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December 2017
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.

β-Lactam/β-Lactamase Inhibitor Combinations for ESBL Infections in Neutropenic Patients
Reviewed by Zeina Kanafani, MD, MS

A multicenter retrospective study recently published in Antimicrobial Agents and Chemotherapy assessed the efficacy of β-lactam/β-lactamase inhibitors (BLBLI) for the treatment of bloodstream infections (BSIs) caused by extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacilli (GNB), compared to carbapenem therapy in an immunocompromised cohort.

A total of 259 hematologic neutropenic patients with BSI due to ESBL-GNB were retrospectively recruited. These patients were divided into two cohorts. The empirical therapy cohort (ETC) included 174 patients who received empiric therapy with BLBLI (n = 48) or a carbapenem (n = 126) and whose isolates were susceptible to the empiric therapy administered. The definitive therapy cohort (DTC) included 251 patients who received definitive therapy with BLBLI (n = 17) or a carbapenem (n = 234). The primary endpoint was the case fatality rate at 30 days from onset of BSI. Secondary outcomes included the case fatality rates at days 7 and 14, persistent and relapse of BSI, superimposed colonization or infection by an organism resistant to the study antibiotics, and any breakthrough infection.

In the ETC group, the 30-day case fatality rate was 20.8 percent in patients who received BLBLI and 13.4 percent in those treated with a carbapenem, while in the DTC group corresponding numbers were 5.8 percent with BLBLI and 15.8 percent with carbapenems. None of the differences were statistically significant. In addition, there was no significant difference in any of the secondary outcomes in the ETC and DTC groups between those treated with a carbapenem and those given BLBLI. Finally, antibiotic assignment was not found to be an independent risk factor for mortality at 30 days.

This is the first study to assess the usefulness of BLBLI for the treatment of BSI caused by ESBL-GNB in an immunocompromised cohort. As the authors concluded, the results suggest that sparing carbapenems in favor of BLBLI may be a useful strategy. However, the study was limited by its retrospective nature and the inability to recruit a larger number of patients treated with BLBLI.

(Gudiola et al. Antimicrob. Agents Chemother. 2017;61(8):e00164-17.)

Do Integrase Inhibitors Cause Weight Gain?
Reviewed by Brian R. Wood, MD

Treatment guidelines for HIV in the United States now prioritize integrase strand transfer inhibitors (INSTIs), and the majority of antiretroviral therapy (ART) starts and switches in clinical practice utilize an INSTI. A principal reason is tolerability. However, new reports raise concern about a possible association between INSTIs and weight gain.

Earlier this year, French investigators published an intriguing but preliminary research letter in AIDS detailing an observed association between dolutegravir (DTG) and weight increases. In this single-center review of 462 patients who received DTG-based ART for more than six months (most as part of an ART switch), after an average follow-up time of 276 days (+/- 76 days), mean weight gain was 3 kg and mean body mass index (BMI) increase was 1 kg/m2. One fifth of individuals experienced a weight increase of 10 percent or more on DTG. Weight gain was particularly pronounced for women, especially if receiving DTG with abacavir (ABC) and lamivudine (3TC).

A more recent report in the Journal of Acquired Immune Deficiency Syndrome adds credence to this association. In this retrospective, observational, single-center cohort analysis, researchers included HIV-infected adults with virologic suppression who had been taking efavirenz-tenofovir disoproxil fumarate-emtricitabine (EFV-TDF-FTC) for at least two years. They assessed weight changes comparing 136 individuals who switched to an INSTI-containing regimen, 34 who switched to a boosted protease inhibitor (PI)-containing regimen, and 325 who continued EFV-TDF-FTC for at least another 18 months. Of those who switched to INSTI-anchored ART, 43 percent switched to DTG-ABC-3TC, 42 percent to elvitegravir-cobicistat-TDF-FTC, and 15 percent to raltegravir plus TDF-FTC. Those who switched to INSTI-based ART gained significantly more weight compared to those who continued the baseline regimen (mean 2.9 kg at 18 months versus 0.9 kg; P = 0.003), and weight gain for those who switched to DTG-ABC-3TC was the most pronounced (mean 5.3 kg; P = 0.001 compared to EFV-TDF-FTC). There was no significant association between switching to a boosted PI and weight gain.

This is another single-center study with relatively small numbers and the findings should be confirmed with additional investigations. However, the findings are noteworthy because it is not unheard of for post-marketing research to reveal prominent ART-related side effects.

Although integrase inhibitors have become a mainstay of initial and salvage ART and offer many advantages over other options, these results indicate a need for further study into possible INSTI-related adipocyte and body composition changes. This includes studies to confirm this early data, to explore a possible biologic mechanism, to differentiate effects of various INSTIs and NRTI combinations, and to identify particular patient groups at highest risk (particularly given recent reports of INSTI discontinuations due to neuropsychiatric side effects, which similarly call out DTG as the worst offender and likewise suggest elevated risks when DTG is combined with ABC and potential elevated risk in women). While currently available INSTIs offer a dramatic improvement in tolerability over previous ART, perhaps there is still room for improvement?

(Menard et al. AIDS. 2017 Jun 19;31(10):1499-1500.)
(Norwood et al. J Acquir Immune Defic Syndr. 2017;76(5):527-531.)

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

November 15

  • The Twain Have Met: Carbapenemase-Producing, Hypervirulent Klebsiella pneumoniae
  • Prevention of Gonorrhea With a Meningococcal Vaccine

November 1

  • The Circulating dsDNA Viral Microbiome in Allogeneic Hematopoietic Stem Cell Transplant Recipients
  • Another Monogenic Defect in Innate Immunity Resulting in Severe Infection: IFIH1 and Respiratory Viruses

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