Alison Laufer Halpin

Intestinal microbiome disruption in patients in a long-term acute care hospital: A case for development of microbiome disruption indices to improve infection prevention

BACKGROUND Composition and diversity of intestinal microbial communities (microbiota) are generally accepted as a risk factor for poor outcomes; however, we cannot yet use this information to prevent adverse outcomes. METHODS Stool was collected from 8 long-term acute care hospital patients experiencing diarrhea and 2 fecal microbiota transplant donors; 16S rDNA V1-V2 hypervariable regions were sequenced. Composition and diversity of each sample were described. Stool was also tested for Clostridium difficile, vancomycin-resistant enterococci (VRE), and carbapenem-resistant Enterobacteriaceae. Associations between microbiota diversity and demographic and clinical characteristics, including antibiotic use, were analyzed. RESULTS Antibiotic exposure and Charlson Comorbidity Index were inversely correlated with diversity (Spearman = -0.7). Two patients were positive for VRE; both had microbiomes dominated by Enterococcus faecium, accounting for 67%-84% of their microbiome. CONCLUSIONS Antibiotic exposure correlated with diversity; however, other environmental and host factors not easily obtainable in a clinical setting are also known to impact the microbiota. Therefore, direct measurement of microbiome disruption by sequencing, rather than reliance on surrogate markers, might be most predictive of adverse outcomes. If and when microbiome characterization becomes a standard diagnostic test, improving our understanding of microbiome dynamics will allow for interpretation of results to improve patient outcomes.

Editorial Commentary: The Dawning of Microbiome Remediation for Addressing Antibiotic Resistance

The Centers for Disease Control and Prevention (CDC) estimates that over 2 million infections in the United States each year are caused by antibiotic-resistant pathogens described as urgent, serious, and concerning threats, leading to 23 000 deaths and billions of dollars in excess medical costs [1]. Nearly half of these 18 antibiotic resistant threats are healthcareassociated pathogens and at least 5 frequently colonize the lower intestinal microbiota of patients. Among the many host and environmental factors that influence the composition of our microbiota, the most significant is the receipt of antibiotics [2–4]. Treatment with antibiotics eliminates not only pathogenic but also beneficial bacteria, resulting in severe disruption of the intestinal microbiota for an extended period of time (>6 months) [2]. This loss of diversity in the intestinal microbial composition places individuals at increased risk for poor outcomes, including colonization by pathogens, such as C. difficile and other multidrugresistant organisms (MDROs), which can give way to their expansion, dominance, and infection and bacteremia [5–8]. Among the almost 500 000 cases of Clostridium difficile infection (CDI) that occur each year, there are an estimated 83 000 recurrences of infection annually [9]. In recent years, the use of fecal microbiota transplantation (FMT) has garnered attention as a method for treating recurrent CDI by restoring the intestinal microbiota to a healthy state, preventing further recurrences [10]. The Food and Drug Administration (FDA) has determined that FMTs are a biological product and a drug, and an investigational new drug (IND) application is required to use FMT for clinical indications, except for recurrent CDI for which an application is encouraged but not required (http:// www.regulations.gov/#!documentDetail; D=FDA-2013-D-0811-0002). This leaves a window open to use FMT for eradication of other MDROs, provided an IND application is submitted. Efforts to treat recurrent CDI have found concomitant eradication of other MDROs [11] and other groups have demonstrated clearance of ongoing colonization or recurrent infection by MDROs through FMT [12, 13]. In this issue of Clinical Infectious Diseases, Millan et al report on a small study (N = 20) of patients who underwent FMT via colonoscopy for recurrent CDI. The investigators demonstrated, using a combination of deep sequencing metagenomics and resistance gene microarray, a reduction in the diversity and number of resistance genes in patients’microbiota (ie, resistome) following FMT. Although this was a small, uncontrolled study, there was additional indirect evidence for a causal role for FMT in shrinking the resistome found in the 9 of 20 patients who failed their initial FMT, requiring a second FMT. This clinical failure correlated with a failure to reduce the resistome, along with a failure to increase bacterial diversity (ie, resistance gene diversity varied inversely with bacterial diversity) and a persistent dominance by Proteobacteria, especially Escherichia coli and Klebsiella pneumoniae. In addition, the investigators demonstrated that the microbiomes of the 3 FMT donors were similar in diversity to a healthy cohort (age 18–40 years) from the Human Microbiome Project. Nonetheless, the study lacks a recurrent CDI control group who did not receive FMT, and therefore one cannot assess how much FMT contributes to shrinkage of the resistome over and above simply avoiding subsequent antibiotic exposure. In addition, current metagenomics methods are unable to link an antibiotic resistance gene to a particular species member of the microbiome and thereby identify potentially pathogenic MDROs present. Finally, the load of antibiotic resistance genes present in these patients and correlation of the load with risk of developing a subsequent MDRO infection or transmitting MDROs or determinants to other patients are unknown. We can anticipate various routes to the future use of microbiome remediation as a means to address antibiotic resistance. Although FMT using screened, healthy donors is currently widely practiced in the treatment of recurrent CDI, one can foresee a possible day when a patient’s own microbiome is electively harvested, frozen or otherwise “banked,” and later used for autologous retransplant following a microbiome-disrupting therapy or Received 11 March 2016; accepted 17 March 2016. Correspondence: L. C. McDonald, 1600 Clifton Rd, MS A31, Atlanta, GA 30333 (ljm3@cdc.gov). Clinical Infectious Diseases Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/ciw187

Mycobacterium chelonae Eye Infections Associated with Humidifier Use in an Outpatient LASIK Clinic--Ohio, 2015.

Laser-assisted in situ keratomileusis (LASIK) eye surgery is increasingly common, with approximately 600,000 procedures performed each year in the United States. LASIK eye surgery is typically performed in an outpatient setting and involves the use of a machine-guided laser to reshape the lens of the eye to correct vision irregularities. Clinic A is an ambulatory surgery center that performs this procedure on 1 day each month. On February 5, 2015, the Toledo-Lucas County Health Department (TLCHD) in Ohio was notified of eye infections in two of the six patients who had undergone LASIK procedures at clinic A on January 9, 2015. The two patients experienced eye pain after the procedures and received diagnoses of infection with Mycobacterium chelonae, an environmental organism found in soil and water.

Evaluation of a Novel Intervention to Reduce Unnecessary Urine Cultures in Intensive Care Units at a Tertiary Care Hospital in Maryland, 2011–2014

We assessed the impact of a reflex urine culture protocol, an intervention aimed to reduce unnecessary urine culturing, in intensive care units at a tertiary care hospital. Significant decreases in urine culturing rates and reported rates of catheter-associated urinary tract infection followed implementation of the protocol.

Risk of Subsequent Sepsis Within 90 Days After a Hospital Stay by Type of Antibiotic Exposure

Background We examined the risk of sepsis within 90 days after discharge from a previous hospital stay by type of antibiotic received during the previous stay. Methods We retrospectively identified a cohort of hospitalized patients from the Truven Health MarketScan Hospital Drug Database. We examined the association between the use of certain antibiotics during the initial hospital stay, determined a priori, and the risk of postdischarge sepsis controlling for potential confounding factors in a multivariable logistic regression model. Our primary exposure was receipt of antibiotics more strongly associated with clinically important microbiome disruption. Our primary outcome was a hospital stay within 90 days of the index stay that included an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis of severe sepsis (ICD-9-CM code 995.92) or septic shock (785.52). Results Among 516 hospitals, we randomly selected a single stay for eligible patients. In 0.17% of these patients, severe sepsis/septic shock developed within 90 days after discharge. The risk of sepsis associated with exposure to our high-risk antibiotics was 65% higher than in those without antibiotic exposure. Conclusions Our study identified an increased risk of sepsis within 90 days of discharge among patients with exposure to high-risk antibiotics or increased quantities of antibiotics during hospitalization. Given that a significant proportion of inpatient antimicrobial use may be unnecessary, this study builds on previous evidence suggesting that increased stewardship efforts in hospitals may not only prevent antimicrobial resistance, Clostridium difficile infection, and other adverse effects, but may also reduce unwanted outcomes potentially related to disruption of the microbiota, including sepsis.

Epidemiologic Investigation of a Cluster of Neuroinvasive Bacillus cereus Infections in 5 Patients With Acute Myelogenous Leukemia.

Background. Five neuroinvasive Bacillus cereus infections (4 fatal) occurred in hospitalized patients with acute myelogenous leukemia (AML) during a 9-month period, prompting an investigation by infection control and public health officials. Methods. Medical records of case-patients were reviewed and a matched case-control study was performed. Infection control practices were observed. Multiple environmental, food, and medication samples common to AML patients were cultured. Multilocus sequence typing was performed for case and environmental B cereus isolates. Results. All 5 case-patients received chemotherapy and had early-onset neutropenic fevers that resolved with empiric antibiotics. Fever recurred at a median of 17 days (range, 9–20) with headaches and abrupt neurological deterioration. Case-patients had B cereus identified in central nervous system (CNS) samples by (1) polymerase chain reaction or culture or (2) bacilli seen on CNS pathology stains with high-grade B cereus bacteremia. Two case-patients also had colonic ulcers with abundant bacilli on autopsy. No infection control breaches were observed. On case-control analysis, bananas were the only significant exposure shared by all 5 case-patients (odds ratio, 9.3; P = .04). Five environmental or food isolates tested positive for B cereus, including a homogenized banana peel isolate and the shelf of a kitchen cart where bananas were stored. Multilocus sequence typing confirmed that all case and environmental strains were genetically distinct. Multilocus sequence typing-based phylogenetic analysis revealed that the organisms clustered in 2 separate clades. Conclusions. The investigation of this neuroinvasive B cereus cluster did not identify a single point source but was suggestive of a possible dietary exposure. Our experience underscores the potential virulence of B cereus in immunocompromised hosts.

Cardiothoracic surgical site phaeohyphomycosis caused by Bipolaris mould, multiple US states, 2008–2013: a clinical description

Bipolaris mould surgical site infections (SSIs) are exceedingly rare. We describe 21 cases of Bipolaris SSIs in pediatric and adult cardiothoracic surgery patients at ten hospitals in Texas, Arkansas, and Florida during 2008-2013. Median case-patient age was 55 years (range: 3 days-82 years), and 19 (90%) were male. Ten (48%) had coronary artery bypass or valve surgery, and seven (33%) had heart transplantation. Fifteen (71%) had more than one cardiothoracic procedure (median: 3, range: 1-11). Thirteen (62%) case-patients (all 5 pediatric patients, and 8 (50%) of 16 adult patients) had delayed sternal closure (chest closed >1 day [median = 8 days; range: 2-22] following the initial cardiothoracic procedure). Thirteen (62%) had mediastinitis. Median time from initial surgery to positive Bipolaris culture was 20 days (range: 6-497). Sixteen (76%) case-patients died.

Genomic Analysis of a Pan-Resistant Isolate of Klebsiella pneumoniae, United States 2016

ABSTRACT Antimicrobial resistance is a threat to public health globally and leads to an estimated 23,000 deaths annually in the United States alone. Here, we report the genomic characterization of an unusual Klebsiella pneumoniae, nonsusceptible to all 26 antibiotics tested, that was isolated from a U.S. patient. The isolate harbored four known beta-lactamase genes, including plasmid-mediated blaNDM-1 and blaCMY-6, as well as chromosomal blaCTX-M-15 and blaSHV-28, which accounted for resistance to all beta-lactams tested. In addition, sequence analysis identified mechanisms that could explain all other reported nonsusceptibility results, including nonsusceptibility to colistin, tigecycline, and chloramphenicol. Two plasmids, IncA/C2 and IncFIB, were closely related to mobile elements described previously and isolated from Gram-negative bacteria from China, Nepal, India, the United States, and Kenya, suggesting possible origins of the isolate and plasmids. This is one of the first K. pneumoniae isolates in the United States to have been reported to the Centers for Disease Control and Prevention (CDC) as nonsusceptible to all drugs tested, including all beta-lactams, colistin, and tigecycline. IMPORTANCE Antimicrobial resistance is a major public health threat worldwide. Bacteria that are nonsusceptible or resistant to all antimicrobials available are of major concern to patients and the public because of lack of treatment options and potential for spread. A Klebsiella pneumoniae strain that was nonsusceptible to all tested antibiotics was isolated from a U.S. patient. Mechanisms that could explain all observed phenotypic antimicrobial resistance phenotypes, including resistance to colistin and beta-lactams, were identified through whole-genome sequencing. The large variety of resistance determinants identified demonstrates the usefulness of whole-genome sequencing for detecting these genes in an outbreak response. Sequencing of isolates with rare and unusual phenotypes can provide information on how these extremely resistant isolates develop, including whether resistance is acquired on mobile elements or accumulated through chromosomal mutations. Moreover, this provides further insight into not only detecting these highly resistant organisms but also preventing their spread. IMPORTANCE Antimicrobial resistance is a major public health threat worldwide. Bacteria that are nonsusceptible or resistant to all antimicrobials available are of major concern to patients and the public because of lack of treatment options and potential for spread. A Klebsiella pneumoniae strain that was nonsusceptible to all tested antibiotics was isolated from a U.S. patient. Mechanisms that could explain all observed phenotypic antimicrobial resistance phenotypes, including resistance to colistin and beta-lactams, were identified through whole-genome sequencing. The large variety of resistance determinants identified demonstrates the usefulness of whole-genome sequencing for detecting these genes in an outbreak response. Sequencing of isolates with rare and unusual phenotypes can provide information on how these extremely resistant isolates develop, including whether resistance is acquired on mobile elements or accumulated through chromosomal mutations. Moreover, this provides further insight into not only detecting these highly resistant organisms but also preventing their spread.

Pseudomonas aeruginosa Outbreak in a Neonatal Intensive Care Unit Attributed to Hospital Tap Water

OBJECTIVE To investigate an outbreak of Pseudomonas aeruginosa infections and colonization in a neonatal intensive care unit. DESIGN Infection control assessment, environmental evaluation, and case-control study. SETTING Newly built community-based hospital, 28-bed neonatal intensive care unit. PATIENTS Neonatal intensive care unit patients receiving care between June 1, 2013, and September 30, 2014. METHODS Case finding was performed through microbiology record review. Infection control observations, interviews, and environmental assessment were performed. A matched case-control study was conducted to identify risk factors for P. aeruginosa infection. Patient and environmental isolates were collected for pulsed-field gel electrophoresis to determine strain relatedness. RESULTS In total, 31 cases were identified. Case clusters were temporally associated with absence of point-of-use filters on faucets in patient rooms. After adjusting for gestational age, case patients were more likely to have been in a room without a point-of-use filter (odds ratio [OR], 37.55; 95% confidence interval [CI], 7.16-∞). Case patients had higher odds of exposure to peripherally inserted central catheters (OR, 7.20; 95% CI, 1.75-37.30) and invasive ventilation (OR, 5.79; 95% CI, 1.39-30.62). Of 42 environmental samples, 28 (67%) grew P. aeruginosa. Isolates from the 2 most recent case patients were indistinguishable by pulsed-field gel electrophoresis from water-related samples obtained from these case-patient rooms. CONCLUSIONS This outbreak was attributed to contaminated water. Interruption of the outbreak with point-of-use filters provided a short-term solution; however, eradication of P. aeruginosa in water and fixtures was necessary to protect patients. This outbreak highlights the importance of understanding the risks of stagnant water in healthcare facilities. Infect Control Hosp Epidemiol 2017;38:801-808.

Complete Genome Sequence of Mycobacteriumchimaera Strain CDC2015-22-71

ABSTRACT Mycobacterium chimaera is a nontuberculous mycobacterium species commonly found in the environment. Here, we report the first complete genome sequence of a strain from the investigation of invasive infections following open-heart surgeries that used contaminated LivaNova Sorin Stockert 3T heater-cooler devices.