Dorothea K. Thompson

Carbapenems comprise a class of β-lactam antibiotics with broad-spectrum hydrolytic activity and are often reserved as last-line agents for the treatment of serious multidrug-resistant (MDR) bacterial infections. Clinically important nosocomial MDR Gram-negative bacteria (GNB) include Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Carbapenem resistance among these organisms is predominantly mediated by the production of β-lactamases called carbapenemases, such as K. pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-β-lactamase (VIM), and selected oxacillinase (OXA)-type carbapenemases. These enzymes degrade carbapenems, significantly compromising their clinical efficacy. To address escalating antimicrobial resistance, novel next-generation β-lactamase inhibitors (BLIs), partnered with established β-lactams (BLs), have been approved or are currently under development to inhibit carbapenemase activity. The present narrative review aims to synthesize the most current information on the major carbapenemases and discusses recently approved and investigational BL/BLI combination therapies in terms of their mechanisms of action, spectrum of activity, gaps in coverage, and available clinical and in vitro evidence. Development of resistance to novel BL/BLI combinations is also examined. Comparative analysis of inhibitory spectra and microbiological coverage indicates a continued need for metallo-β-lactamase inhibitors with direct pan-inhibitory activity, pathogen-specific BL/BLI regimens for carbapenem-resistant A. baumannii, and carbapenemase-targeted agents effective in the context of non-enzymatic resistance mechanisms. Treatment-emergent resistance to novel BL/BLIs and limitations in activity profiles underscore the critical need for continued innovation in pipeline development, vigilant global and local surveillance of carbapenemase epidemiology, and robust antimicrobial stewardship strategies to aid in preserving the efficacy of the antibacterial drug armamentarium.

Interest in virtual laboratory simulations as a pedagogical tool continues to grow, given the advantages of flexibility, scalability, technology integration, and interactive visualizations. We developed a laboratory model that integrates virtual lab simulations (VLS) and traditional in-person (IP) lab experiences for targeted skill development. In this study, we aimed to compare the effectiveness of VLS versus IP labs in the promotion of procedural, conceptual, and critical thinking levels of understanding. A second research objective was to explore students’ perceptions in using VLS compared to IP labs in an undergraduate microbiology course. Study participants comprised students ( n = 49) enrolled in a foundational microbiology course at a private university in the Fall semesters of 2022 and 2023. Identical quizzes were administered to assess learning performance of students who received the VLS first and those who completed the IP lab first. Focus group discussions were conducted, and participant responses were audio recorded for accuracy purposes, transcribed, and analyzed thematically using open and axial coding. The results indicated differences in performance scores between the VLS and IP groups were not statistically significant, suggesting both lab modalities are effective in enhancing learning. Overall, students expressed positive perceptions of VLS, noting detailed explanations, repetition, time management, and visual learning as primary benefits. Furthermore, students indicated an interest in using VLS in a hybrid structure as either a pre-laboratory exercise or a supplemental lab. These findings support the utility of a hybrid laboratory model in a foundational microbiology course for training pre-clinical students.

Gastrointestinal (GI) disturbances such as abdominal pain, nausea, and diarrhea are infrequently attributed to food allergies as an initial diagnosis in the absence of more traditional allergic reactions like hives, angioedema, or anaphylaxis. Alpha-gal syndrome (AGS) is an atypical and under-recognized allergy characterized by a delayed hypersensitivity reaction to the oligosaccharide galactose-α-1,3-galactose, a carbohydrate found in non-primate mammalian meat and derived products. This review of the current literature on AGS focuses on GI manifestations and diagnostic challenges. While clinical presentations of AGS vary widely, predominant or isolated GI symptoms, when manifested, can overlap with other disorders, thus making a timely and accurate diagnosis challenging. Here we provide an updated review of the epidemiology, pathophysiology, clinical presentation, and management of AGS. Current diagnostic approaches, treatment strategies, and areas requiring further research are also discussed.

Sexually transmitted infections (STIs) constitute a major public health issue in the United States. North Carolina (NC) in the southeastern U.S. ranks among the highest in STI incidence. We aimed to describe the incidence rates and identify potential risk factors of STIs in NC. The STI data reported by the NC Department of Health and Human Services for 2018 were compiled for chlamydia, gonorrhea, syphilis, and HIV infections for all 100 NC counties. Linear regression modeling was used to assess the association of STIs with predefined county-level variables. The mean STI incidence rates per 100,000 persons were highest for chlamydia (592.43 ± 30.02), followed by gonorrhea (212.06 ± 13.75), HIV (12.66 ± 0.947), and syphilis (3.33 ± 0.439). For chlamydia, higher risk was significantly associated with income (β = −0.008, SE = 0.003; p = 0.006), education (some college; β = 10.02, SE = 3.15, p = 0.002), race (Black; β = 12.17, SE = 1.57, p < 0.0001), and number of truck stops (β = 20.20, SE = 6.75, p = 0.004). The same variables, except for education, were associated with higher gonorrhea risk. Only race (being Black) was significantly associated with higher syphilis risk. Racial disparities in STI burden were significant, with race (being Black) constituting a risk factor for all four STIs. Interventions targeted to identified risk factors may help to reduce the STI burden in NC.

The genus Cedecea (family Enterobacteriaceae) causes a wide spectrum of acute infections in immunocompromised hosts, from pneumonia and bacteremia to oral ulcers and dialysis-related peritonitis. While Cedecea infections are reported infrequently in the literature, documented clinical cases of this emerging opportunistic human pathogen have occurred worldwide. Cedecea neteri has clinical significance and exhibits antimicrobial drug resistance. However, little is known about the molecular basis underlying the resistance phenotypes in C. neteri. We previously hypothesized that the open-reading frame cnt10470 in the C. neteri SSMD04 genome encodes a chromosomal Ambler class C (AmpC) β-lactamase based on sequence homology. In this study, recombinant polyhistidine-tagged proteins were created by cloning the putative ampC genes from SSMD04 and C. neteri ATCC 33855 (a clinical isolate) into the pET-6xHN expression vector, overexpressing the proteins, and then purifying the recombinant AmpCs (rAmpCs) using immobilized metal affinity chromatography (Ni-NTA). The in vitro enzymatic analysis of the purified rAmpCs was performed to determine the K_m and k_cat for various β-lactam substrates. The rAmpCs are functional class C β-lactamases when assayed using the chromogenic β-lactamase substrate, nitrocefin. The presence of functional AmpCs in both C. neteri strains underscores the necessity of performing antibiotic susceptibility testing in the management of C. neteri infections.

Background: Since the successful development, approval, and administration of vaccines against SARS-CoV-2, the causative agent of COVID-19, there have been reports in the published literature, passive surveillance systems, and other pharmacovigilance platforms of a broad spectrum of adverse events following COVID-19 vaccination. A comprehensive review of the more serious adverse events associated with the Pfizer-BioNTech and Moderna mRNA vaccines is warranted, given the massive number of vaccine doses administered worldwide and the novel mechanism of action of these mRNA vaccines in the healthcare industry. Methods: A systematic review of the literature was conducted to identify relevant studies that have reported mRNA COVID-19 vaccine-related adverse events. Results: Serious and severe adverse events following mRNA COVID-19 vaccinations are rare. While a definitive causal relationship was not established in most cases, important adverse events associated with post-vaccination included rare and non-fatal myocarditis and pericarditis in younger vaccine recipients, thrombocytopenia, neurological effects such as seizures and orofacial events, skin reactions, and allergic hypersensitivities. Conclusions: As a relatively new set of vaccines already administered to billions of people, COVID-19 mRNA-based vaccines are generally safe and efficacious. Further studies on long-term adverse events and other unpredictable reactions in close proximity to mRNA vaccination are required.

Cedecea, a genus in the Enterobacteriaceae family, includes several opportunistic pathogens reported to cause an array of sporadic acute infections, most notably of the lung and bloodstream. One species, Cedecea neteri, is associated with cases of bacteremia in immunocompromised hosts and has documented resistance to different antibiotics, including β-lactams and colistin. Despite the potential to inflict serious infections, knowledge about drug resistance determinants in Cedecea is limited. In this study, we utilized whole-genome sequence data available for three environmental strains (SSMD04, M006, ND14a) of C. neteri and various bioinformatics tools to analyze drug resistance genes in this bacterium. All three genomes harbor multiple chromosome-encoded β-lactamase genes. A deeper analysis of β-lactamase genes in SSMD04 revealed four metallo-β-lactamases, a novel variant, and a CMY/ACT-type AmpC putatively regulated by a divergently transcribed AmpR. Homologs of known resistance-nodulation-cell division (RND)-type multidrug efflux pumps such as OqxB, AcrB, AcrD, and MdtBC were also identified. Genomic island prediction for SSMD04 indicated that tolC, involved in drug and toxin export across the outer membrane of Gram-negative bacteria, was acquired by a transposase-mediated genetic transfer mechanism. Our study provides new insights into drug resistance mechanisms of an environmental microorganism capable of behaving as a clinically relevant opportunistic pathogen.

Since the outbreak and subsequent declaration of COVID-19 as a global pandemic in March 2020, concerted efforts have been applied by the scientific community to curtail the spread of the disease and find a cure. While vaccines constitute a vital part of the public health strategy to reduce the burden of COVID-19, the management of this disease will continue to rely heavily on pharmacotherapy. This study aims to provide an updated review of pharmacological agents that have been developed and/or repurposed for the treatment of COVID-19. To this end, a comprehensive literature search was conducted using the PubMed, Google Scholar, and LitCovid databases. Relevant clinical studies on drugs used in the management of COVID-19 were identified and evaluated in terms of evidence of efficacy and safety. To date, the FDA has approved three therapies for the treatment of COVID-19 Emergency Use Authorization: convalescent plasma, remdesivir, and casirivimab/imdevimab (REGN-COV2). Drugs such as lopinavir/ritonavir, umifenovir, favipiravir, anakinra, chloroquine, hydroxychloroquine, tocilizumab, interferons, tissue plasminogen activator, intravenous immunoglobulins, and nafamosat have been used off-label with mixed therapeutic results. Adjunctive administration of corticosteroids is also very common. The clinical experience with these approved and repurposed drugs is limited, and data on efficacy for the new indication are not strong. Overall, the response of the global scientific community to the COVID-19 pandemic has been impressive, as evident from the volume of scientific literature elucidating the molecular biology and pathophysiology of SARS-CoV-2 and the approval of three new drugs for clinical management. Reviewed studies have shown mixed data on efficacy and safety of the currently utilized drugs. The lack of standard treatment for COVID-19 has made it difficult to interpret results from most of the published studies due to the risk of attribution error. The long-term effects of drugs can only be assessed after several years of clinical experience; therefore, the efficacy and safety of current COVID-19 therapeutics should continue to be rigorously monitored as part of post-marketing studies.