Latania K. Logan

Carbapenem-Resistant Enterobacteriaceae: An Emerging Problem in Children

Antibiotic resistance among gram-negative bacteria has reached critical levels. The rise of carbapenem resistance in Enterobacteriaceae carrying additional resistance genes to multiple antibiotic classes has created a generation of organisms nearly resistant to all available therapy. Carbapenem-resistant Enterobacteriaceae (CRE) infections are known to be associated with significant morbidity and mortality, and these pathogens have now made their way to the most vulnerable populations, including children. This review provides a brief overview of CRE, with a focus on CRE infections in children, and highlights available data on the epidemiology, clinical characteristics, carbapenemase types, risk factors, treatment, and outcomes of these multi-drug resistant infections in the pediatric population.

The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace

Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Mechanisms of drug resistance in gram-negative bacteria (GNB) are numerous; β-lactamase genes carried on mobile genetic elements are a key mechanism for the rapid spread of antibiotic-resistant GNB worldwide. Transmissible carbapenem-resistance in Enterobacteriaceae has been recognized for the last 2 decades, but global dissemination of carbapenemase-producing Enterobacteriaceae (CPE) is a more recent problem that, once initiated, has been occurring at an alarming pace. In this article, we discuss the evolution of CRE, with a focus on the epidemiology of the CPE pandemic; review risk factors for colonization and infection with the most common transmissible CPE worldwide, Klebsiella pneumoniae carbapenemase-producing K. pneumoniae; and present strategies used to halt the striking spread of these deadly pathogens.

Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae in Children: Old Foe, Emerging Threat

Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae present an ever-growing burden in the hospital and community settings, across all ages and demographics. Infections due to ESBL-containing pathogens continue to be associated with significant morbidity and mortality worldwide. With widespread empiric broad-spectrum β-lactam use creating selective pressure, and the resultant emergence of stable, rapidly proliferating ESBL-producing clones with continued horizontal gene transfer across genera, addressing this issue remains imperative. Although well characterized in adults, the epidemiology, risk factors, outcomes, therapies, and control measures for ESBL-producing bacteria are less appreciated in children. This analysis provides a brief summary of ESBL-producing Enterobacteriaceae in children, with a focus on recent clinical and molecular data regarding colonization and infection in nonoutbreak settings.

Type III Secretion of ExoU Is Critical during Early Pseudomonas aeruginosa Pneumonia

ABSTRACT The Pseudomonas aeruginosa type III secretion system has been associated with poor outcomes in both animal models and human patients. Despite a large number of studies exploring the regulation of type III secretion in vitro, little is known about the timing of secretion during mammalian infection. Here we demonstrate that the exoU gene, which encodes the highly cytotoxic type III effector ExoU, is induced early during acute P. aeruginosa pneumonia. Immunofluorescence microscopy indicated that the amount of ExoU protein in the lung also increased over time. The importance of early expression was examined using a strain of P. aeruginosa with inducible production of ExoU. Delays in expression as short as 3 h led to reduced bacterial burdens in the lungs of mice and improved survival. Our results demonstrate that early expression of exoU is critical to bacterial survival during pneumonia and suggest that therapeutic interventions that delay ExoU secretion for even short periods of time may be efficacious. IMPORTANCE Pseudomonas aeruginosa is a major contributor to the large numbers of health care-associated infections occurring annually, particularly for immunocompromised patients. Although this organism possesses many virulence factors, the type III secretion system plays an especially important role in both animal models and humans. This system forms a needle-like apparatus that injects toxins directly into eukaryotic cells. The most toxic protein secreted by this molecular machine is ExoU, which causes rapid cell death. In this study, we demonstrated that exoU was expressed and ExoU was produced early during acute pneumonia in a mouse model. Delaying expression of exoU by as little as 3 h enhanced clearance of bacteria and survival of infected mice. Our findings highlight the importance of understanding the regulation of virulence factor expression during infection when designing therapeutic strategies to inhibit the toxic effects of these proteins. Pseudomonas aeruginosa is a major contributor to the large numbers of health care-associated infections occurring annually, particularly for immunocompromised patients. Although this organism possesses many virulence factors, the type III secretion system plays an especially important role in both animal models and humans. This system forms a needle-like apparatus that injects toxins directly into eukaryotic cells. The most toxic protein secreted by this molecular machine is ExoU, which causes rapid cell death. In this study, we demonstrated that exoU was expressed and ExoU was produced early during acute pneumonia in a mouse model. Delaying expression of exoU by as little as 3 h enhanced clearance of bacteria and survival of infected mice. Our findings highlight the importance of understanding the regulation of virulence factor expression during infection when designing therapeutic strategies to inhibit the toxic effects of these proteins.

Extended-Spectrum β-Lactamase-Producing and Third-Generation Cephalosporin-Resistant Enterobacteriaceae in Children: Trends in the United States, 1999-2011

BACKGROUND Enterobacteriaceae infections resistant to extended-spectrum β-lactams are an emerging problem in children. We used a large database of clinical isolates to describe the national epidemiology of extended-spectrum β-lactamase (ESBL)-producing and third-generation cephalosporin-resistant (G3CR) Enterobacteriaceae. METHODS Antimicrobial susceptibilities of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis reported to ∼300 laboratories participating in The Surveillance Network (TSN) between January 1999 and December 2011 were used to phenotypically identify G3CR and ESBL isolates cultured from patients <18 years. Bi-annual trends in the prevalence of each phenotype were stratified by species, patient location, culture site, age, and region. Children of age 0-1 years were excluded from analysis as data were only available from 2010 onwards. RESULTS Out of 368,398 pediatric isolates, 1.97% (7255) were identified as G3CR, and 0.47% (1734) as ESBL producers. The prevalence of both phenotypes increased, respectively, from 1.39% and 0.28% in 1999-2001 to 3% and 0.92% in 2010-2011. Trends were significant across all demographic and age groups, including outpatients, with the highest proportion of isolates in the 1-5-year-old age group. The majority of G3CR and ESBL isolates were E. coli (67.8% and 65.2%, respectively). Among ESBLs, resistance to ≥3 antibiotic classes was 74%. The lower regional prevalence of ESBL-producing bacteria in the upper Midwest relative to the rest of the country is consistent with recent local data. CONCLUSIONS Rates of G3CR and ESBL infections in children are increasing in both inpatient and ambulatory settings nationally. The identification of host factors and exposures leading to infection in children is essential.

Macrolide Treatment Failure in Streptococcal Pharyngitis Resulting in Acute Rheumatic Fever

Macrolide resistance (MR) in group A Streptococcus (GAS) has been well documented in several countries and has become clinically significant since the large increases in macrolide usage during the 1970s. Macrolides are recommended as an alternative therapy for GAS pharyngitis, the most common cause of bacterial pharyngitis. Macrolide resistance has been associated with certain emm types, a sequence-based typing system of the hypervariable region of the GAS M-protein gene. Clinical failure of macrolide treatment of GAS infections can be associated with complications including acute rheumatic fever and rheumatic heart disease, the leading cause of acquired heart disease in children worldwide. Here we report 2 pediatric cases of MR and/or treatment failure in the treatment of GAS pharyngitis with the subsequent development of acute rheumatic fever. We also review the literature on worldwide MR rates, molecular classifications, and emm types, primarily associated with GAS pharyngeal isolates between the years of 2000 and 2010. The use of macrolides in the management of GAS pharyngitis should be limited to patients with significant penicillin allergy.

Carbapenem-Resistant Enterobacteriaceae in Children, United States, 1999-2012.

Infection rates have increased in all age groups and settings nationally.

The ADP-Ribosyltransferase Domain of the Effector Protein ExoS Inhibits Phagocytosis of Pseudomonas aeruginosa during Pneumonia

ABSTRACT Pseudomonas aeruginosa is a Gram-negative pathogen commonly associated with nosocomial infections such as hospital-acquired pneumonia. It uses a type III secretion system to deliver effector proteins directly into the cytosol of host cells. Type III secretion in P. aeruginosa has been linked to severe disease and worse clinical outcomes in animal and human studies. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. Numerous in vitro studies have investigated the targets and cellular effects of ExoS, linking both its enzymatic activities with inhibition of bacterial internalization. However, little is known about how this toxin facilitates the progression of infection in vivo. In this study, we used a mouse model to investigate the role of ExoS in inhibiting phagocytosis during pneumonia. We first confirmed previous findings that the ADP-ribosyltransferase activity of ExoS, but not the GTPase-activating protein activity, was responsible for bacterial persistence and decreased host survival in this model. We then used two distinct assays to demonstrate that ExoS inhibited phagocytosis during pneumonia. In contrast to the findings of several in vitro studies, this in vivo inhibition was also dependent on the ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS. These results demonstrate for the first time the antiphagocytic function of ExoS in the context of an actual infection and indicate that blocking the ADP-ribosyltransferase activity of ExoS may have potential therapeutic benefit. IMPORTANCE Pseudomonas aeruginosa is a major cause of hospital-acquired infections. To cause severe disease, this bacterium uses a type III secretion system that delivers four effector proteins, ExoS, ExoT, ExoU, and ExoY, into host cells. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. In cell culture models, both enzymatic activities have been associated with decreased bacterial internalization. However, our study is the first to examine a role for ExoS in blocking phagocytosis in an animal model. We report that ExoS does inhibit phagocytosis during pneumonia. The ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS is necessary for this effect. Our findings highlight the ability of P. aeruginosa to manipulate the inflammatory response during pneumonia to facilitate bacterial survival. Pseudomonas aeruginosa is a major cause of hospital-acquired infections. To cause severe disease, this bacterium uses a type III secretion system that delivers four effector proteins, ExoS, ExoT, ExoU, and ExoY, into host cells. The majority of P. aeruginosa strains secrete ExoS, a bifunctional toxin with GTPase-activating protein and ADP-ribosyltransferase activities. In cell culture models, both enzymatic activities have been associated with decreased bacterial internalization. However, our study is the first to examine a role for ExoS in blocking phagocytosis in an animal model. We report that ExoS does inhibit phagocytosis during pneumonia. The ADP-ribosyltransferase activity, but not the GTPase-activating protein activity, of ExoS is necessary for this effect. Our findings highlight the ability of P. aeruginosa to manipulate the inflammatory response during pneumonia to facilitate bacterial survival.

Ventilator-Associated Events in Neonates and Children--A New Paradigm.

Objectives:To identify a pediatric ventilator-associated condition definition for use in neonates and children by exploring whether potential ventilator-associated condition definitions identify patients with worse outcomes. Design:Retrospective cohort study and a matched cohort analysis. Setting:Pediatric, cardiac, and neonatal ICUs in five U.S. hospitals. Patients:Children 18 years old or younger ventilated for at least 1 day. Interventions:None. Measurements and Main Results:We evaluated the evidence of worsening oxygenation via a range of thresholds for increases in daily minimum fraction of inspired oxygen (by 0.20, 0.25, and 0.30) and daily minimum mean airway pressure (by 4, 5, 6, and 7 cm H2O). We required worsening oxygenation be sustained for at least 2 days after at least 2 days of stability. We matched patients with a ventilator-associated condition to those without and used Cox proportional hazard models with frailties to examine associations with hospital mortality, hospital and ICU length of stay, and duration of ventilation. The cohort included 8,862 children with 10,209 hospitalizations and 77,751 ventilator days. For the fraction of inspired oxygen 0.25/mean airway pressure 4 definition (i.e., increase in minimum daily fraction of inspired oxygen by 0.25 or mean airway pressure by 4), rates ranged from 2.9 to 3.2 per 1,000 ventilator days depending on ICU type; the fraction of inspired oxygen 0.30/mean airway pressure 7 definition yielded ventilator-associated condition rates of 1.1–1.3 per 1,000 ventilator days. All definitions were significantly associated with greater risk of hospital death, with hazard ratios ranging from 1.6 (95% CI, 0.7–3.4) to 6.8 (2.9–16.0), depending on thresholds and ICU type. Each definition was associated with prolonged hospitalization, time in ICU, and duration of ventilation, among survivors. The advisory board of the study proposed using the fraction of inspired oxygen 0.25/mean airway pressure 4 thresholds to identify pediatric ventilator-associated conditions in ICUs. Conclusions:Pediatric patients with ventilator-associated conditions are at substantially higher risk for mortality and morbidity across ICUs, regardless of thresholds used. Next steps include identification of risk factors, etiologies, and preventative measures for pediatric ventilator-associated conditions.

A multicenter retrospective study of childhood brucellosis in Chicago, Illinois from 1986 to 2008.

OBJECTIVES To determine risk factors in children for the acquisition of Brucella, clinical presentation, treatment, and disease outcomes. METHODS A retrospective multicenter chart review was undertaken of children identified with brucellosis from 1986 to 2008 at three tertiary care centers in Chicago, Illinois, USA. The charts were reviewed for data regarding risk factors for acquisition, clinical presentation, and outcomes. RESULTS Twenty-one charts were available for review. The median age was 6.5 years (range 2-14 years); 62% were female. Ethnic background was 67% Hispanic and 24% Arabic. Risk factors included travel to an endemic area (86%), particularly Mexico, and consumption of unpasteurized milk products (76%). Common findings included fever (95%), bacteremia (86%), elevated liver transaminases (80%), constitutional symptoms (76%), splenomegaly (60%), and hepatomegaly (55%). Relapse occurred in three of six subjects started on single drug treatment, but in only one of 15 subjects who started on two or more drugs (p=0.053). No relapses occurred in children whose initial therapy included rifampin or those administered three-drug regimens. CONCLUSIONS Brucella is an infrequent pathogen but should be considered in children with compatible epidemiologic and clinical characteristics. Blood cultures should be obtained, and initial therapy with two or more drugs may decrease the risk of relapse.