Lisa E. Davidson

Gut microbial colonisation in premature neonates predicts neonatal sepsis

Background Neonatal sepsis due to intestinal bacterial translocation is a major cause of morbidity and mortality. Understanding microbial colonisation of the gut in prematurity may predict risk of sepsis to guide future strategies to manipulate the microbiome. Methods Prospective longitudinal study of premature infants. Stool samples were obtained weekly. DNA was extracted and the V6 hypervariable region of 16S rRNA was amplified followed by high throughput pyrosequencing, comparing subjects with and without sepsis. Results Six neonates were 24–27 weeks gestation at birth and had 18 samples analysed. Two subjects had no sepsis during the study period, two developed late-onset culture-positive sepsis and two had culture-negative systemic inflammation. 324 350 sequences were obtained. The meconium was not sterile and had predominance of Lactobacillus, Staphylococcus and Enterobacteriales. Overall, infants who developed sepsis began life with low microbial diversity, and acquired a predominance of Staphylococcus, while healthy infants had more diversity and predominance of Clostridium, Klebsiella and Veillonella. Conclusions In very low birth weight infants, the authors found that meconium is not sterile and is less diverse from birth in infants who will develop late-onset sepsis. Empiric, prolonged antibiotics profoundly decrease microbial diversity and promote a microbiota that is associated not only with neonatal sepsis, but the predominant pathogen previously identified in the microbiome. Our data suggest that there may be a ‘healthy microbiome’ present in extremely premature neonates that may ameliorate risk of sepsis. More research is needed to determine whether altered antibiotics, probiotics or other novel therapies can re-establish a healthy microbiome in neonates.

Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebo-controlled trial

Background/Objectives:Live-attenuated influenza vaccine (LAIV) protects against influenza by mucosal activation of the immune system. Studies in animals and adults have demonstrated that probiotics improve the immune response to mucosally delivered vaccines. We hypothesized that Lactobacillus GG (LGG) would function as an immune adjuvant to increase rates of seroconversion after LAIV administration.Subjects/Methods:We conducted a randomized double-blind placebo-controlled pilot study to determine whether LGG improved rates of seroconversion after administration of LAIV. We studied 42 healthy adults during the 2007–2008 influenza season. All subjects received LAIV and then were randomized to LGG or placebo, twice daily for 28 days. Hemagglutinin inhibition titers were assessed at baseline, at day 28 and at day 56 to determine the rates of seroconversion. Subjects were assessed for adverse events throughout the study period.Results:A total of 39 subjects completed the per-protocol analysis. Both LGG and LAIV were well tolerated. Protection rates against the vaccine H1N1 and B strains were suboptimal in subjects receiving LGG and placebo. For the H3N2 strain, 84% receiving LGG vs 55% receiving placebo had a protective titer 28 days after vaccination (odds of having a protective titer was 1.84 95% confidence interval 1.04–3.22, P=0.048).Conclusion:Lactobacillus GG is potential as an important adjuvant to improve influenza vaccine immunogenicity. Future studies of probiotics as immune adjuvants might need to specifically consider examining vaccine-naïve or sero-negative subjects, target mucosal immune responses or focus on groups known to have poor response to influenza vaccines.

SYMPOSIUM ON ANTIMICROBIAL THERAPYAntimicrobial Stewardship

Antimicrobial resistance is increasing; however, antimicrobial drug development is slowing. Now more than ever before, antimicrobial stewardship is of the utmost importance as a way to optimize the use of antimicrobials to prevent the development of resistance and improve patient outcomes. This review describes the why, what, who, how, when, and where of antimicrobial stewardship. Techniques of stewardship are summarized, and a plan for implementation of a stewardship program is outlined.

Open-Label, Dose Escalation Phase I Study in Healthy Volunteers to Evaluate the Safety and Pharmacokinetics of a Human Monoclonal Antibody to Clostridium difficile Toxin A

BACKGROUND Recent data suggest that Clostridium difficile-associated diarrhea is becoming more severe and difficult to treat. Antibody responses to C. difficile toxin A are protective against symptomatic disease and recurrence. We examined the safety and pharmacokinetics (pk) of a novel neutralizing human monoclonal antibody against C. difficile toxin A (CDA1) in healthy adults. METHODS Five cohorts with 6 subjects each received a single intravenous infusion of CDA1 at escalating doses of 0.3, 1, 5, 10, and 20 mg/kg. Safety evaluations took place on days 1, 2, 3, 7, 14, 28, and 56 post-infusion. Samples for pk analysis were obtained before and after infusion, and at each safety evaluation. Serum CDA1 antibody concentrations and human anti-human antibody (HAHA) titers were measured with enzyme-linked immunosorbent assays. A noncompartmental model was used for pk analysis. RESULTS Thirty subjects were enrolled. The median age was 27.5 yrs. There were no serious adverse events (AE) related to CDA1. Twenty-one of the 48 reported non-serious adverse events were possibly related to CDA1, and included transient blood pressure changes requiring no treatment, nasal congestion, headache, abdominal cramps, nausea, and self-limited diarrhea. Serum CDA1 concentrations increased with escalating doses: mean C(max) ranged from 6.82 microg/ml for the 0.3 mg/kg cohort to 511 microg/ml for the 20 mg/kg cohort. The geometric mean values of the half-life of CDA1 ranged between 25.3 and 31.8 days, and the volume of distribution approximated serum. No subject formed detectable HAHA titers. CONCLUSION Administration of CDA1 as a single intravenous infusion was safe and well tolerated. C(max) increased proportionally with increasing doses. A randomized study of CDA1 in patients with C. difficile associated diarrhea is underway.

A Nationwide Survey of Antimicrobial Stewardship Practices

OBJECTIVE The goal of this study was to characterize hospital antimicrobial stewardship practices nationwide and to identify factors associated with the presence of these programs. METHODS The first web-based survey was sent in 2009 to members of the Yankee Alliance and the Premier Healthcare Alliance, nationwide organizations of health-care providers. The second survey, a slightly modified version of the first, was sent in 2010 to a commercially purchased list of hospital pharmacy director e-mail addresses. RESULTS A total of 406 responses were received from ~5890 providers targeted, for an overall response rate of ~7%. More than one half (206 of 406) of the respondents reported having what they considered to be a formal antimicrobial stewardship program (ASP). Among all respondents regardless of presence or absence of an ASP, 96.4% (351 of 364) were using some form of antimicrobial stewardship technique. Of those respondents working in hospitals without an ASP, 63.3% (114 of 180) had considered implementing one. After controlling for all significant variables, those that remained which were significantly associated with having an ASP were survey (Premier vs commercial), having an infectious disease consultation service, and having an infectious disease pharmacist. CONCLUSIONS In this survey of 406 respondents from across the country, we found that just more than one half of hospitals had what they considered to be formal ASPs; however, the vast majority were using stewardship techniques to optimize the use of antibiotics. Common barriers to implementation of ASPs included staffing constraints and insufficient funding.

Tigecycline-induced acute pancreatitis: case report and literature review

Tigecycline is a broad-spectrum antimicrobial agent structurally related to minocycline. Pancreatitis has been associated with the tetracycline class of antibiotics and concerns about tigecycline-induced acute pancreatitis have recently been raised. We describe a 69-year-old female who received tigecycline for treatment of a complicated skin and skin-structure infection. Following 7 days of tigecycline she developed severe abdominal pain and elevated pancreatic enzymes suggesting acute pancreatitis. According to the Naranjo adverse drug reaction probability scale, tigecycline was the probable cause of her acute pancreatitis. Clinicians should be aware of this potential adverse effect of tigecycline. We recommend that clinicians monitor patients for signs and symptoms of pancreatitis, including abdominal pain, during treatment with tigecycline.

Risk factors for death after sepsis in patients immunosuppressed before the onset of sepsis.

Few studies have focused on sepsis in patients with pre-existing immunosuppression. Since the numbers and the incidence of sepsis are increasing, sepsis in immunosuppressed patients will increase in importance. We studied the epidemiology of sepsis and risk factors for 28-d mortality in patients immunosuppressed prior to the onset of sepsis using data from the Academic Medical Center Consortiums (AMCC) prospective observational cohort study of sepsis. We compared characteristics of immunosuppressed (n =412) and immunocompetent (n =754) patients. Immunosuppressed patients were younger and more likely to have underlying liver or lung disease, and nosocomial infection or bloodstream infection of unknown source when presenting with sepsis. They were also more likely to die within 28 d compared to immunocompetent patients (adjusted relative risk 1.62, 95% CI 1.38 – 1.91). Septic shock, hypothermia, cancer and invasive fungal infections were associated with increased mortality in immunosuppressed patients. Black race and the presence of rigors were independent predictors of survival in immunosuppressed patients. We conclude that sepsis among patients immunosuppressed prior to the onset of sepsis was associated with higher mortality than in immunocompetent patients. As the numbers of immunosuppressed patients continue to grow, more studies on the epidemiology of sepsis in this group will become increasingly important.

Probiotic Foods and Drugs: Impact of US Regulatory Status on Design of Clinical Trials

Probiotics have been in widespread use since ancient times and are increasingly being consumed to maintain health and to prevent and treat a wide range of conditions. In the United States, probiotics are considered to be foods or biologics, depending on their intended use. This article addresses the similarities and differences between approaches to conducting clinical trials of probiotics as foods (which leads to health claims) or as biologics (which leads to therapeutic claims). Most probiotics are manufactured as foods, which makes it challenging for academic investigators in the United States to meet the requirements of an Investigational New Drug application that enables them to study the therapeutic effects of these novel agents. Although it is important to ensure the safety and quality of probiotic products, there also may be value in adapting the US Food and Drug Administrations Guidance for Industry for Botanical Products to probiotic products, in part to allow the research agenda to move forward with products for which there are no safety concerns.

The role of primary care prescribers in the diagnosis and management of community-associated methicillin-resistant Staphylococcus aureus skin and soft tissue infections.

Nosocomial infections caused by methicillin-resistant Staphylococcus aureus were first reported in the United States in the early 1960s. Beginning in the 1990s, healthy individuals from the community with no risk factors for resistant bacteria began presenting with methicillin-resistant Staphylococcus aureus infections, acquiring the name “community-associated methicillin-resistant Staphylococcus aureus” (CA-MRSA). CA-MRSA has a tendency to affect the skin and skin structures, generally in the form of abscesses and furuncles, carbuncles, and cellulitis. Cases of invasive infections including bacteremia, endocarditis, and necrotizing pneumonia have also been reported. A patient complaint of a “spider bite” is frequently associated with CA-MRSA. CA-MRSA and the traditional health care-associated methicillin-resistant Staphylococcus aureus are distinguished by their genetic composition, virulence factors, and susceptibility patterns to non-beta-lactam antibiotics. Appropriate management of CA-MRSA skin and skin structure infections includes incision and drainage of infected tissue and appropriate antimicrobial therapy. It has been suggested that when prevalence of CA-MRSA within a community eclipses 10%-15%, empiric use of non-beta-lactam antibiotics with in vitro activity against CA-MRSA be initiated when treating skin and skin structure infections. CA-MRSA retains susceptibility to a range of older antibiotics available in oral formulations such as minocycline, doxycycline, sulfamethoxazole-trimethoprim, moxifloxacin, levofloxacin, and clindamycin. Local susceptibility patterns and individual patient factors should guide the selection of antibiotics.

Antimicrobial Stewardship in a Long-Term Acute Care Hospital Using Offsite Electronic Medical Record Audit

OBJECTIVE To offer antimicrobial stewardship to a long-term acute care hospital using telemedicine. METHODS We conducted an uninterrupted time-series analysis to measure the impact of antimicrobial stewardship on hospital-acquired Clostridium difficile infection (CDI) rates and antimicrobial use. Simple linear regression was used to analyze changes in antimicrobial use; Poisson regression was used to estimate the incidence rate ratio in CDI rates. The preimplementation period was April 1, 2010-March 31, 2011; the postimplementation period was April 1, 2011-March 31, 2014. RESULTS During the preimplementation period, total antimicrobial usage was 266 defined daily doses (DDD)/1,000 patient-days (PD); it rose 4.54 (95% CI, -0.19 to 9.28) per month then significantly decreased from preimplementation to postimplementation (-6.58 DDD/1,000 PD [95% CI, -11.48 to -1.67]; P=.01). The same trend was observed for antibiotics against methicillin-resistant Staphylococcus aureus (-2.97 DDD/1,000 PD per month [95% CI, -5.65 to -0.30]; P=.03). There was a decrease in usage of anti-CDI antibiotics by 50.4 DDD/1,000 PD per month (95% CI, -71.4 to -29.2; P<.001) at program implementation that was maintained afterwards. Anti-Pseudomonas antibiotics increased after implementation (30.6 DDD/1,000 PD per month [95% CI, 4.9-56.3]; P=.02) but with ongoing education this trend reversed. Intervention was associated with a decrease in hospital-acquired CDI (incidence rate ratio, 0.57 [95% CI, 0.35-0.92]; P=.02). CONCLUSION Antimicrobial stewardship using an electronic medical record via remote access led to a significant decrease in antibacterial usage and a decrease in CDI rates.