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HYPRESS Trial (2016): Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis

HYPRESS trial visual abstract

HYPRESS Trial Summary: Keh D, et al. randomized 380 patients with sepsis defined by ≥2 SIRS criteria, proven infection, and ≥1 organ with new dysfunction to either IV hydrocortisone or placebo. The objective was to assess if early hydrocortisone therapy reduces progression to septic shock compared to placebo in patients with severe sepsis. The results showed no difference in the development of septic shock in both groups P=0.70. The authors of HYPRESS trial concluded that among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days.

Source: JAMA

SEPSISPAM Trial (2014): High versus low blood-pressure target in patients with septic shock

SEPSISPAM Trial visual abstract

SEPSISPAM Trial Summary: Asfar P et al. randomized 776 patients ≥18 years with septic shock with sepsis defined by ≥2 SIRS criteria, likely or proven infection, and ≥1 organ with new dysfunction to either higher MAP goal (80-85 mmHg) or lower MAP goal (65-70 mmHg). The objective was to assess if goal MAP of 80-85 mmHg reduce all-cause mortality at 28 days when compared to a goal MAP of 65-70 mmHg in patients with septic shock. The results showed no difference in all-cause mortality or other outcomes with respect to both groups. The authors of the SEPSISPAM trial concluded that for patients with septic shock, a goal MAP of 80-85 mmHg does not reduce all-cause mortality at 28 days when compared to a goal of 65-70 mmHg.

Source: NEJM

Project CLEAR Trial (2019): Decolonization to Reduce Postdischarge Infection Risk among MRSA Carriers

Project CLEAR trial summary: Huang et al. randomized 2,141 patients colonized with MRSA to hygiene education or hygiene education + decontamination. Decolonization involved chlorhexidine mouthwash, baths or showers with chlorhexidine, and nasal mupirocin for 5 days twice per month for 6 months. The primary objective was to assess the efficacy of postdischarge hygiene education, as compared with education plus decolonization, in patients colonized with MRSA (carriers). The results showed a significant decrease in MRSA infections in the decontamination group (P=0.03, NNT=30). The authors of the Project CLEAR trial concluded that postdischarge MRSA decolonization with chlorhexidine and mupirocin led to a 30% lower risk of MRSA infection than education alone.

Source: NEJM

PLACIDE Trial (2013): Lactobacilli and bifidobacteria in preventing antibiotic-associated and C.diff diarrhea

PLACIDE trial probiotics

PLACIDE trial summary: Allen SJ et al. conducted a multicenter, randomized, double blind, placebo-controlled trial to assess the efficacy of probiotics in preventing antiobiotics associated (AAD) or C.diff associated diarrhea (CDAD) in elderly hospitalized patients. Over 2,941 elderly patients with age >65 and exposure to antibiotics were enrolled and randomized to either a probiotic therapy or placebo therapy. The primary outcome of the PLACIDE trial was diarrhea onset within 8 weeks (if antibiotics assocaited) or 12 weeks if C.diff associated. The results showed no difference in outcomes and thus the study concluded that adding probiotics does not prevent AAD or CDAD.

Source: Lancet

OPTIC Trial (2019): Omadacycline for Community-Acquired Bacterial Pneumonia

OPTIC trial visual summary

OPTIC Trial Summary: Stets et al. randomized 774 patients with community-acquired bacterial pneumonia (PSI risk class II, III, or IV) diagnosed clinically and with imaging to either omadacycline IV or moxifloxacin IV. The objective was to assess the role of omadacycline, a new tetracycline drug in the treatment of community-acquired bacterial pneumonia. The results showed similar early clinical response in both groups. The authors of OPTIC trial concluded that Omadacycline was noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia in adults.

Source: NEJM

STOP-IT Trial (2015): Short Course of Antibiotics for Intraabdominal Infections

stop it trial visual summary graphic abstract

2015, Short-Course Antimicrobial Therapy for Intraabdominal Infection, NEJM

STOP-IT Trial Key Points:

  1. A shorter course (3-5 days) of antibiotics was found to be non-inferior when compared to traditional course of 4 to 7 or 7 to 14 days.
  2. Important point was to adequately control the source which means draining the abscess in case there is one or any other nidus of infection.

Guidelines Related to STOP-IT trial

The 2009 IDSA guidelines suggested 4-7 days course of antibiotics once the source is adequately controlled. The STOP-IT trial tested more restrictive therapy of 3 to 5 days of antibiotics and found no difference in outcomes. The study addressed an important issue of antibiotic stewardship and cost containment especially in patients who came to hospital with intraabdominal infections.

PRORATA: Procalcitonin guided antibiotic therapy in critically ill patients

2010, Procalcitonin guided antibiotic therapy in critically ill patients, The Lancet

CAPSTONE-1: Baloxavir Marboxil for Uncomplicated Influenza

2018, Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents, NEJM

Albumin in Spontaneous Bacterial Peritonitis

1999, Effect of IV Albumin on Renal Impairment in Patients with Cirrhosis and SBP, NEJM

Fidaxomicin in C. difficile Diarrhea

2011, Fidaxomicin versus vancomycin for Clostridium difficile infection | NEJM

MERINO Trial: Piperacillin-Tazobactam vs Meropenem in ESBL infections

MERINO Trial of using pip tazo for patients with ESBL infection

MERINO Trial: 2018, Pip-Tazo vs Meropenem in patients with E-coli or Klebsiella infections,  JAMA

Earlier cohort studies yielded conflicting results when it comes to treating ceftriaxone-resistant E-coli and Klebsiella infections. Some studies reported noninferiority of piperacillin-tazobactam when compared to meropenem while others reported almost doubling of mortality.

In the MERINO trial, the patients were randomized to assess for non-inferiority of pip-tazo IV therapy versus IV meropenem. The results showed 12.3% 30-day mortality in the pip-tazo group compared to 3.7% with meropenem. Therefore, the study concluded that for E-coli and Klebsiella bloodstream infections, pip-tazo antibiotic is inferior to meropenem in terms of 30 days mortality.

POET Trial: IV vs PO Antibiotics in Left Heart Endocarditis

2018, POET Trial: Partial Oral vs Intravenous Antibiotic Treatment of Endocarditis | NEJM

VALENCE Trial: Sofosbuvir and ribavirin in HCV genotypes 2 and 3

 

2014, Sofosbuvir + ribavirin for HCV, NEJM

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B

Summarized by / Author: Rooma Nankani MD (1), Rohini Manaktala MD (1)

Summary Reviewer: Paul Robert Anthony Jr. MD (2)

Contribution To Literature:

This trial showed that the maternal use of tenofovir in hepatitis B positive mothers did not result in significantly lower rate of perinatal hepatitis B transmission. However, it is known that the rate of mother to child HBV transmission is low with the use of hepatitis B immune globulin and hepatitis B vaccine in infants from hepatitis B positive mothers.

Description:

The goal of the trial was to determine the effect of tenofovir in preventing hepatitis B transmission from mother to infant. The trial was an effort to explore other alternatives besides hepatitis B immunoglobulin administration and hepatitis B vaccine in infants as the risk of transmission of hepatitis B remains elevated despite these measures.

Study Design

It was a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial performed at 17 public hospitals in Thailand from January 2013 to August 2015.

Patients enrolled in the study were hepatitis B e antigen (HBeAg) positive pregnant women with an ALT level of 60 IU/L or less who were randomly assigned in 1:1 ratio to receive 300 mg of tenofovir disoproxil fumarate (TDF) daily (n=168) or matching placebo (n=163) which involved taking similar tablets but without the active pharmaceutical ingredient. Both group were received their respective medication from 28 weeks of gestation to 2 months post partum. Infants of both groups received hepatitis B immune globulin at birth and hepatitis B vaccine at birth as well as at 1, 2, 4, and 6 months.

  • Total number of patients: 331
  • Duration of follow-up (maternal visits): 28, 32 and 36 weeks of gestation, at delivery and at 1, 2, 3, 4, 6 and 12 months post partum
  • Duration of follow-up (infant visits): birth and 1, 2, 4, 6, 9 and 12 months of age for physical examination and blood work for determination of HBV infection status; and for recording of vaccinations until 6 months of age; and for signs/conditions suggestive of possible mitochondrial dysfunction at 6 and 12 months of age
  • Median gestational age: 28.3 weeks
  • Median HBV DNA level: 8log (10) IU/mL
  • Median time from birth to administration of hepatitis B immune globulin: 1.3 hours
  • Median time from birth to administration of hepatitis B vaccine: 1.2 hours
  • Mode of infant delivery: 26% were Cesarean sections

 

Inclusion criteria:

  • Pregnant women (from age 18 years or older) at 28 weeks of gestational age (within a window of +/- 10 days)
  • Positive HbsAg and HBeAg tests
  • ALT level of 30 IU/L or less at screening and 60 IU/L or less at trial entry

Exclusion criteria:

  • Positive serologic test for HIV or hepatitis C virus
  • Received TDF at any time
  • Received any other anti-HBV treatment during the current pregnancy
  • Estimated creatinine clearance of less than 50 mL per minute or had confirmed proteinuria or normoglycemic glycosuria
  • Evidence of fetal anomaly that was incompatible with life

Other salient features/characteristics:

  • Women with an elevated ALT level (>60 IU/L) at any trial visit had their level tested again within 2 weeks
  • Pregnancies that resulted in multiple births were counted as one mother-infant pair and were counted as having HBV infection if at least one infant was infected
  • Amniocentesis and Cesarean section delivery may be associated with increased risk of HBV transmission

Primary outcomes:

  • The positive status of hepatitis B surface antigen (HBsAg) in the infant confirmed by the HBV DNA level at 6 months of age. Results found that none of the 147 infants in the TDF group were infected (0%, [CI] 0 to 2) as compared with three of 147 (2%, [CI] 0 to 6) in the placebo group (p=0.12).
  • At 6 months follow up, 99% of the TDF and placebo groups had an HbsAg antibody level of at least 10 IU/L.

Secondary outcomes:

  • Adverse events that were measured included: maternal hepatic flares (ALT level of >300 IU/L) after discontinuation of the trial regimen, and infant growth at 6 months.
  • The incidence of maternal ALT level of more than 300 IU/L after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (p=0.29).
  • Overall, the rate of adverse events did not differ significantly between the two groups.

 

Interpretation:

Findings from this trial did not reach statistical significance with regards to detection of HBV infection in infants whose mothers received TDF. Although the observed rate of mother to child transmission in the TDF group was not statistically significant at short term follow up, the long-term risk of transmission among these infants was predicted to be less than 2.5%.

With regards to safety concerns of TDF, there was no significant maternal or infant safety incidence reported. Only notable events reported were maternal asymptomatic hepatic flares.

Moreover, prior to the completion of the trial it was expected in general that the rate of HBV transmission would be 7% or more among infants who received HBV vaccine, hepatitis B immune globulin and had been born to mothers with higher HBV DNA levels. Surprisingly, this trial found an overall lower rate of HBV transmission. This difference could be due to sampling variations (for example: sample size, differences in population baseline characteristics and duration of time between infant birth and first administration of the hepatitis B vaccine) compared to other similar studies.

Overall, this trial did not show a lower rate of HBV transmission from mother to infant with the administration of TDF in addition to hepatitis B immune globulin and vaccine to infant compared to placebo.

Jourdain G., Ngo-Giang-Huong, L., Harrison, L, et al. Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B. NEJM. 2018, 378 (10): 911-923. Source

 

Authors Affiliation:

1. Department of Internal Medicine, University of Connecticut Health Center

2. Department of Infectious Disease, Saint Francis Hospital, Hartford, Connecticut

 

Helicobacter Pylori Treatment for the Prevention of Metachronous Gastric Cancer

metachronous gastric cancer, helicobacter pylori

Summarized by / Author: Rohini Manaktala MD (1), Rooma Nankani MD (1)

Summary Reviewer: Paul Robert Anthony Jr. MD (2)

Contribution To Literature:

This trial revealed the beneficial outcome of treating early gastric cancer with H.pylori eradication therapy and the reduction in future development of metachronous gastric cancer compared to placebo.

Description:

The goal of the trial was to determine the incidence of metachronous gastric cancer detected on endoscopy performed at 1-year follow up or later and improvement from baseline in the grade of glandular atrophy in the gastric corpus lesser curvature at the 3 year follow up for individuals with early gastric cancer status post resection and treatment with H.pylori eradication therapy.

Study Design

It was a prospective, single-center, double-blinded, placebo-controlled and randomized trial performed at the National Cancer Center in South Korea that enrolled patients from August 2003 through March 2013.

Patients were randomized in a 1:1 fashion before endoscopic resection to either H.pylori eradication therapy (n = 236) or placebo (n = 234). The treatment group received amoxicillin 1000 mg, clarithromycin 500 mg and proton-pump inhibitor rabeprazole 10 mg which were given twice daily for a week. The placebo group received rabeprazole 10 mg and placebo pills. Both groups received proton-pump inhibitor for additional 4 weeks to promote ulcer healing.

  • Total number of patients: 470
  • Duration of follow-up (endoscopy evaluation): at 3 months, 6 months, 1 year and then every 6 months or 12 months until the last enrolled patient reached the 3 year follow up point
  • Mean patient age: 59 years
  • Percentage male: 75%

Inclusion criteria:

  • Between the ages of 18 and 75 years
  • Histologically confirmed diagnosis of differentiated early gastric cancer or high grade adenoma
  • Endoscopic localization of a mucosal tumor without ulceration and no lymph-node or distant organ metastasis on CT scan
  • Confirmed scheduled endoscopic resection procedure
  • Current H.pylori infection

 

Other salient features/characteristics:

  • The stratification factor for group assignment was the severity of the baseline grade of histologic atrophy at the antrum
  • Paients started the assigned trial medication within 1 week after endoscopic resection
  • Quadruple antibiotic therapy (proton-pump inhibitor, bismuth, metronidazole, tetracycline) was provided for 10 days if H.pylori infection was detected at closeout endoscopic examination

Primary outcomes:

  • The development of metachronous gastric cancer was found to have occurred in 7.2% of the treatment group and in 13.4% of the placebo group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.26-0.94; P=0.03).
  • The proportion of patients who had an improved grade of atrophy in the corpus lesser curvature was higher in the treatment group than in the placebo group (48.4% vs. 15.0%, P <0.001). The odds ratio for such improvement was 5.30 (95% CI, 3.08 to 9.13) in the treatment group as compared with the placebo group.
  • The proportion of patients who had an improved grade of intestinal metaplasia at the same site was also higher in the treatment group than in the placebo group (36.6% vs. 18.3%, P <0.001). However, no significant difference in grade was found for either glandular atrophy or intestinal metaplasia at the antrum.

Secondary outcomes:

  • Major adverse events included death from any cause which was reported in 11 patients in the treatment group and in 6 in the placebo group (HR, 1.95; 95% CI, 0.72-5.27; P=0.19).
  • Minor adverse events included: taste alteration, nausea, vomiting, diarrhea, abdominal pain, hypersensitivity, dizziness, headache and insomnia. These events were more common in the treatment group than placebo (42.0% vs. 10.2%, P<0.001).

Interpretation:

The trial demonstrated a significant reduction in metachronous gastric cancer development among patients who had received treatment for H.pylori infection than those who had received placebo. This is because persistent inflammation of gastric mucosa from H.pylori infection promotes carcinogenesis and increases tumor growth/invasion. Findings from this trial are in agreement with results from previous systemic reviews and open label trials.  Additionally, this trial found that the proportion of patients with improvement in the grade of gastric corpus atrophy from baseline was significantly higher in the treatment group than placebo at the 3 year follow up.

An advantage of this trial was a longer duration of follow up than previous trials (median follow up 5.9 years versus <3 years). However there are some limitations to the trial which include: (i) disappearance of preventive effect of H.pylori treatment on metachronous cancer after follow up duration of more than 5 years and (ii) exclusion of patients with synchronous gastric cancers that were initially missed but detected within 1 year after treatment. Moreover, in this trial hazard ratio for incidence of metachronous gastric cancer was found to be higher than previous trials which could be explained by the fact that H.pylori eradication was not confirmed and salvage treatment was not given to patients who failed eradication therapy due to the limitation of blinded process.

In conclusion, H.pylori therapy reduces but cannot completely eradicate the risk of metachronous gastric cancer. Also, it was found that H.pylori treatment did not affect the subsequent incidence of gastric adenoma or overall survival.

Choi I., Kook M., Kim Y., et al. Helicobacter Pylori Therapy for the Prevention of Metachronous Gastric Cancer. NEJM. 2018, 378 (12): 1085-1095. Source

 

Authors Affiliation:

1. Department of Internal Medicine, University of Connecticut Health Center

2. Department of Infectious Disease, Saint Francis Hospital, Hartford, Connecticut

 

ProACT Trial: Procalcitonin-Guided Antibiotics for Lower Respiratory Tract Infection

Procalcitonin has proven to be a great marker for guiding antibiotics treatment in patients with concern for lower respiratory tract infections. However, it’s not yet established how much does clinicians adhere to using the antibiotic therapy based on procalcitonin results. The ProACT trial recently got published in NEJM. It showed that despite it’s usefulness, clinicians still base their antibiotic use on clinical suspicion. Take a look at our visual abstract for the findings.

APROCCHSS Trial: Hydrocortisone plus Fludrocortisone for Adults with Septic Shock

aprocchss trial visual abstract on hydrocortisone plus fludrocortisone in septic shock

The APROCCHSS trial clinically analyze the combination of steroid therapy in patients with septic shock and shows significant mortality benefit.

Source: NEJM

STEP Trial: Adjunct prednisone therapy for patients with community-acquired pneumonia

Source: The LANCET

Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock

 

Source: CHEST

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