Selection of Antibiotics as Prophylaxis for Close Contacts of Patients with Meningococcal Disease in Areas with Ciprofloxacin Resistance - United States, 2024.

Meningococcal disease, caused by the bacterium Neisseria meningitidis, is a rare but life-threatening illness that requires prompt antibiotic treatment for patients and antibiotic prophylaxis for their close contacts. Historically, N. meningitidis isolates in the United States have been largely susceptible to the antibiotics recommended for prophylaxis, including ciprofloxacin. Since 2019, however, the number of meningococcal disease cases caused by ciprofloxacin-resistant strains has increased. Antibiotic prophylaxis with ciprofloxacin in areas with ciprofloxacin resistance might result in prophylaxis failure. Health departments should preferentially consider using antibiotics other than ciprofloxacin as prophylaxis for close contacts when both of the following criteria have been met in a local catchment area during a rolling 12-month period: 1) the reporting of two or more invasive meningococcal disease cases caused by ciprofloxacin-resistant strains, and 2) ≥20% of all reported invasive meningococcal disease cases are caused by ciprofloxacin-resistant strains. Other than ciprofloxacin, alternative recommended antibiotic options include rifampin, ceftriaxone, or azithromycin. Ongoing monitoring for antibiotic resistance of meningococcal isolates through surveillance and health care providers' reporting of prophylaxis failures will guide future updates to prophylaxis considerations and recommendations.

Cases of Meningococcal Disease Associated with Travel to Saudi Arabia for Umrah Pilgrimage - United States, United Kingdom, and France, 2024.

Invasive meningococcal disease (IMD), caused by infection with the bacterium Neisseria meningitidis, usually manifests as meningitis or septicemia and can be severe and life-threatening (1). Six serogroups (A, B, C, W, X, and Y) account for most cases (2). N. meningitidis is transmitted person-to-person via respiratory droplets and oropharyngeal secretions. Asymptomatic persons can carry N. meningitidis and transmit the bacteria to others, potentially causing illness among susceptible persons. Outbreaks can occur in conjunction with large gatherings (3,4). Vaccines are available to prevent meningococcal disease. Antibiotic prophylaxis for close contacts of infected persons is critical to preventing secondary cases (2).

Yeast Chaperone Hsp70-Ssb Modulates a Variety of Protein-Based Heritable Elements.

Prions are transmissible self-perpetuating protein isoforms associated with diseases and heritable traits. Yeast prions and non-transmissible protein aggregates (mnemons) are frequently based on cross-ß ordered fibrous aggregates (amyloids). The formation and propagation of yeast prions are controlled by chaperone machinery. Ribosome-associated chaperone Hsp70-Ssb is known (and confirmed here) to modulate formation and propagation of the prion form of the Sup35 protein [PSI+]. Our new data show that both formation and mitotic transmission of the stress-inducible prion form of the Lsb2 protein ([LSB+]) are also significantly increased in the absence of Ssb. Notably, heat stress leads to a massive accumulation of [LSB+] cells in the absence of Ssb, implicating Ssb as a major downregulator of the [LSB+]-dependent memory of stress. Moreover, the aggregated form of Gγ subunit Ste18, [STE+], behaving as a non-heritable mnemon in the wild-type strain, is generated more efficiently and becomes heritable in the absence of Ssb. Lack of Ssb also facilitates mitotic transmission, while lack of the Ssb cochaperone Hsp40-Zuo1 facilitates both spontaneous formation and mitotic transmission of the Ure2 prion, [URE3]. These results demonstrate that Ssb is a general modulator of cytosolic amyloid aggregation, whose effect is not restricted only to [PSI+].

Prion induction by the short-lived, stress-induced protein Lsb2 is regulated by ubiquitination and association with the actin cytoskeleton.

Yeast prions are self-perpetuating, QN-rich amyloids that control heritable traits and serve as a model for mammalian amyloidoses. De novo prion formation by overproduced prion protein is facilitated by other aggregated QN-rich protein(s) and is influenced by alterations of protein homeostasis. Here we explore the mechanism by which the Las17-binding protein Lsb2 (Pin3) promotes conversion of the translation termination factor Sup35 into its prion form, [PSI(+)]. We show that Lsb2 localizes with some Sup35 aggregates and that Lsb2 is a short-lived protein whose levels are controlled via the ubiquitin-proteasome system and are dramatically increased by stress. Loss of Lsb2 decreases stability of [PSI(+)] after brief heat shock. Mutations interfering with Lsb2 ubiquitination increase prion induction, while a mutation eliminating association of Lsb2 with the actin cytoskeleton blocks its aggregation and prion-inducing ability. These findings directly implicate the UPS and actin cytoskeleton in regulating prions via a stress-inducible QN-rich protein.

Fluoroquinolone susceptibility testing of Salmonella enterica: detection of acquired resistance and selection of zone diameter breakpoints for levofloxacin and ofloxacin.

Fluoroquinolones (e.g., ciprofloxacin) have become a mainstay for treating severe Salmonella infections in adults. Fluoroquinolone resistance in Salmonella is mostly due to mutations in the topoisomerase genes, but plasmid-mediated quinolone resistance (PMQR) mechanisms have also been described. In 2012, the Clinical and Laboratory Standards Institute (CLSI) revised the ciprofloxacin interpretive criteria (breakpoints) for disk diffusion and MIC test methods for Salmonella. In 2013, the CLSI published MIC breakpoints for Salmonella to levofloxacin and ofloxacin, but breakpoints for assigning disk diffusion results to susceptible (S), intermediate (I), and resistant (R) categories are still needed. In this study, the MICs and inhibition zone diameters for nalidixic acid, ciprofloxacin, levofloxacin, and ofloxacin were determined for 100 clinical isolates of nontyphi Salmonella with or without resistance mechanisms. We confirmed that the new levofloxacin MIC breakpoints resulted in the highest category agreement (94%) when plotted against the ciprofloxacin MICs and that the new ofloxacin MIC breakpoints resulted in 92% category agreement between ofloxacin and ciprofloxacin. By applying the new MIC breakpoints in the MIC zone scattergrams for levofloxacin and ofloxacin, the following disk diffusion breakpoints generated the least number of errors: ≥28 mm (S), 19 to 27 mm (I), and ≤18 mm (R) for levofloxacin and ≥25 mm (S), 16 to 24 mm (I), and ≤15 mm (R) for ofloxacin. Neither the levofloxacin nor the ofloxacin disk yielded good separation of isolates with and without resistance mechanisms. Further studies will be needed to develop a disk diffusion assay that efficiently detects all isolates with acquired resistance to fluoroquinolones.

Discovery of 8-Hydroxyquinoline as a Histamine Receptor 2 Blocker Scaffold.

Histamine receptor 2 (HRH2) activation in the stomach results in gastric acid secretion, and HRH2 blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HRH2 blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HRH2 blocker scaffold to serve in the development of next-generation HRH2 blockers, we developed an HRH2-based sensor in yeast by linking human HRH2 activation to cell luminescence. We used the HRH2-based sensor to screen a 403-member anti-infection chemical library and identified three HRH2 blockers, chlorquinaldol, chloroxine, and broxyquinoline, all sharing an 8-hydroxyquinoline scaffold, which is not found among known HRH2 antagonists. Critically, we validate their HRH2-blocking ability in mammalian cells. Molecular docking suggests that the HRH2 blockers bind the histamine binding pocket and structure-activity data point toward these blockers acting as competitive antagonists. Chloroxine and broxyquinoline are antimicrobials that can be found in the gastrointestinal tract at concentrations that would block HRH2, thus likely modulating gastric acid secretion. Taken together, this work demonstrates the utility of GPCR-based sensors for rapid drug discovery applications, identifies a novel HRH2 blocker scaffold, and provides further evidence that antimicrobials not only target the human microbiota but also the human host.

Meningococcal disease in North America: Updates from the Global Meningococcal Initiative.

This review summarizes the recent Global Meningococcal Initiative (GMI) regional meeting, which explored meningococcal disease in North America. Invasive meningococcal disease (IMD) cases are documented through both passive and active surveillance networks. IMD appears to be decreasing in many areas, such as the Dominican Republic (2016: 18 cases; 2021: 2 cases) and Panama (2008: 1 case/100,000; 2021: <0.1 cases/100,000); however, there is notable regional and temporal variation. Outbreaks persist in at-risk subpopulations, such as people experiencing homelessness in the US and migrants in Mexico. The recent emergence of ß-lactamase-positive and ciprofloxacin-resistant meningococci in the US is a major concern. While vaccination practices vary across North America, vaccine uptake remains relatively high. Monovalent and multivalent conjugate vaccines (which many countries in North America primarily use) can provide herd protection. However, there is no evidence that group B vaccines reduce meningococcal carriage. The coronavirus pandemic illustrates that following public health crises, enhanced surveillance of disease epidemiology and catch-up vaccine schedules is key. Whole genome sequencing is a key epidemiological tool for identifying IMD strain emergence and the evaluation of vaccine strain coverage. The Global Roadmap on Defeating Meningitis by 2030 remains a focus of the GMI.

Salmonella isolates with decreased susceptibility to extended-spectrum cephalosporins in the United States.

OBJECTIVE: We describe the antimicrobial susceptibility to extended-spectrum cephalosporins in non-Typhi Salmonella (NTS) isolated from humans in the United States and explore resistance mechanisms for isolates displaying decreased susceptibility to ceftriaxone or ceftiofur. We further explore the concordance between the newly revised Clinical and Laboratory Standards Institute (CLSI) breakpoints for ceftriaxone and the presence of a ß-lactamase. METHODS: In 2005 and 2006, public health laboratories in all U.S. state health departments forwarded every 20th NTS isolate from humans to Centers for Disease Control and Prevention as part of the National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria. Minimum inhibitory concentrations (MICs) were determined by broth microdilution. Isolates displaying decreased susceptibility (MIC ≥ 2 mg/L) to ceftriaxone or ceftiofur were included in the study. The presence of ß-lactamase genes was investigated by polymerase chain reaction amplification and sequencing, targeting six different genes (bla(TEM), bla(OXA), bla(SHV), bla(CTX-M), bla(PSE), and bla(CMY)). Plasmid location of bla(CMY) was confirmed by transforming plasmids into Escherichia coli. RESULTS: Among the 4236 isolates of NTS submitted to NARMS in 2005 and 2006, 175 (4.1%) displayed decreased susceptibility to either ceftriaxone or ceftiofur. By polymerase chain reaction screening, one or more ß-lactamase genes could be detected in 139 (80.8%) isolates. The most prevalent resistance mechanism detected was the AmpC ß-lactamase gene bla(CMY.) Other ß-lactamase genes detected included 11 bla(TEM-1), 3 bla(PSE-1), 2 bla(OXA-1), and 1 bla(CTX-M-15). The ceftriaxone MIC values for the bla(CMY)-containing isolates ranged from 4 to 64 mg/L; all bla(CMY)-bearing isolates were classified as ceftriaxone resistant according to current CLSI guidelines. CONCLUSIONS: Among NTS isolates submitted to NARMS in 2005 and 2006, cephamycinase ß-lactamases are the predominant cause of decreased susceptibility to ceftriaxone. The fact that all bla(CMY)-containing isolates were classified as resistant to ceftriaxone (MIC ≥ 4 mg/L) supports the newly revised CLSI breakpoints for cephalosporins and Enterobacteriaceae.

Role of the Cell Asymmetry Apparatus and Ribosome-Associated Chaperones in the Destabilization of a Saccharomyces cerevisiae Prion by Heat Shock.

Self-perpetuating transmissible protein aggregates, termed prions, are implicated in mammalian diseases and control phenotypically detectable traits in Saccharomyces cerevisiae Yeast stress-inducible chaperone proteins, including Hsp104 and Hsp70-Ssa that counteract cytotoxic protein aggregation, also control prion propagation. Stress-damaged proteins that are not disaggregated by chaperones are cleared from daughter cells via mother-specific asymmetric segregation in cell divisions following heat shock. Short-term mild heat stress destabilizes [PSI+ ], a prion isoform of the yeast translation termination factor Sup35 This destabilization is linked to the induction of the Hsp104 chaperone. Here, we show that the region of Hsp104 known to be required for curing by artificially overproduced Hsp104 is also required for heat-shock-mediated [PSI+ ] destabilization. Moreover, deletion of the SIR2 gene, coding for a deacetylase crucial for asymmetric segregation of heat-damaged proteins, also counteracts heat-shock-mediated destabilization of [PSI+ ], and Sup35 aggregates are colocalized with aggregates of heat-damaged proteins marked by Hsp104-GFP. These results support the role of asymmetric segregation in prion destabilization. Finally, we show that depletion of the heat-shock noninducible ribosome-associated chaperone Hsp70-Ssb decreases heat-shock-mediated destabilization of [PSI+ ], while disruption of a cochaperone complex mediating the binding of Hsp70-Ssb to the ribosome increases prion loss. Our data indicate that Hsp70-Ssb relocates from the ribosome to the cytosol during heat stress. Cytosolic Hsp70-Ssb has been shown to antagonize the function of Hsp70-Ssa in prion propagation, which explains the Hsp70-Ssb effect on prion destabilization by heat shock. This result uncovers the stress-related role of a stress noninducible chaperone.

Occurrence of ß-lactamase genes among non-Typhi Salmonella enterica isolated from humans, food animals, and retail meats in the United States and Canada.

Non-Typhi Salmonella cause over 1.7 million cases of gastroenteritis in North America each year, and food-animal products are commonly implicated in human infections. For invasive infections, antimicrobial therapy is indicated. In North America, the antimicrobial susceptibility of Salmonella is monitored by the U.S. National Antimicrobial Resistance Monitoring System (NARMS) and The Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS). In this study, we determined the susceptibility to cephalosporins by broth microdilution among 5,041 non-Typhi Salmonella enterica isolated from food animals, retail meats, and humans. In the United States, 109 (4.6%) of isolates collected from humans, 77 (15.7%) from retail meat, and 140 (10.6%) from food animals displayed decreased susceptibility to cephalosporins (DSC). Among the Canadian retail meat and food animal isolates, 52 (13.0%) and 42 (9.4%) displayed DSC. All isolates displaying DSC were screened for ß-lactamase genes (bla(TEM), bla(SHV), bla(CMY), bla(CTX-M), and bla(OXA-1)) by polymerase chain reaction. At least one ß-lactamase gene was detected in 74/109 (67.9%) isolates collected from humans, and the bla(CMY) genes were most prevalent (69/109; 63.3%). Similarly, the bla(CMY) genes predominated among the ß-lactamase-producing isolates collected from retail meats and food animals. Three isolates from humans harbored a bla(CTX-M-15) gene. No animal or retail meat isolates harbored a bla(CTX-M) or bla(OXA-1) gene. A bla(TEM) gene was found in 5 human, 9 retail meat, and 17 animal isolates. Although serotype distributions varied among human, retail meat, and animal sources, overlap in bla(CMY)-positive serotypes across sample sources supports meat and food-animal sources as reservoirs for human infection.