In vitro activity of cefepime-taniborbactam against carbapenemase producing Enterobacterales and Pseudomonas aeruginosa isolates recovered in Spain

Novel β-lactam-β-lactamase inhibitor combinations currently approved for clinical use are poorly active against metallo-β-lactamase (MBL)-producing strains. We evaluated the in vitro activity of cefepime-taniborbactam (FTB, formerly cefepime/VNRX-5133) and comparator agents against carbapenemase-producing Enterobacterales (n=247) and carbapenem-resistant Pseudomonas spp. (n=170) clinical isolates prospectively collected from different clinical origin in patients admitted to 8 Spanish hospitals. FTB was the most active agent in both Enterobacterales (97.6% MIC FTB ≤8/4 mg/L) and Pseudomonas populations (67.1% MIC FTB ≤8/4 mg/L). MIC FTB was >8 mg/L in 6/247 (2.4%) Enterobacterales isolates (3 KPC- Klebsiella pneumoniae , 1 VIM- Enterobacter cloacae , 1 IMP- E. cloacae and 1 NDM- Escherichia coli ) and in 56/170 (32.9%) Pseudomonas spp., 19 of them carbapenemase producers (15 VIM, 2 GES, 1 GES+VIM, 1 GES+KPC). Against the Enterobacterales isolates with meropenem MIC>2 mg/L (138/247), FTB was the most active agent against both serine-β-lactamases (107/138) and MBL producers (31/138) (97.2% and 93.5% MIC FTB ≤8/4 mg/L, respectively) whereas the activity of comparators was reduced, particularly against the MBL producers (ceftazidime-avibactam, 94.4% and 12.9%; meropenem-vaborbactam, 85.0% and 64.5%; imipenem-relebactam, 76.6% and 9.7%; ceftolozane-tazobactam, 1.9% and 0%; piperacillin-tazobactam, 0% and 0%, respectively). Among the meropenem-resistant Pseudomonas spp. isolates (163/170, MIC>2 mg/L), activity of FTB against serine-β-lactamase (35/163) and MBL producers (43/163) was 88.6% and 65.1%, respectively, whereas the susceptibility of comparators was: ceftazidime-avibactam, 88.5% and 16.0%; meropenem-vaborbactam, 8.5% and 7.0%; imipenem-relebactam, 2.9% and 2.3%; ceftolozane-tazobactam, 0% and 2.3%; and piperacillin-tazobactam, 0% and 0%, respectively. Microbiological results suggest FTB as a potential therapeutic option in patients infected with carbapenemase-producing Enterobacterales and carbapenem-resistant Pseudomonas isolates, including MBL producers.

A multiwell-plate Caenorhabditis elegans assay for assessing the therapeutic potential of Bacteriophages against Clinical Pathogens

In order to establish phage therapy as a standard clinical treatment for bacterial infections, testing of every phage to ensure the suitability and safety of the biological compound is required. While some issues have been addressed over recent years, standard and easy-to-use animal models to test phages are still rare. Testing of phages in highly suitable mammalian models such as mice is subjected to strict ethical regulations, while insect larvae such as the Galleria mellonella model suffers from batch-to-batch variations and requires manual operator skills to inject bacteria, resulting in unreliable experimental outcomes. A much simpler model is the nematode Caenorhabditis elegans which feeds on bacteria, a fast growing and easy to handle organism which can be used in high-throughput screening. In this study, two clinical bacterial strains of Escherichia coli, one Klebsiella pneumoniae and one Enterobacter cloacae strain were tested on the model system together with lytic bacteriophages that we isolated previously. We developed a liquid-based assay, in which the efficiency of phage treatment was evaluated using a scoring system based on microscopy and counting of the nematodes, allowing increasing statistical significance compared to other assays such as larvae or mice. Our work demonstrates the potential to use Caenorhabditis elegans to test the virulence of strains of Klebsiella pneumoniae, Enterobacter cloacae and EHEC/ EPEC as well as the efficacy of bacteriophages to treat or prevent infections, allowing a more reliable evaluation for the clinical therapeutic potential of lytic phages.

Formation, collective motion, and merging of macroscopic bacterial aggregates

Chemotactic bacteria form emergent spatial patterns of variable cell density within cultures that are initially spatially uniform. These patterns are the result of chemical gradients that are created from the directed movement and metabolic activity of billions of cells. A recent study on pattern formation in wild bacterial isolates has revealed unique collective behaviors of the bacteria Enterobacter cloacae. As in other bacterial species, Enterobacter cloacae form macroscopic aggregates. Once formed, these bacterial clusters can migrate several millimeters, sometimes resulting in the merging of two or more clusters. To better understand these phenomena, we examine the formation and dynamics of thousands of bacterial clusters that form within a 22 cm square culture dish filled with soft agar over two days. At the macroscale, the aggregates display spatial order at short length scales, and the migration of cell clusters is superdiffusive, with a merging acceleration that is correlated with aggregate size. At the microscale, aggregates are composed of immotile cells surrounded by low density regions of motile cells. The collective movement of the aggregates is the result of an asymmetric flux of bacteria at the boundary. An agent-based model is developed to examine how these phenomena are the result of both chemotactic movement and a change in motility at high cell density. These results identify and characterize a new mechanism for collective bacterial motility driven by a transient, density-dependent change in motility.

NDM Production as a Dominant Feature in Carbapenem-Resistant Enterobacteriaceae Isolates from a Tertiary Care Hospital

The worldwide spread and increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) is of utmost concern and a problem for public health. This resistance is mainly conferred by carbapenemase production. Such strains are a potential source of outbreaks in healthcare settings and are associated with high rates of morbidity and mortality. In this study, we aimed to determine the dominance of NDM-producing Enterobacteriaceae at a teaching hospital in Karachi. A total of 238 Enterobacteriaceae isolates were collected from patients admitted to Jinnah Postgraduate Medical Centre (Unit 4) in Karachi, Pakistan, a tertiary care hospital. Phenotypic and genotypic methods were used for detection of metallo-β-lactamase. Out of 238 isolates, 52 (21.8%) were CRE and 50 isolates were carbapenemase producers, as determined by the CARBA NP test; two isolates were found negative for carbapenemase production by CARB NP and PCR. Four carbapenemase-producing isolates phenotypically appeared negative for metallo-β-lactamase (MBL). Of the 52 CRE isolates, 46 (88.46%) were blaNDM positive. Most of the NDM producers were Klebsiella pneumoniae, followed by Enterobacter cloacae and Escherichia coli. In all the NDM-positive isolates, the blaNDM gene was found on plasmid. These isolates were found negative for the VIM and IPM MBLs. All the CRE and carbapenem-sensitive isolates were sensitive to colistin. It is concluded that the NDM is the main resistance mechanism against carbapenems and is dominant in this region.

Distinctive features of ertapenem mono-resistant carbapenem-resistant Enterobacterales in the United States: A cohort study

Background Carbapenem-resistant Enterobacterales (CRE) are highly antibiotic-resistant bacteria. Whether CRE resistant only to ertapenem among carbapenems (ertapenem “mono-resistant”) represent a unique CRE subset with regards to risk factors, carbapenemase genes, and outcomes is unknown. Methods We analyzed surveillance data from nine CDC Emerging Infections Program (EIP) sites. A case was the first isolation of a carbapenem-resistant Enterobacter cloacae complex, Escherichia coli, Klebsiella aerogenes, K. oxytoca, K. pneumoniae, or K. variicola from a normally sterile site or urine in an EIP catchment area resident in 2016-2017. We compared risk factors, carbapenemase genes, antibiotic susceptibility, and mortality of ertapenem “mono-resistant” cases to “other” CRE cases (resistant to ≥1 carbapenem other than ertapenem), and analyzed risk factors for mortality. Results Of 2009 cases, 1249 (62.2%) were ertapenem mono-resistant and 760 (37.8%) were other CRE. Ertapenem mono-resistant CRE cases were more frequently ≥80 years old (29.1% vs. 19.5%, p<0.0001) and female (67.9% vs 59.0%, p<0.0001). Ertapenem mono-resistant isolates were more likely to be Enterobacter cloacae complex (48.4% vs. 15.4%, p<0.0001) but less likely to be isolated from a normally sterile site (7.1% vs. 11.7%, p<0.01) or have a carbapenemase gene (2.4% vs. 47.4%, p<0.0001). Ertapenem mono-resistance was not associated with 90-day mortality in logistic regression models. Carbapenemase-positive isolates were associated with mortality (odds ratio 1.93, 95% confidence interval 1.30-2.86). Conclusions Ertapenem mono-resistant CRE rarely have carbapenemase genes and have distinct clinical and microbiologic characteristics from other CRE. These findings may inform antibiotic choice and infection prevention practices, particularly when carbapenemase testing is not available.

Análise das infecções de sítio cirúrgico em pacientes ortopédicos de um hospital do Paraná

As infecções de sítio cirúrgico são encontradas em 14-16% dos pacientes hospitalizados, sendo que, as relacionadas a cirurgias ortopédicas são consideradas severas. Portanto, a determinação de fatores de risco, é necessária, pois permite identificar situações que predisponham o desenvolvimento dessa infecção. Com o objetivo de elencar os fatores de riscos relacionados as infecções de sítio cirúrgico em um hospital universitário do Paraná, em um estudo transversal descritivo retrospectivo, foram analisados 125 prontuários de indivíduos submetidos a cirurgias ortopédicas e que desenvolveram a infecção no pós-operatório. Assim, foi possível encontrar um perfil de pacientes mais susceptível a desenvolver essa complicação, na qual, 41,0% dos pacientes foram identificados como saudáveis no pré-operatório, 61,6% das cirurgias tinham um caráter limpo, 63,2% utilizaram implante ortopédico no seu tratamento e o tratamento cirúrgico de fraturas fechadas prevaleceu. A incidência global da infecção foi de 2,0% e os micro-organismos mais prevalentes na amostra foram o Staphylococcus aureus, Enterobacter cloacae e Escherichia coli com 7,2% cada. Comparando-se com a literatura abordada, diferenças são encontradas na prevalência dos fatores de risco, devido às diferenças de cada população. A identificação desses fatores de risco é de suma importância para a prevenção das infecções de sítio cirúrgico. Por fim, novos estudos ainda devem ser realizados com o objetivo de validar os fatores de risco encontrados.

Incidencia de infecciones en el postrasplante renal inmediato

Introducción: El receptor de un trasplante renal es un paciente de alto riesgo para sufrir infección debido a las potenciales complicaciones quirúrgicas y al tratamiento inmunosupresor que reciben.El desarrollo de infecciones supone un riesgo aumentado de pérdida del injerto y de la mortalidad. Objetivos: El objetivo principal fue conocer la incidencia de las infecciones más frecuentes en el paciente con un trasplante renal, durante el periodo postrasplante inmediato.Los objetivos secundarios fueron describir los gérmenes responsables de las infecciones más frecuentes y analizar la relación entre los tipos de infección estudiados y sus posibles factores de riesgo. Metodología: Estudio observacional retrospectivo en pacientes trasplantados renales entre enero de 2018 y diciembre de 2019 durante el periodo del postrasplante inmediato.Resultados: La incidencia de infección fue 69,4%, los síndromes descritos fueron infección del tracto urinario (48%), bacteriemia (9,2%), infección relacionada con catéter (8,2%) e infección por citomegalovirus (4,1%). Los microorganimos más frecuentemente implicados, en estos procesos infecciosos fueron Escherichia coli (16,3%), Enterococus faecium (12,2%) y Enterobacter cloacae (8,1%).Se ha encontrado relación significativa entre la aparición de infección y la duración del ingreso, así como con la presencia o no del antecedente personal de hipertensión arterial. También entre la incidencia de infección relacionada con el catéter venoso central y el tiempo que permaneció insertado. Conclusiones: La infección más frecuente encontrada en el postrasplante renal inmediato fue la infección del tracto urinario, mientras que el microorganismo más presente habitualmente en los procesos infecciosos fue la Escherichia coli.