Joshua T. Thaden

Rising Rates of Carbapenem-Resistant Enterobacteriaceae in Community Hospitals: A Mixed-Methods Review of Epidemiology and Microbiology Practices in a Network of Community Hospitals in the Southeastern United States

OBJECTIVE Describe the epidemiology of carbapenem-resistant Enterobacteriaceae (CRE) and examine the effect of lower carbapenem breakpoints on CRE detection. DESIGN Retrospective cohort. SETTING Inpatient care at community hospitals. PATIENTS All patients with CRE-positive cultures were included. METHODS CRE isolated from 25 community hospitals were prospectively entered into a centralized database from January 2008 through December 2012. Microbiology laboratory practices were assessed using questionnaires. RESULTS A total of 305 CRE isolates were detected at 16 hospitals (64%). Patients with CRE had symptomatic infection in 180 cases (59%) and asymptomatic colonization in the remainder (125 cases; 41%). Klebsiella pneumoniae (277 isolates; 91%) was the most prevalent species. The majority of cases were healthcare associated (288 cases; 94%). The rate of CRE detection increased more than fivefold from 2008 (0.26 cases per 100,000 patient-days) to 2012 (1.4 cases per 100,000 patient-days; incidence rate ratio (IRR), 5.3 [95% confidence interval (CI), 1.22-22.7]; P = .01). Only 5 hospitals (20%) had adopted the 2010 Clinical and Laboratory Standards Institute (CLSI) carbapenem breakpoints. The 5 hospitals that adopted the lower carbapenem breakpoints were more likely to detect CRE after implementation of breakpoints than before (4.1 vs 0.5 cases per 100,000 patient-days; P < .001; IRR, 8.1 [95% CI, 2.7-24.6]). Hospitals that implemented the lower carbapenem breakpoints were more likely to detect CRE than were hospitals that did not (3.3 vs 1.1 cases per 100,000 patient-days; P = .01). CONCLUSIONS The rate of CRE detection increased fivefold in community hospitals in the southeastern United States from 2008 to 2012. Despite this, our estimates are likely underestimates of the true rate of CRE detection, given the low adoption of the carbapenem breakpoints recommended in the 2010 CLSI guidelines.

Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae

ABSTRACT Antimicrobial resistance has been identified by the World Health Organization as “one of the three greatest threats to human health.” Gram negative bacteria in particular drive this alarming trend. Carbapenem-resistant Enterobacteriaceae (CRE) such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter species are of particular importance as they are associated with poor clinical outcomes and are common causes for a variety of infections including bacteremia, urinary tract infection, intra-abdominal infections and pneumonia. CRE are difficult to treat as carbapenem resistance is often accompanied by resistance to additional drug classes. For example, CRE may be extensively drug resistant or even pandrug resistant. Unfortunately, CRE infections have increased over the past 15 y while new and effective antibiotics have not kept pace. Recently, however, new agents have become available to help treat CRE infection, and several more are under development. This article reviews the efficacy, safety, and pharmacokinetic issues around 4 emerging agents to treat CRE – ceftazidime-avibactam, fosfomycin, tigecycline, and minocycline. In addition, an overview of agents in the antibiotic pipeline – meropenem-vaborbactam, imipenem-relebactam, plazomicin, and eravacycline is provided. More established agents, such as those in the polymyxin class and aminoglycoside class (other than the pipeline agent plazomicin), are not addressed here.

Increasing Incidence of Extended-Spectrum β-Lactamase-Producing Escherichia coli in Community Hospitals throughout the Southeastern United States

OBJECTIVE To describe the epidemiology of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli (ESBL-EC) and Klebsiella pneumoniae (ESBL-KP) infections DESIGN Retrospective cohort SETTING Inpatient care at community hospitals PATIENTS All patients with ESBL-EC or ESBL-KP infections METHODS ESBL-EC and ESBL-KP infections from 26 community hospitals were prospectively entered into a centralized database from January 2009 to December 2014. RESULTS A total of 925 infections caused by ESBL-EC (10.5 infections per 100,000 patient days) and 463 infections caused by ESBL-KP (5.3 infections per 100,000 patient days) were identified during 8,791,243 patient days of surveillance. The incidence of ESBL-EC infections increased from 5.28 to 10.5 patients per 100,000 patient days during the study period (P=.006). The number of community hospitals with ESBL-EC infections increased from 17 (65%) in 2009 to 20 (77%) in 2014. The median ESBL-EC infection rates among individual hospitals with ≥1 ESBL-EC infection increased from 11.1 infections/100,000 patient days (range, 2.2-33.9 days) in 2009 to 22.1 infections per 100,000 patient days (range, 0.66-134 days) in 2014 (P=.05). The incidence of ESBL-KP infections remained constant over the study period (P=.14). Community-associated and healthcare-associated ESBL-EC infections trended upward (P=.006 and P=.02, respectively), while hospital-onset infections remained stable (P=.07). ESBL-EC infections were more common in females (54% vs 44%, P<.001) and Caucasians (50% vs 40%, P<.0001), and were more likely to be isolated from the urinary tract (61% vs 52%, P<.0001) than ESBL-KP infections. CONCLUSIONS The incidence of ESBL-EC infection has increased in community hospitals throughout the southeastern United States, while the incidence of ESBL-KP infection has remained stable. Community- and healthcare-associated ESBL-EC infections are driving the upward trend. Infect. Control Hosp. Epidemiol. 2015;37(1):49-54.

Quorum-Sensing Regulation of a Copper Toxicity System in Pseudomonas aeruginosa

The LasR/LasI quorum-sensing system in Pseudomonas aeruginosa influences global gene expression and mediates pathogenesis. In this study, we show that the quorum-sensing system activates, via the transcriptional regulator PA4778, a copper resistance system composed of 11 genes. The quorum-sensing global regulator LasR was recently shown to directly activate transcription of PA4778, a cueR homolog and a MerR-type transcriptional regulator. Using molecular genetic methods and bioinformatics, we verify the interaction of LasR with the PA4778 promoter and further demonstrate the LasR binding site. We also identify a putative PA4778 binding motif and show that the protein directly binds to and activates five promoters controlling the expression of 11 genes--PA3519 to -15, PA3520, mexPQ-opmE, PA3574.1, and cueA, a virulence factor in a murine model. Using gene disruptions, we show that PA4778, along with 7 of 11 gene targets of PA4778, increases the sensitivity of P. aeruginosa to elevated copper concentrations. This work identifies a cellular function for PA4778 and four other previously unannotated genes (PA3515, PA3516, PA3517, and PA3518) and suggests a potential role for copper in the quorum response. We propose to name PA4778 cueR.

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

ABSTRACT Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 μg/ml, versus failure, 1.09 μg/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study.

Gram-negative bacterial infections: Research priorities, accomplishments, and future directions of the Antibacterial Resistance Leadership Group

Antimicrobial resistance in pathogenic gram-negative bacteria is one of the most pressing challenges in the field of infectious diseases and is one of 4 key areas of unmet medical need identified by the Antibacterial Resistance Leadership Group (ARLG). The mission of the Gram-Negative Committee is to advance our knowledge of these challenging infections and implement studies to improve patient outcomes. Studies have fallen primarily into 2 broad categories: prospective cohort studies and interventional trials. Among the observational studies, CRACKLE (Consortium on Resistance Against Carbapenems in Klebsiella pneumoniae and Other Enterobacteriaceae) has contributed seminal multicenter data describing risk factors and clinical outcomes of carbapenem-resistant Enterobacteriaceae (CRE) in sentinel US hospitals. Building on this success, CRACKLE II will expand the network to hospitals across the United States and Colombia. Similar protocols have been proposed to include Acinetobacter baumannii and Pseudomonas aeruginosa (SNAP and POP studies). In addition, the CREST study (Carbapenem-Resistant Enterobacteriaceae in Solid Organ Transplant Patients) has provided pivotal data on extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and CRE carriage among solid organ transplant recipients to inform management of this vulnerable patient population. Two clinical trials to define novel ways of using an existing antibiotic, fosfomycin, to treat ESBL-producing Enterobacteriaceae (one that has completed enrollment and the other in late protocol development) will determine the clinical efficacy of fosfomycin as step-down oral therapy to treat complicated urinary tract infections. Additional clinical studies and trials using immunotherapeutic or newly approved agents are also in the planning stage, with the main goals of generating actionable data that will inform clinical decision making and facilitate development of new treatment options for highly resistant gram-negative bacterial infections.

Impact of Bacterial and Human Genetic Variation on Staphylococcus aureus Infections.

The clinical diversity of syndromes caused by Staphylococcus aureus arises from a complex interplay between host and pathogen. Genetic variation can result in increased susceptibility to infection within the host and an increased capacity for virulence within the pathogen, resulting in a wide array of clinical syndromes. This review presents evidence for the role of bacterial and human genetic variation in influencing the clinical outcome of S. aureus infections.

No survival benefit with empirical vancomycin therapy for coagulase-negative staphylococcal bloodstream infections in infants.

Background: Coagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available. Methods: All infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1–3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy versus delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support and inotropic support on the day the first positive culture was obtained. Results: A total of 4364 infants with CoNS BSI were identified; 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy [166/2848 (6%) vs. 69/1516 (4%); P = 0.08]. There was no significant difference in 30-day mortality on multivariable analysis [odds ratio: 1.14 (0.84, 1.56)]. The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy [4 days (interquartile range: 2, 6) vs. 3 days (2, 5); P < 0.0001]. Conclusions: The median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.

Dusp3 and Psme3 Are Associated with Murine Susceptibility to Staphylococcus aureus Infection and Human Sepsis

Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus –infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection.

Survival Benefit of Empirical Therapy for Staphylococcus aureus Bloodstream Infections in Infants.

Background: The impact of early adequate empirical antibiotic therapy on outcomes of infants in the neonatal intensive care unit (NICU) who develop Staphylococcus aureus bloodstream infections (BSI) is unknown. Methods: Infants with S. aureus BSI discharged in 1997–2012 from 348 NICUs managed by the Pediatrix Medical Group were identified. Early adequate empirical antibiotic therapy was defined as exposure to ≥1 antibiotic with anti-staphylococcal activity on the day the first positive blood culture was obtained. All other cases were defined as inadequate empirical antibiotic therapy. We evaluated the association between inadequate empirical antibiotic therapy on outcomes controlling for gestational age, small for gestational age status, gender, discharge year, mechanical ventilation, inotropic support and use of supplemental oxygen. The primary outcome was 30-day mortality. Secondary outcomes were 7-day mortality, death before hospital discharge and length of bacteremia. Results: Of the 3339 infants with S. aureus BSI, 2492 (75%) had methicillin-susceptible S. aureus (MSSA) BSI and 847 (25%) had methicillin-resistant S. aureus (MRSA) BSI. Inadequate empirical antibiotic therapy was administered in 725 (22%) cases. Inadequate empirical antibiotic therapy was associated with increased 30-day mortality (odds ratio: 2.03; 95% confidence interval: 1.08–3.82) among infants with MRSA BSI. Inadequate empirical antibiotic therapy was not associated with increases in mortality among infants with MSSA BSI. Conclusions: After controlling for confounders, inadequate empirical antibiotic therapy was associated with a modestly increased mortality at 30 days for infants with MRSA BSI.