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January 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.

Here is the December version 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.

Sepsis Readmissions: Second Verse, Not the Same as the First
Reviewed by Kelly Cawcutt, MD

Sepsis is a common cause of hospitalization. However, sepsis survivors often suffer from multiple post-sepsis complications including hospital readmission. Many of these readmissions are attributed to infection, yet it is largely unknown if the secondary infections are due to relapse or new infection. The authors of a recent article in Critical Care Medicine aimed to answer this question by studying a single-center, retrospective cohort of patients hospitalized with sepsis from 2013 to 2015.

Hospital readmissions were evaluated within the first 90 days of index hospitalization for sepsis readmission. Of 1,588 patients discharged with an index hospitalization of sepsis, there were 472 readmissions and 137 (29.1 percent) were due to sepsis. Of these, 68.6 percent had infection at the same anatomical location. Only 19 percent of the readmissions were identified as having both the same site and organism. The most common sites of infection were urinary (39.7 percent), gastrointestinal (18.0 percent), respiratory (15.9 percent), and skin and soft tissue (10.6 percent). Of the discordant sites, the most common were gastrointestinal and respiratory. There was a statistically significant decrease in Gram-positive infections among the readmissions (P = 0.03). About 30 percent were culture-negative. Among those with 90-day readmissions, there was a 21.2 percent mortality for sepsis readmissions compared to 10.5 percent for non-sepsis readmissions (P = 0.002).

Overall, approximately two-thirds of sepsis readmissions presented with infection at the same anatomic site, with the minority having definitive infection with the same organism, suggesting that it was not relapsed infection but perhaps new infections that resulted in readmission. Culture-negative sepsis comprised approximately one-third of these readmissions and may have been due to new infection, relapsed infection, or, possibly, noninfectious syndromes. Given the increased mortality in these patients readmitted with sepsis, further research on causation and strategies for preventing recurrent sepsis is needed.

(DeMerle et al. Crit Care Med. 2017;45(10):1702–1708.)

Increased Immune Activation in Patients with HIV and Long-term PPI Use
Reviewed by Lauren Richey, MD, MPH, FIDSA

Translocation of gut microbial products is a driver of immune activation. HIV infection has been associated with structural damage of the intestinal mucosa, leading to increased mucosal permeability. Additional alterations in the gut microbiota can worsen this damage. Proton pump inhibitors (PPIs) reduce stomach acid and have been shown in some studies to predispose to microbial overgrowth and alterations of the gut microbiome. Biomarkers which reflect innate immune activation include: activated CD8+ T-cells (CD38+HLA-DR+); lipopolysaccharide (LPS), a component of Gram-negative bacteria; LPS binding protein (LBP), which is induced by the presence of LPS; soluble CD14 (sCD14), which reflects monocyte activation; and intestinal fatty acid binding protein (I-FABP), which reflects enterocyte turnover.

In a recent study in Clinical Infectious Diseases, the authors hypothesized that among patients living with HIV who have suppressed viral loads, long-term PPI use would result in bacterial overgrowth and immune activation. Study participants were male veterans with HIV and viral load suppression for at least 12 months. Participants were divided into two groups: those on long-term PPIs and those not taking acid suppression medication. Twenty healthy volunteers were also recruited.

Patients with HIV on long-term PPIs had statistically higher levels of sCD14 and LBP, but lower levels of I-FABP. They also had higher levels of LPS, which did not reach significance, and similar levels of activated CD8+ T-cells. Patients with HIV on long-term PPIs showed a median decrease of CD4 cells by 18 in the year prior to enrollment, whereas those not taking acid suppression medication showed an increase of 54 cells (P = .03). The healthy volunteers had significantly lower levels of sCD14, LBP, and activated CD8+ T-cells than either of the groups with HIV. These findings indicate increased innate immune activation in patients with HIV and long-term PPI use.

Although this is a small observational study, these findings show that PPIs may have negative consequences with long-term use. Further research is needed to quantify those consequences, particularly in patients living with HIV who may be more susceptible to gut microbial overgrowth and translocation.

(Serpa et al. Clin Infect Dis. 2017;65(10):1638–1643.)

Probiotics for the Prevention of Neonatal Sepsis
Reviewed by A. Krishna Rao, MD, MS

With improved global health initiatives over the past two decades, overall childhood mortality has declined but infant mortality remains high. Since neonatal sepsis still causes nearly 1 million deaths worldwide each year, even modestly effective interventions can have a large impact. Probiotics for sepsis prevention have been proposed but have not been well studied in neonates.

Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.” Prebiotics are non-digestible sugar polymers that promote the growth of beneficial microbes and constitute a synbiotic when co-formulated with a probiotic. Prior studies on probiotics for the prevention of neonatal sepsis were small, heterogeneous in the formulations used, and/or did not show a benefit. Many did not use a preclinical, mechanistic approach to rationally design the probiotic formulation under study.

A more recent Nature study describes a randomized, placebo-controlled, double-blind trial assessing the Lactobacillus plantarum/fructooligosaccharide synbiotic for prevention of neonatal sepsis. This study of 4,556 infants was conducted in the state of Odisha in India, which has high infant mortality. Infants were randomized to start the 7-day course of the study drug or placebo on days 2–4 of life. The sepsis/death risk was 5.4 percent in the synbiotic arm, compared to 9 percent for the placebo group (number needed to treat = 27), and the treatment was well tolerated. Since this regimen costs $1 USD, the potential impact on neonatal sepsis in the developing world is great. Limitations include the inability to generalize results to preterm and low birthweight infants, who are among the highest risk for sepsis but were excluded.

Why do these results differ from previous studies? A possible explanation is the use of preclinical and early phase clinical data to choose the agent. L. plantarum was included based on its ability to colonize the infant gut long-term. It also adheres to gut mucosa, potentially interfering with bacterial translocation, and co-formulating it with fructooligosaccharide may potentiate its impact. Future studies on probiotics for infections and other conditions may benefit from a similar rational, ground-up approach.

(Panigrahi et al. Nature. 2017;548(7668):407-412.)

Antibiotic Susceptibility Test Results in 30 Minutes: A View of the Future?Reviewed by Michael T. Melia, MD

In the setting of suspected or confirmed infection, empiric antimicrobial therapy is administered pending drug susceptibility data that are often not available for several days. This reality is associated with uncertainty regarding the appropriateness of empiric therapy. While not yet ready for prime time, a recent publication in Proceedings of the National Academy of Sciences highlights the possibility of markedly accelerated drug susceptibility timelines.

The authors designed a microfluidic chip to capture individual Escherichia coli in two parallel rows of 2,000 cell traps. The higher the bacterial concentration, the greater the proportion of traps that filled within minutes; with a concentration of 10,000 cfu/mL, the authors state a sufficient number of traps fill within 5 minutes. They applied antibiotic-free medium to one row of cells and antibiotic-containing media to the second, and they compared the growth-rate characteristics of each of the traps. When the growth rates for the individual traps were averaged and normalized by the average growth rate of the reference population, differential growth rates were detected in as few as 3 minutes for agents including fluoroquinolones, nitrofurantoin, and trimethoprim-sulfamethoxazole.

They then tested 50 clinical isolates of uropathogenic E. coli and found that a ciprofloxacin-treated population grouped separately from an untreated reference population after 10 minutes; their results were 100 percent concordant with clinical microbiology laboratory disk diffusion test results. Including time needed to set up and run the test, total time until susceptibility results were available was as short as 30 minutes.

While this technology is not yet ready for clinical use—the chip used was designed to capture E. coli, polymicrobial infection and contaminants pose challenges, and the time until meaningful results were available was longer for K. pneumoniae and S. saprophyticus—it is nevertheless provocative to consider the game-changing aspects of this kind of technology.

(Baltekin et al. Proc Natl Acad Sci. 2017;114(34):9170-9175.)

Oritavancin Noninferior to Vancomycin for Acute Bacterial Skin Infections
Reviewed by A. Krishna Rao, MD, MS

Acute bacterial skin and skin structure infections (ABSSTIs) account for nearly 3 million U.S. emergency department visits and 870,000 inpatient admissions each year. Oritavancin is a semisynthetic lipoglycopeptide antibiotic with activity against resistant Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus. One dose is often sufficient treatment and could help avoid inpatient ABSSTI admissions.

In an Open Forum Infectious Diseases article, researchers provide a secondary analysis including only outpatients from the SOLO I and II clinical trials of oritavancin. These were identical multicountry, multicenter, randomized, double blind, noninferiority designs comparing one intravenous (IV) 1,200 mg dose of oritavancin to 7–10 days of twice daily IV vancomycin. Subjects included adults with ABSSTIs known or suspected to be from Gram-positive organisms. The primary endpoint was met when 1) there was cessation of spread of the baseline lesion, 2) fever was absent, and 3) no rescue antibiotic was needed. There were two main secondary endpoints: ≥ 20 percent reduction in lesion size and clinical cure as assessed by a clinician, both at the 48–72 hour visit.

Oritavancin met noninferiority criteria, with 80.4 percent meeting the primary endpoint versus 77.5 percent for vancomycin. Noninferiority was also met for the main secondary endpoints of clinical cure and reduction in lesion size. Among adverse events, notable differences were hypersensitivity reactions in 22.8 percent and 8.9 percent, and pruritus in 14 percent and 3.3 percent, for vancomycin and oritavancin, respectively. There were no notable differences in subgroup analyses.

This study has some limitations affecting its generalizability. The outpatients in the SOLO trials were younger, predominantly of white race, and had a higher prevalence of IV drug abuse and abscess. Additionally, the decision to treat in the outpatient setting was at the clinician’s discretion, which could have introduced bias towards noninferiority. In contrast, even the low rate of adverse events in the oritavancin arm could be an overestimate, since those patients came in twice daily for placebo injections. Overall, however, this trial shows outpatient oritavancin to be a compelling alternative to inpatient admission and treatment for ABSSTIs, which, as the study authors noted, cost between $6,000–$10,000, on average, per case, while outpatient treatment could save $2,500–$6,500 per patient.

(Lodise et al. Open Forum Infect Dis. 2017;4(1).)

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:

Jan. 15

  • Human Polyomavirus, Peacock Plumage, and Chronic Pruritic Dermatitis
  • Tedizolid, Linezolid, and Thrombocytopenia
  • Rapid Diagnosis of Tuberculous Meningitis

Jan. 1

  • Plasmodium simium: Another Cause of Primate Malaria That Also Infects Humans
  • Liposomal Amphotericin B on Top: Visceral Leishmaniasis in Brazil
  • Case Vignette: Granulomatous Gastritis due to Aspergillus

Dec. 15

  • Brincidofovir and Adenovirus Viremia
  • Synbiotic Administration Is Associated With Dramatic Reduction in Neonatal Sepsis

Dec. 1

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

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