Urgent Public Health Threat Research Articles

Evaluation of ceftazidime/avibactam for treatment of carbapenemase-producing carbapenem-resistant Enterobacterales with OXA-48 and/or NDM genes with or without combination therapy.

BackgroundCarbapenem-resistant Enterobacterales (CRE) is an urgent public health threat of significant global concern. Few observational studies have evaluated the clinical outcomes for treatment of CRE harbouring OXA-48 or NDM genes with ceftazidime/avibactam. Previous findings showed lower 30 day mortality with ceftazidime/avibactam ranges between 8.3% and 22%.MethodThis single-centre retrospective cohort study included adult patients aged ≥18 years admitted to King Abdulaziz Medical City (KAMC) who had received ceftazidime/avibactam for at least 72 h for infections caused by CRE with genes encoding for carbapenemase production (CP-CRE).ResultsA total of 211 patients, mostly male (57%), having CP-CRE infections treated with ceftazidime/avibactam were included, with an average age of 62 years. More than 50% of patients were critically ill, for which 46% received invasive ventilation and 36% were on inotropes. The most frequent infectious disease was hospital/ventilator-acquired pneumonia with Klebsiella pneumoniae being the most frequent causative pathogen. The majority of isolates harboured OXA-48 (81%), followed by NDM ± OXA-48 (19%). The overall clinical cure and 30 day mortality was 78% and 21% respectively (stratified per gene: 79% and 21.6% for OXA-48 and 75% and 17.5% for NDM ± OXA-48).ConclusionsThis was the largest study that evaluated clinical outcomes associate with CP-CRE harbouring OXA-48 gene infections treated with ceftazidime/avibactam. Clinical cure and 30 day mortality were consistent with those of previous studies. Findings suggested that combination therapy with ceftazidime/avibactam had no direct impact on clinical outcomes for CP-CRE with OXA-48.

Optimal ceftazidime/avibactam dosing exposure against KPC-producing Klebsiella pneumoniae.

Infections due to carbapenem-resistant Enterobacterales are considered urgent public health threats and often treated with a β-lactam/β-lactamase inhibitor combination. However, clinical treatment failure and resistance emergence have been attributed to inadequate dosing. We used a novel framework to provide insights of optimal dosing exposure of ceftazidime/avibactam. Seven clinical isolates of Klebsiella pneumoniae producing different KPC variants were examined. Ceftazidime susceptibility (MIC) was determined by broth dilution using escalating concentrations of avibactam. The observed MICs were characterized as response to avibactam concentrations using an inhibitory sigmoid Emax model. Using the best-fit parameter values, %fT>MICi was estimated for various dosing regimens of ceftazidime/avibactam. A hollow-fibre infection model (HFIM) was subsequently used to ascertain the effectiveness of selected regimens over 120 h. The drug exposure threshold associated with bacterial suppression was identified by recursive partitioning. In all scenarios, ceftazidime MIC reductions were well characterized with increasing avibactam concentrations. In HFIM, bacterial regrowth over time correlated with emergence of resistance. Overall, suppression of bacterial regrowth was associated with %fT>MICi ≥ 76.1% (100% versus 18.2%; P < 0.001). Using our framework, the optimal drug exposure could be achieved with ceftazidime/avibactam 2.5 g every 12 h in 5 out of 7 isolates. Furthermore, ceftazidime/avibactam 2.5 g every 8 h can suppress an isolate deemed resistant based on conventional susceptibility testing method. An optimal drug exposure to suppress KPC-producing bacteria was identified. The novel framework is informative and may be used to guide optimal dosing of other β-lactam/β-lactamase inhibitor combinations. Further in vivo investigations are warranted.

Health care consequences of hospitalization with Clostrioides difficile infection: a propensity score matching study

BackgroundClostridiodies difficile infection (CDI) has been characterized by the Center for Disease Control and Prevention (CDC) as an urgent public health threat and a major concern in hospital, outpatient and extended-care facilities worldwide.MethodsA retrospective cohort study of patients aged ≥ 18 hospitalized with CDI in New York State (NYS) between January 1, 2014–December 31, 2016. Data were extracted from NY Statewide Planning and Research Cooperative (SPARCS) and propensity score matching was performed to achieve comparability of the CDI (exposure) and non-CDI (non-exposure) groups. Of the 3,714,486 hospitalizations, 28,874 incidence CDI cases were successfully matched to 28,874 non-exposures.ResultsThe matched pairs comparison demonstrated that CDI cases were more likely to be readmitted to the hospital at 30 (28.26% vs. 19.46%), 60 (37.65% vs. 26.02%), 90 (42.93% vs. 30.43) and 120 days (46.47% vs. 33.74), had greater mortality rates at 7 (3.68% vs. 2.0%) and 180 days (20.54% vs. 11.96%), with significant increases in length of stay and total hospital charges (p < .001, respectively).ConclusionsCDI is associated with a large burden on patients and health care systems, significantly increasing hospital utilization, costs and mortality.

TP0586532, a Novel Non-Hydroxamate LpxC Inhibitor: Potentiating Effect on In Vitro Activity of Meropenem against Carbapenem-Resistant Enterobacteriaceae.

ABSTRACTCarbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat to public health requiring the development of novel therapies. TP0586532 is a novel non-hydroxamate LpxC inhibitor that inhibits the synthesis of lipopolysaccharides, which are components of the outer membranes of Gram-negative bacteria. Based on the mechanism of action of TP0586532, we hypothesized that it might enhance the antibacterial activity of other antibiotics by increasing the permeability of the outer bacterial membrane. The combination of TP0586532 with meropenem, amikacin, cefepime, piperacillin, and tigecycline showed synergistic and additive effects against carbapenem-susceptible Klebsiella pneumoniae and Escherichia coli. Checkerboard experiments against 21 carbapenem-resistant K. pneumoniae and E. coli strains (13 blaKPC+, 5 blaNDM-1+, 2 blaVIM+, and 1 blaIMP+) showed that the combination of TP0586532 with meropenem yielded synergistic and additive effects against 9 and 12 strains, respectively. In a time-kill assay examining 12 CRE strains, synergistic effects were observed when TP0586532 was combined with meropenem against many of the strains. A membrane permeability assay using ethidium bromide (EtBr) was performed to investigate the mechanism of the potentiating effect. TP0586532 increased the influx of EtBr into a CRE strain, suggesting that TP0586532 increased membrane permeability and facilitated intracellular access for the antibiotics. Our study demonstrates that TP0586532 potentiates the in vitro antibacterial activity of meropenem against CRE. Combination therapy consisting of TP0586532 and meropenem has potential as a treatment for CRE infections.IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent public health threat, as therapeutic options are limited. TP0586532 is a novel LpxC inhibitor that inhibits the synthesis of lipopolysaccharides in the outer membranes of Gram-negative bacteria. Here, we demonstrated the potentiating effects of TP0586532 on the antibacterial activity of meropenem against CRE harboring various types of carbapenemase genes (blaKPC+, blaNDM-1+ blaVIM+, and blaIMP+). TP0586532 also augmented the bactericidal effects of meropenem against CRE strains, even against those with a high level of resistance to meropenem. The potentiating effects were suggested to be mediated by an increase in bacterial membrane permeability. Our study revealed that a combination therapy consisting of TP0586532 and meropenem has the potential to be a novel therapeutic option for CRE infections.

Mortality rates among non-Hispanic Black and White persons in carbapenemase-producing Enterobacterales, Tennessee, 2015–2019

Background: Carbapenem-resistant Enterobacterales (CRE) are an urgent public health threat, particularly those that produce carbapenemase (CP-CRE). Certain risk factors associated with CRE acquisition have been well described, such as older age, indwelling devices, prior hospitalizations, and underlying conditions. However, data are limited regarding the association of CRE and health disparities, such as race and ethnicity. Published literature has consistently shown that minority groups, including but not limited to Non-Hispanic Black persons, have higher risks of developing adverse health outcomes. To better understand the impact of race and ethnicity in CP-CRE cases, we compared 1-year mortality rates among Non-Hispanic Blacks and Non-Hispanic Whites. Methods: CRE are reportable in Tennessee; isolates must be sent to the State Public Health Laboratory for carbapenemase detection and resistance mechanism testing. We linked 2015–2019 CP-CRE surveillance cases and laboratory data from our statewide surveillance system, the National Disease Surveillance System (NEDDS)-Base System, with the Tennessee Hospital Discharge Data System (HDDS) and vital records databases. Database linkage and data analyses were performed using SAS version 9.4 software. Results: Among 615 CP-CRE cases, the mean age was lower among non-Hispanic Blacks (59 years; SD, 16.6) compared to non-Hispanic Whites (mean, 65 years; SD, 15.7). Among 156 non-Hispanic Blacks with CP-CRE, 101 (64.7%) were nursing home residents, whereas 281 (71.1%) among the 395 non-Hispanic Whites were nursing home residents. Also, 64 Non-Hispanic Blacks (41%) died within 1 year of their first specimen collection date compared to 92 Non-Hispanic Whites (23.3%). Non-Hispanic Blacks with CP-CRE who died within 1 year had a mortality rate of 5.6 per 100,000 (95% CI, 4.21–6.94) Black population, which was 1.6 times higher than Non-Hispanic White persons at 3.5 per 100,000 (95% CI, 2.94–3.95; χ2P &lt; .001) White population. Conclusions: Despite a lower mean age, non-Hispanic Black CP-CRE cases had a higher 1-year mortality rate than non-Hispanic Whites. Racial and ethnicity data often are missing or incomplete from surveillance data. Data linkages can be a valuable tool to gather additional clinical and demographic data that may be missing from public health surveillance data to improve our understanding of health disparities. Recognition of these health disparities among CRE can provide an opportunity for public health to create more targeted interventions and educational outreach.Funding: NoneDisclosures: None

Outbreak investigation of CRAB at an acute-care hospital ICU during the COVID-19 pandemic–Chicago, Illinois, March 2020–September 2021

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) is primarily associated with hospital-acquired infections and is an urgent public health threat due to its ability to contaminate the environment and cause severe disease. In 2019, Illinois began pilot surveillance for CRAB requiring select laboratories to submit specimens for molecular characterization. On July 17, 2020, the Chicago Department of Public Health (CDPH) was notified of an increase in CRAB infections in a 20-bed ICU at an acute-care hospital in Chicago (hospital A) during the initial COVID-19 surge. We summarize the outbreak investigation findings and infection control recommendations. Methods: Clinical cultures were collected from patients in hospital A, and CRAB-positive isolates were sent to the Wisconsin State Laboratory of Hygiene for mechanism of resistance and antibiotic susceptibility testing. On-site assessments and remote follow-ups were conducted by CDPH infection preventionists to evaluate infection control practices including environmental cleaning, hand hygiene compliance, and use of personal protective equipment (PPE). The Illinois Department of Public Health and CDPH summarized the testing results, facilitated a containment response, and provided recommendations for infection control. Results: From March 18, 2020, to September 30, 2021, 56 patients with CRAB infections were identified from hospital A, and 33 (59%) of these cases were pan-nonsusceptible. Most specimen sources were sputum (n = 30, 54%), followed by blood (n = 13, 23%), urine (n = 6, 11%) and other (n = 7, 13%). Among isolates with mechanism testing (n = 54), 45 (83%) were positive for OXA-24/40 and 9 (17%) were positive for OXA-23. Of the CRAB-positive patients, 28 (50%) were previously positive for SARS-CoV-2. To date, 25 of these patients (45%) have been discharged and 31 (55%) have died. Two onsite visits and 7 remote-assistance sessions were conducted as part of the investigation. In response to increased COVID-19 hospitalizations, hospital A moved to crisis-capacity PPE use and encountered staffing shortages, which led to compromised infection control measures. Cleaning agents (Quat disinfectant cleaner) were also found to be ineffective against CRAB and required long contact times. Conclusions: In response to the CRAB outbreak at hospital A, CDPH recommended that the hospital stop crisis-capacity protocols for PPE, conduct admission screening and point-prevalence testing for CRAB, implement a hand hygiene campaign, and use an EPA-registered List K product for environmental cleaning. These recommendations were implemented in May 2021, and no CRAB cases have been reported since July 2021. To reduce CRAB transmission during the pandemic, facility leadership must commit resources to educate staff on effective infection control practices including conventional use of PPE, appropriate cleaning agents, and improved hand hygiene.Funding: NoneDisclosures: None

Screening for Antibacterial Activity of Chemical Extracts from Puerto Rican Plants.

Antibiotic resistance is one of the world’s most urgent public health threats. According to the Centers for Disease Control and Prevention, at least 2.8 million people get an antibiotic-resistant infection each year, and more than 35,000 people die in the United States from these infections. The development of new antibiotics is essential to combat this crisis and prevent the loss of additional lives. Natural products have historically been an essential source for the discovery of novel antibacterial agents. Furthermore, several studies have shown Puerto Rican plant extracts possess biologically active compounds. Therefore, we sought to determine whether extracts derived from Puerto Rican plants have broad-spectrum antimicrobial activity against a variety of pathogenic bacteria. Using a broth microdilution assay, we screened thirteen extracts generated from different plant species for antibacterial activity. Each extract was tested against the ESKAPE pathogens, Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp, which are known to exhibit multidrug resistance. All extracts tested thus far were ineffective at inhibiting bacterial growth with the exception of the Bucida buceras leaf extract which showed broad spectrum antibacterial activity against E. faecalis, K. pneumoniae, and E. aerogenes. We are currently validating the antimicrobial activity of B. buceras extract through other antibiotic susceptibility assays. Here, we have shown that Puerto Rican plants have potential as a source of novel antimicrobial agents.

Accessory Genomes Drive Independent Spread of Carbapenem-Resistant Klebsiella pneumoniae Clonal Groups 258 and 307 in Houston, TX.

ABSTRACTCarbapenem-resistant Klebsiella pneumoniae (CRKp) is an urgent public health threat. Worldwide dissemination of CRKp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CRKp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 (CRACKLE-2) study. Hybrid short-read and long-read genome assemblies were generated from 119 CRKp isolates (95 originated from Houston hospitals). A comprehensive characterization of phylogenies, gene transfer, and plasmid content with pan-genome analysis was performed on all CRKp isolates. Plasmid mating experiments were performed with CG307 and CG258 isolates of interest. Dissection of the accessory genomes suggested independent evolution and limited horizontal gene transfer between CG307 and CG258 lineages. CG307 contained a diverse repertoire of mobile genetic elements, which were shared with other non-CG258 K. pneumoniae isolates. Three unique clades of Houston CG307 isolates clustered distinctly from other global CG307 isolates, indicating potential selective adaptation of particular CG307 lineages to their respective geographical niches. CG307 strains were often isolated from the urine of hospitalized patients, likely serving as important reservoirs for genes encoding carbapenemases and extended-spectrum β-lactamases. Our findings suggest parallel cocirculation of high-risk lineages with potentially divergent evolution.

Loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae: a genome-wide association study

SummaryBackgroundNeisseria gonorrhoeae poses an urgent public health threat because of increasing antimicrobial resistance; however, much of the circulating population remains susceptible to historical treatment regimens. Point-of-care diagnostics that report susceptibility could allow for reintroduction of these regimens, but development of such diagnostics has been restricted to ciprofloxacin, for which susceptibility can be predicted from a single locus. We aimed to define genetic variants associated with susceptibility to penicillin and tetracycline.MethodsWe collected publicly available global whole-genome sequencing data (n=12 045) from clinical N gonorrhoeae isolates, with phenotypic resistance data for penicillin (n=6935), and tetracycline (n=5727). Using conditional genome-wide association studies, we defined genetic variants associated with susceptibility to penicillin and tetracycline. We excluded isolates that could not be classified as either susceptible or resistant. To validate our results, we assembled 1479 genomes from the US Centers for Disease Control and Prevention (CDC)’s Gonococcal Isolate Surveillance Project, for which urethral specimens are collected at sentinel surveillance sites across the USA. We evaluated the sensitivity and specificity of susceptibility-associated alleles using Clinical & Laboratory Standards Institute breakpoints for susceptibility and non-resistance in both the global and validation datasets.FindingsIn our conditional penicillin genome-wide association study, the presence of a genetic variant defined by a non-mosaic penA allele without an insertion at codon 345 was associated with penicillin susceptibility and had the highest negative effect size (β) of significant variants (p=5·0×10–14, β –2·5). In combination with the absence of blaTEM, this variant predicted penicillin susceptibility with high specificity (99·8%) and modest sensitivity (36·7%). For tetracycline, the wildtype allele at rpsJ codon 57, encoding valine, was associated with tetracycline susceptibility (p=5·6×10–16, β –1·6) after conditioning on the presence of tetM. The combination of rpsJ codon 57 allele and tetM absence predicted tetracycline susceptibility with high specificity (97·2%) and sensitivity (88·7%).InterpretationAs few as two genetic loci can predict susceptibility to penicillin and tetracycline in N gonorrhoeae with high specificity. Molecular point-of-care diagnostics targeting these loci have the potential to increase available treatments for gonorrhoea.FundingNational Institute of Allergy and Infectious Diseases, the National Science Foundation, and the Smith Family Foundation.

Molecular Detection and Antibiogram of ESBL-Producing and Carbapenem-Resistant Escherichia coli from Rabbit, Swine, and Poultry in Malaysia

The emergence of multidrug-resistance Enterobacteriaceae such as extended-spectrum β-lactamase (ESBL) producing Escherichia coli ( E. coli ) and carbapenem-resistant E. coli (CREC) has become an urgent veterinary and public health threat. These multidrug-resistant microorganisms are frequently associated with diseases that have high mortality with limited treatment options. This study aims to investigate the prevalence of ESBL producing E. coli and CREC from the rabbit, swine, and poultry and to determine the antibiogram profile of these E. coli isolates. In this study, 400 fecal swab samples were collected from rabbits, swine, and poultry from several selected animal farms in Malaysia. After incubation and isolation processes, suspected E. coli isolates were subjected to a PCR test to confirm the identity of the bacteria. The antibiogram of the E. coli isolates was determined via the Kirby Bauer disk diffusion method. A total of 212 (53%) E. coli isolates were isolated from rabbits (51 isolates), poultry (110 isolates), and swine (51 isolates). Screening of antimicrobial resistance genes revealed twelve ESBL producing E. coli (3%; 12/400). Two ESBL producing E. coli were also carrying carbapenemase gene (BlaNDM), indicating ESBL producing and carbapenem-resistant E. coli (ESBL-CREC) in poultry fecal swab samples. The bacteria isolates were found to show resistance against nine antibiotics, including ertapenem, ampicillin, and amoxicillin-clavulanate. A total of 3.3% (7/212) of the E. coli isolates were found to be multidrug-resistance. This study demonstrated the presence of ESBL-producing E. coli and ESBL-producing CREC from poultry fecal swabs in Malaysia.

High Prevalence of Klebsiella pneumoniae in European Food Products: a Multicentric Study Comparing Culture and Molecular Detection Methods.

ABSTRACTThe Klebsiella pneumoniae species complex (KpSC) is a leading cause of multidrug-resistant human infections. To better understand the potential contribution of food as a vehicle of KpSC, we conducted a multicentric study to define an optimal culture method for its recovery from food matrices and to characterize food isolates phenotypically and genotypically. Chicken meat (n = 160) and salad (n = 145) samples were collected in five European countries and screened for the presence of KpSC using culture-based and zur-khe intergenic region (ZKIR) quantitative PCR (qPCR) methods. Enrichment using buffered peptone water followed by streaking on Simmons citrate agar with inositol (44°C for 48 h) was defined as the most suitable selective culture method for KpSC recovery. A high prevalence of KpSC was found in chicken meat (60% and 52% by ZKIR qPCR and the culture approach, respectively) and salad (30% and 21%, respectively) samples. Genomic analyses revealed high genetic diversity with the dominance of phylogroups Kp1 (91%) and Kp3 (6%). A total of 82% of isolates presented a natural antimicrobial susceptibility phenotype and genotype, with only four CTX-M-15-producing isolates detected. Notably, identical genotypes were found across samples—same food type and same country (15 cases), different food types and same country (1), and same food type and two countries (1)—suggesting high rates of transmission of KpSC within the food sector. Our study provides a novel isolation strategy for KpSC from food matrices and reinforces the view of food as a potential source of KpSC colonization in humans.IMPORTANCE Bacteria of the Klebsiella pneumoniae species complex (KpSC) are ubiquitous, and K. pneumoniae is a leading cause of antibiotic-resistant infections in humans. Despite the urgent public health threat represented by K. pneumoniae, there is a lack of knowledge of the contribution of food sources to colonization and subsequent infection in humans. This is partly due to the absence of standardized methods for characterizing the presence of KpSC in food matrices. Our multicentric study provides and implements a novel isolation strategy for KpSC from food matrices and shows that KpSC members are highly prevalent in salads and chicken meat, reinforcing the view of food as a potential source of KpSC colonization in humans. Despite the large genetic diversity and the low levels of resistance detected, the occurrence of identical genotypes across samples suggests high rates of transmission of KpSC within the food sector, which need to be further explored to define possible control strategies.

In vivo efficacy of acetazolamide in a mouse model of Neisseria gonorrhoeae infection

Gonococcal infections represent an urgent public health threat worldwide due to the increasing incidence of infections that has been accompanied by an increase in bacterial resistance to most antibiotics. This has resulted in a dwindling number of effective treatment options. Undoubtedly, there is a critical need to develop new, effective anti-gonococcal agents. In an effort to discover new anti-gonococcal therapeutics, we previously identified acetazolamide, a carbonic anhydrase inhibitor, as a novel inhibitor of Neisseria gonorrhoeae. Acetazolamide exhibited potent anti-gonococcal activity in vitro as it inhibited growth of strains of N. gonorrhoeae at concentrations that ranged from 0.5 to 4 μg/mL. The aim of this study was to investigate the in vivo efficacy of acetazolamide in a mouse model of N. gonorrhoeae genital tract infection. Compared to vehicle-treated mice, acetazolamide significantly reduced the gonococcal burden by 90% in the vagina of infected mice after three days of treatment. These results indicate that acetazolamide warrants further investigation as a promising treatment option to supplement the limited pipeline of anti-gonococcal therapeutics.

Identifying Higher-Volume Antibiotic Outpatient Prescribers Using Publicly Available Medicare Part D Data - United States, 2019.

Antibiotic prescribing can lead to adverse drug events and antibiotic resistance, which pose ongoing urgent public health threats (1). Adults aged ≥65 years (older adults) are recipients of the highest rates of outpatient antibiotic prescribing and are at increased risk for antibiotic-related adverse events, including Clostridioides difficile and antibiotic-resistant infections and related deaths (1). Variation in antibiotic prescribing quality is primarily driven by prescribing patterns of individual health care providers, independent of patients' underlying comorbidities and diagnoses (2). Engaging higher-volume prescribers (the top 10% of prescribers by antibiotic volume) in antibiotic stewardship interventions, such as peer comparison audit and feedback in which health care providers receive data on their prescribing performance compared with that of other health care providers, has been effective in reducing antibiotic prescribing in outpatient settings and can be implemented on a large scale (3-5). This study analyzed data from the Centers for Medicare & Medicaid Services (CMS) Part D Prescriber Public Use Files (PUFs)* to describe higher-volume antibiotic prescribers in outpatient settings compared with lower-volume prescribers (the lower 90% of prescribers by antibiotic volume). Among the 59.4 million antibiotic prescriptions during 2019, 41% (24.4 million) were prescribed by the top 10% of prescribers (69,835). The antibiotic prescribing rate of these higher-volume prescribers (680 prescriptions per 1,000 beneficiaries) was 60% higher than that of lower-volume prescribers (426 prescriptions per 1,000 beneficiaries). Identifying health care providers responsible for a higher volume of antibiotic prescribing could provide a basis for additional assessment of appropriateness and outreach. Public health organizations and health care systems can use publicly available data to guide focused interventions to optimize antibiotic prescribing to limit the emergence of antibiotic resistance and improve patient outcomes.

A Survey of Current Activities and Technologies Used to Detect Carbapenem Resistance in Bacteria Isolated from Companion Animals at Veterinary Diagnostic Laboratories-United States, 2020.

Carbapenems are antimicrobial drugs reserved for the treatment of severe multidrug-resistant Gram-negative bacterial infections. Carbapenem-resistant organisms (CROs) are an urgent public health threat and have been made reportable to public health authorities in many jurisdictions. Recent reports of CROs in companion animals and veterinary settings suggest that CROs are a One Health problem. However, standard practices of U.S. veterinary diagnostic laboratories (VDLs) to detect CROs are unknown. We assessed the capacity of VDLs to characterize carbapenem resistance in isolates from companion animals. Among 74 VDLs surveyed in 42 states, 23 laboratories (31%) from 22 states responded. Most (22/23, 96%) included ≥1 carbapenem on their primary antimicrobial susceptibility testing panel, and approximately one-third (9/23, 39%) performed phenotypic carbapenemase production testing or molecular identification of carbapenemase genes. Overall, 35% (8/23) of VDLs across eight states reported they would notify public health if a CRO was detected. Most (17/21, 81%) VDLs were not aware of CRO reporting mandates, and some expressed uncertainty about whether the scope of known mandates included CROs from veterinary sources. Although nearly all surveyed VDLs tested for carbapenem resistance, fewer had the capacity for mechanism testing or awareness of public health reporting requirements. Addressing these gaps is critical to monitoring CRO incidence and trends in veterinary medicine, preventing spread in veterinary settings, and mounting an effective One Health response. Improved collaboration and communication between public health and veterinary medicine is critical to inform infection control practices in veterinary settings and conduct a public health response when resistant isolates are detected.

MycoSNP: A Portable Workflow for Performing Whole-Genome Sequencing Analysis of Candida auris.

Candida auris is an urgent public health threat characterized by high drug-resistant rates and rapid spread in healthcare settings worldwide. As part of the C. auris response, molecular surveillance has helped public health officials track the global spread and investigate local outbreaks. Here, we describe whole-genome sequencing analysis methods used for routine C. auris molecular surveillance in the United States; methods include reference selection, reference preparation, quality assessment and control of sequencing reads, read alignment, and single-nucleotide polymorphism calling and filtration. We also describe the newly developed pipeline MycoSNP, a portable workflow for performing whole-genome sequencing analysis of fungal organisms including C. auris.

Use of hospital resources in ICU inpatients with infections caused by carbapenem-resistant Gram-negative bacteria: A real clinical practice-based study in Spain

IntroductionCarbapenem-resistant Gram-negative bacteria (CRGN) are an urgent public health threat because of the limited treatment options, its rapid spreading and high clinical impact and mortality rates. However, the burden and the use of resources of these infections have not been investigated. The aim of the current study is to understand the use of resources associated to the clinical management of CRGN infections in real clinical practice conditions. MethodsAn observational retrospective chart review study was performed. Data regarding patient demographics, clinical management and use of resources associated to hospitalization were retrieved from clinical charts of ICU inpatients with a confirmed CRGN infection. Three reference Spanish hospitals were selected according to their patient volume and geographical coverage. Descriptive analyses of the clinical management and the use of resources and its cost were performed and then total costs by type of resource were calculated. ResultsA total of 130 patients were included in the study. The higher number of patients (n=43; 33%) were between 61 and 70 years old. Ninety-four (72%) patients were male and 115 (88%) suffered from comorbidities. The mean total cost associated to the resources used in patients with CRGN infections hospitalized in ICU was 96,878€ per patient. These total costs included 84,140€ of total hospital stay, 11,021€ of treatments (558€ of antibiotics; 10,463€ of other treatments) and 1717€ costs of diagnostic tests. ConclusionsCRGN infection causes a high use of hospital resources, being the length of stay either in hospital wards or ICU the driver of the total costs. Diagnostic tests and treatments, including antibiotics, represent the lowest part of the use of resources and costs (13% of total costs).

Socioeconomic Burden of Bloodstream Infections Caused by Carbapenem-Resistant Enterobacteriaceae.

BackgroundAlthough infection with carbapenem-resistant Enterobacteriaceae (CRE) has become an urgent public health threat worldwide, the socioeconomic burden of CRE bloodstream infection (BSI) remains to be clarified.MethodsThis retrospective study included all patients infected with Escherichia coli or Klebsiella pneumoniae who were hospitalized for BSI from 2013 to 2015. Socioeconomic burden, including direct and indirect economic burden, was compared in patients infected with carbapenem-sensitive Enterobacteriaceae (CSE) and CRE following 1:1 propensity score matching (PSM) to control for confounding variables.ResultsData from 879 patients with Enterobacteriaceae BSI were evaluated, including 152 (17.3%) patients infected with CRE and 727 (82.7%) infected with CSE. PSM yielded 112 pairs of 224 patients. Median hospital length of stay did not differ significantly in the CRE and CSE groups (35 vs 29 days, P = 0.089), but in-hospital 28-day mortality rate was significantly higher in patients infected with CRE than with CSE (45.5% vs 32.1%, P = 0.040). Median direct economic burden was significantly greater in patients with CRE-BSI than with CSE-BSI during hospitalization ($24,940.1 vs 16,864.0, P = 0.017) but not during the period after infection ($10,403.4 vs 8498.0, P = 0.178). Drug expenditure accounted for the largest proportion of costs in both groups. The median disability-adjusted life year (DALY) was higher in CRE-BSI than in CSE-BSI patients, but the difference was not statistically significant (7.9 vs 6.7 years, P = 0.190). Median indirect economic burden did not differ significantly in these two groups ($3848.5 vs 1139.9, P = 0.304), although indirect economic burden increased significantly from 2013 to 2015 in patients with CRE-BSI.ConclusionCarbapenem resistance had a major impact on the clinical and socioeconomic burden of patients with Enterobacteriaceae BSI. The higher mortality rate in patients with CRE-BSI was associated with increased direct healthcare burden and indirect socioeconomic loss.

A host-directed macrocyclic peptide therapeutic for MDR gram negative bacterial infections

The emergence of infections by carbapenem resistant Enterobacteriaceae (CRE) pathogens has created an urgent public health threat, as carbapenems are among the drugs of last resort for infections caused by a growing fraction of multi-drug resistant (MDR) bacteria. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. Here, we report on the efficacy of a novel macrocyclic peptide, minimized theta-defensin (MTD)-12813 in CRE sepsis. MTD12813 is a theta-defensin inspired cyclic peptide that is highly effective against CRE pathogens K. pneumoniae and E. coli in vivo. In mouse septicemia models, single dose administration of MTD12813 significantly enhanced survival by promoting rapid host-mediated bacterial clearance and by modulating pathologic cytokine responses, restoring immune homeostasis, and preventing lethal septic shock. The peptide lacks direct antibacterial activity in the presence of mouse serum or in peritoneal fluid, further evidence for its indirect antibacterial mode of action. MTD12813 is highly stable in biological matrices, resistant to bacterial proteases, and nontoxic to mice at dose levels 100 times the therapeutic dose level, properties which support further development of the peptide as a first in class anti-infective therapeutic.

Regional differences in carbapenem-resistant Klebsiella pneumoniae

Klebsiella pneumoniae is a major cause of health care-associated infections worldwide and a well known contributor to the global antimicrobial resistance crisis. Carbapenem-resistant K pneumoniae (CRKP) is considered an urgent public health threat, and has been identified by WHO as a crucial priority for the development of novel control strategies. Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort studyGlobal CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. Full-Text PDF

Antimicrobial susceptibility testing of Neisseria gonorrhoeae using a phenotypic-molecular assay and lyophilized antimicrobials

Gonorrhea is an urgent global public health threat as Neisseria gonorrhoeae (Ng) has progressively developed resistance to all antibiotics commonly used for treatment. Surveillance of antimicrobial susceptibility trends is critical to monitor the emergence and spread of antimicrobial resistance. The gold standard methods for antimicrobial susceptibility testing (AST) of Ng are laborious and time-consuming. We evaluated a phenotypic molecular approach, involving a short cultivation step and quantitative PCR, with lyophilized antimicrobials to characterize antimicrobial susceptibility in Ng. There was excellent concordance between AST performed with liquid and lyophilized ciprofloxacin, penicillin, and tetracycline using the pheno-molecular assay, following a 4-hour incubation step. The categorical agreement between the pheno-molecular assay and the gold standard AST results was 92.4% for characterization of antimicrobial susceptibility. Essential agreement between the 2 methods was 91.9%. Characterization of ceftriaxone susceptibility in Ng using the pheno-molecular assay required a 6-hour incubation step.