for the secondary outcome of sepsis. For both the primary and secondary outcomes, a compelling result was the “dose response” relationship seen for all three methods used to quantify exposure.

Though difficult to infer causality from epidemiologic studies, this study fulfils many of the Bradford-Hill criteria and links antibiotic exposure to subsequent sepsis. While the absolute risk increase at the individual patient/hospital level is low, this translates into a large excess morbidity/mortality nationally. Since inappropriate antibiotic use remains high, many of these cases of sepsis and death are potentially preventable. This provides additional impetus for developing effective antibiotic stewardship programs.

(Baggs et al. Clin Infect Dis. 2018;66(7):1004–12.)

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Lauren Richey, MD, MPH, FIDSANew Data on the Safety of Dolutegravir Started During Pregnancy

Reviewed by Lauren Richey, MD, MPH, FIDSA

Initial antiretroviral therapy (ART) options are limited for pregnant women.  Current U.S. guidelines include two protease inhibitor-based regimens and one integrase inhibitor-based regimen (raltegravir). Dolutegravir is an alternative regimen and represents the only once daily integrase inhibitor option in the guidelines for pregnant women. Dolutegravir-based regimens are also the only once daily initial ART option recommended for pregnant women and non-pregnant adults. 

A recent preliminary analysis from an observational study group in Botswana prompted a warning in May 2018 from the U.S. Department of Health and Human Services about the use of dolutegravir during conception. This alerted providers about a possible increase in neural tube defects among women who conceived while taking a dolutegravir-based regimen. The warning recommended a regimen switch for women desiring pregnancy and a negative pregnancy test prior to initiating the regimen until more information was available.  

The first publication from the Botswana study recently appeared in The Lancet Global Health and evaluated the safety of a dolutegravir-based regimen initiated in pregnancy. In 2016, Botswana’s national treatment guidelines recommended a dolutegravir/emtricitabine/tenofovir regimen in all adults with HIV, including pregnant women. Data from women who delivered in eight government maternity wards, representing 45 percent of all births in the country, were included in the study. Data was extracted for women starting a dolutegravir-based regimen (N=1,729) and an efavirenz-based regimen (N=4,593) for comparison as this was the previous recommended regimen. The primary outcomes were the combined endpoints of any adverse outcomes and any severe adverse outcome. 

Results showed an adverse outcome for 34.5 percent of infants born to women living with HIV, with 11.1 percent having a severe adverse outcome.  For HIV-negative women, 28.9 percent had adverse outcomes and 9.9 percent had a severe adverse outcome. The adverse outcomes were similar among women initiating a dolutegravir-based regimen (33.2 percent) versus an efavirenz-based regimen (35 percent), and severe adverse outcomes were also similar, 10.7 percent and 11.3 percent, respectively. No major congenital abnormalities were seen among the infants of the women taking the dolutegravir-based regimen. 

Outcomes in women on dolutegravir-based regimens were comparable to outcomes under the previous treatment standard in Botswana, which is reassuring. While more information is needed on outcomes during conception, this study provides evidence for the safety of a dolutegravir-based regimen started in pregnancy. This allows women the option of a simple, once daily, well-tolerated, integrase-based regimen.  

(Zash et al. Lancet Global Health. 2018; 6:e804-10.) 

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Daniel Mendoza, MD, PhDA Single Dose of an Inactivated Whole-cell Vaccine Provides Moderate Protection Against Cholera for at Least Two Years

Reviewed by Daniel Mendoza, MD, PhD

A live-attenuated oral cholera vaccine (Vaxchora) is available in the U.S. for prevention of cholera caused by serogroup O1 in adults traveling to areas of cholera transmission. An earlier trial found that the efficacy of a single dose against cholera was 90 percent 10 days following vaccination. However, Vaxchora has not been shown to protect against disease caused by other serogroups, how long protection lasts beyond 3-6 months is unknown, and it is contraindicated in immunocompromised individuals. 

A recent report in The Lancet Infectious Diseases describes two years of follow-up of a randomized, double-blind, placebo-controlled clinical trial of a single dose of an inactivated whole-cell oral cholera vaccine (OCV, Shanchol). Shanchol contains killed whole cells of several serotypes of V. cholerae O1 and V. cholerae O139. Individuals aged 1 year or older received a single dose of Shanchol or placebo. Passive surveillance for diarrhea was done in 13 health centers in Bangladesh for two years after the last dose. Investigators assessed efficacy against culture-confirmed cholera occurring 7–730 days after dosing with multivariable per-protocol analyses. 

The investigators randomized 205,513 subjects to receive Shanchol or placebo. All cases of cholera were due to serogroup O1. Overall incidence rates of initial cholera episodes were 0.22 (95 percent confidence interval [CI] 0.18 to 0.27) per 100,000 person-days in vaccine recipients versus 0.36 (CI 0.31 to 0.42) per 100,000 person-days in placebo recipients (adjusted efficacy 39 percent, 95 percent CI 23 to 52). The overall incidence of severe cholera was 0.09 (CI 0.07 to 0.12) per 100,000 person-days versus 0.19 (CI 0.15 to 0.23; adjusted efficacy 50 percent, CI 29 to 65). The vaccine did not protect children younger than 5 years. Adjusted efficacy against all cholera was 52 percent for 5- to 15-year-olds and 59 percent for those 15 years or older.

The results indicate that a single dose of Shanchol can provide moderate protection against cholera for at least two years. Shanchol is a bivalent vaccine that potentially provides protection against both serogroups O1 and O139. As it is not a live-attenuated vaccine, it could also be used in the immunocompromised but further studies are needed.

(Qadri et al. Lancet Infect Dis. 2018;18: 666–74.)

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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

July 15

  • Antimicrobial Stewardship: How Many FTEs Are Needed to Do It Right?
  • Reconsidering Ribavirin Therapy of Respiratory Syncytial Virus Infection in Immunocompromised Patients

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