Notes from the Field: Potential Outbreak of Extrapulmonary Mycobacterium abscessus subspecies massiliense Infections from Stem Cell Treatment Clinics in Mexico - Arizona and Colorado, 2022.

Mycobacterium abscessus is an intrinsically drug-resistant, rapidly growing, nontuberculous mycobacterium; extrapulmonary infections have been reported in association with medical tourism (1). During November-December 2022, two Colorado hospitals (hospitals A and B) treated patient A, a Colorado woman aged 30-39 years, for M. abscessus meningitis. In October 2022, she had received intrathecal donor embryonic stem cell injections in Baja California, Mexico to treat multiple sclerosis and subsequently experienced headaches and fevers, consistent with meningitis. Her cerebrospinal fluid revealed neutrophilic pleocytosis and grew M. abscessus in culture at hospital A. Hospital A's physicians consulted hospital B's infectious diseases (ID) physicians to co-manage this patient (2).

Extensively Drug-Resistant Pseudomonas aeruginosa Outbreak associated with Artificial Tears.

BACKGROUND: Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) are extensively drug resistant bacteria. We investigated the source of a multistate CP-CRPA outbreak. METHODS: Cases were defined as a U.S. patient's first isolation of P. aeruginosa sequence type 1203 with the carbapenemase gene blaVIM-80 and cephalosporinase gene blaGES-9 from any specimen source collected and reported to CDC between January 1, 2022-May 15, 2023. We conducted a 1:1 matched case-control study at the post-acute care facility with the most cases, assessed exposures associated with case status for all case-patients, and tested products for bacterial contamination. RESULTS: We identified 81 case-patients from 18 states, 27 of whom were identified through surveillance cultures. Four (7%) of 54 case-patients with clinical cultures died within 30 days of culture collection, and four (22%) of 18 with eye infections underwent enucleation. In the case-control study, case-patients had increased odds of receiving artificial tears compared to controls (crude matched OR: 5.0, 95% CI: 1.1, 22.8). Overall, artificial tears use was reported by 61 (87%) of 70 case-patients with information; 43 (77%) of 56 case-patients with brand information reported use of Brand A, an imported, preservative-free, over-the-counter (OTC) product. Bacteria isolated from opened and unopened bottles of Brand A were genetically related to patient isolates. FDA inspection of the manufacturing plant identified likely sources of contamination. CONCLUSIONS: A manufactured medical product serving as the vehicle for carbapenemase-producing organisms is unprecedented in the U.S. The clinical impacts from this outbreak underscore the need for improved requirements for U.S. OTC product importers.

Phenotypic adaptation to temperature in the mosquito vector, Aedes aegypti.

Most models exploring the effects of climate change on mosquito-borne disease ignore thermal adaptation. However, if local adaptation leads to changes in mosquito thermal responses, "one size fits all" models could fail to capture current variation between populations and future adaptive responses to changes in temperature. Here, we assess phenotypic adaptation to temperature in Aedes aegypti, the primary vector of dengue, Zika, and chikungunya viruses. First, to explore whether there is any difference in existing thermal response of mosquitoes between populations, we used a thermal knockdown assay to examine five populations of Ae. aegypti collected from climatically diverse locations in Mexico, together with a long-standing laboratory strain. We identified significant phenotypic variation in thermal tolerance between populations. Next, to explore whether such variation can be generated by differences in temperature, we conducted an experimental passage study by establishing six replicate lines from a single field-derived population of Ae. aegypti from Mexico, maintaining half at 27°C and the other half at 31°C. After 10 generations, we found a significant difference in mosquito performance, with the lines maintained under elevated temperatures showing greater thermal tolerance. Moreover, these differences in thermal tolerance translated to shifts in the thermal performance curves for multiple life-history traits, leading to differences in overall fitness. Together, these novel findings provide compelling evidence that Ae. aegypti populations can and do differ in thermal response, suggesting that simplified thermal performance models might be insufficient for predicting the effects of climate on vector-borne disease transmission.

Second Nationwide Tuberculosis Outbreak Caused by Bone Allografts Containing Live Cells - United States, 2023.

During July 7-11, 2023, CDC received reports of two patients in different states with a tuberculosis (TB) diagnosis following spinal surgical procedures that used bone allografts containing live cells from the same deceased donor. An outbreak associated with a similar product manufactured by the same tissue establishment (i.e., manufacturer) occurred in 2021. Because of concern that these cases represented a second outbreak, CDC and the Food and Drug Administration worked with the tissue establishment to determine that this product was obtained from a donor different from the one implicated in the 2021 outbreak and learned that the bone allograft product was distributed to 13 health care facilities in seven states. Notifications to all seven states occurred on July 12. As of December 20, 2023, five of 36 surgical bone allograft recipients received laboratory-confirmed TB disease diagnoses; two patients died of TB. Whole-genome sequencing demonstrated close genetic relatedness between positive Mycobacterium tuberculosis cultures from surgical recipients and unused product. Although the bone product had tested negative by nucleic acid amplification testing before distribution, M. tuberculosis culture of unused product was not performed until after the outbreak was recognized. The public health response prevented up to 53 additional surgical procedures using allografts from that donor; additional measures to protect patients from tissue-transmitted M. tuberculosis are urgently needed.

Social vulnerability and county stay-at-home behavior during COVID-19 stay-at-home orders, United States, April 7-April 20, 2020.

PURPOSE: Early COVID-19 mitigation relied on people staying home except for essential trips. The ability to stay home may differ by sociodemographic factors. We analyzed how factors related to social vulnerability impact a community's ability to stay home during a stay-at-home order. METHODS: Using generalized, linear mixed models stratified by stay-at-home order (mandatory or not mandatory), we analyzed county-level stay-at-home behavior (inferred from mobile devices) during a period when a majority of United States counties had stay-at-home orders (April 7-April 20, 2020) with the Centers for Disease Control and Prevention Social Vulnerability Index (CDC SVI). RESULTS: Counties with higher percentages of single-parent households, mobile homes, and persons with lower educational attainment were associated with lower stay-at-home behavior compared with counties with lower respective percentages. Counties with higher unemployment, higher percentages of limited-English-language speakers, and more multi-unit housing were associated with increases in stay-at-home behavior compared with counties with lower respective percentages. Stronger effects were found in counties with mandatory orders. CONCLUSIONS: Sociodemographic factors impact a community's ability to stay home during COVID-19 stay-at-home orders. Communities with higher social vulnerability may have more essential workers without work-from-home options or fewer resources to stay home for extended periods, which may increase risk for COVID-19. Results are useful for tailoring messaging, COVID-19 vaccine delivery, and public health responses to future outbreaks.

County-Level COVID-19 Vaccination Coverage and Social Vulnerability - United States, December 14, 2020-March 1, 2021.

The U.S. COVID-19 vaccination program began in December 2020, and ensuring equitable COVID-19 vaccine access remains a national priority.* COVID-19 has disproportionately affected racial/ethnic minority groups and those who are economically and socially disadvantaged (1,2). Thus, achieving not just vaccine equality (i.e., similar allocation of vaccine supply proportional to its population across jurisdictions) but equity (i.e., preferential access and administra-tion to those who have been most affected by COVID-19 disease) is an important goal. The CDC social vulnerability index (SVI) uses 15 indicators grouped into four themes that comprise an overall SVI measure, resulting in 20 metrics, each of which has national and state-specific county rankings. The 20 metric-specific rankings were each divided into lowest to highest tertiles to categorize counties as low, moderate, or high social vulnerability counties. These tertiles were combined with vaccine administration data for 49,264,338 U.S. residents in 49 states and the District of Columbia (DC) who received at least one COVID-19 vaccine dose during December 14, 2020-March 1, 2021. Nationally, for the overall SVI measure, vaccination coverage was higher (15.8%) in low social vulnerability counties than in high social vulnerability counties (13.9%), with the largest coverage disparity in the socioeconomic status theme (2.5 percentage points higher coverage in low than in high vulnerability counties). Wide state variations in equity across SVI metrics were found. Whereas in the majority of states, vaccination coverage was higher in low vulnerability counties, some states had equitable coverage at the county level. CDC, state, and local jurisdictions should continue to monitor vaccination coverage by SVI metrics to focus public health interventions to achieve equitable coverage with COVID-19 vaccine.

The influence of feeding behaviour and temperature on the capacity of mosquitoes to transmit malaria.

Insecticide-treated bed nets reduce malaria transmission by limiting contact between mosquito vectors and human hosts when mosquitoes feed during the night. However, malaria vectors can also feed in the early evening and in the morning when people are not protected. Here, we explored how the timing of blood feeding interacts with environmental temperature to influence the capacity of Anopheles mosquitoes to transmit the human malaria parasite Plasmodium falciparum. In laboratory experiments, we found no effect of biting time itself on the proportion of mosquitoes that became infectious (vector competence) at constant temperature. However, when mosquitoes were maintained under more realistic fluctuating temperatures, there was a significant increase in competence for mosquitoes feeding in the evening (18:00), and a significant reduction in competence for those feeding in the morning (06:00), relative to those feeding at midnight (00:00). These effects appear to be due to thermal sensitivity of malaria parasites during the initial stages of parasite development within the mosquito, and the fact that mosquitoes feeding in the evening experience cooling temperatures during the night, whereas mosquitoes feeding in the morning quickly experience warming temperatures that are inhibitory to parasite establishment. A transmission dynamics model illustrates that such differences in competence could have important implications for malaria prevalence, the extent of transmission that persists in the presence of bed nets, and the epidemiological impact of behavioural resistance. These results indicate that the interaction of temperature and feeding behaviour could be a major ecological determinant of the vectorial capacity of malaria mosquitoes.

Use of alternative bioassays to explore the impact of pyrethroid resistance on LLIN efficacy.

BACKGROUND: There is substantial concern that the spread of insecticide resistance will render long-lasting insecticide-treated nets (LLINs) ineffective. However, there is limited evidence supporting a clear association between insecticide resistance and malaria incidence or prevalence in the field. We suggest that one reason for this disconnect is that the standard WHO assays used in surveillance to classify mosquito populations as resistant are not designed to determine how resistance might impact LLIN efficacy. The standard assays expose young, unfed female mosquitoes to a diagnostic insecticide dose in a single, forced exposure, whereas in the field, mosquitoes vary in their age, blood-feeding status, and the frequency or intensity of LLIN exposure. These more realistic conditions could ultimately impact the capacity of "resistant" mosquitoes to transmit malaria. METHODS: Here, we test this hypothesis using two different assays that allow female mosquitoes to contact a LLIN as they host-seek and blood-feed. We quantified mortality after both single and multiple exposures, using seven different strains of Anopheles ranging in pyrethroid resistance intensity. RESULTS: We found that strains classified as 1×-resistant to the pyrethroid insecticide deltamethrin in the standard WHO assay exhibited > 90% mortality over 24 h following more realistic LLIN contact. Mosquitoes that were able to blood-feed had increased survival compared to their unfed counterparts, but none of the 1×-resistant strains survived for 12 days post-exposure (the typical period for malaria parasite development within the mosquito). Mosquitoes that were 5×- and 10×-resistant (i.e. moderate or high intensity resistance based on the WHO assays) survived a single LLIN exposure well. However, only about 2-3% of these mosquitoes survived multiple exposures over the course of 12 days and successfully blood-fed during the last exposure. CONCLUSIONS: These results suggest that the standard assays provide limited insight into how resistance might impact LLIN efficacy. In our laboratory setting, there appears little functional consequence of 1×-resistance and even mosquitoes with moderate (5×) or high (10×) intensity resistance can suffer substantial reduction in transmission potential. Monitoring efforts should focus on better characterizing intensity of resistance to inform resistance management strategies and prioritize deployment of next generation vector control products.

Thermal biology of mosquito-borne disease.

Mosquito-borne diseases cause a major burden of disease worldwide. The vital rates of these ectothermic vectors and parasites respond strongly and nonlinearly to temperature and therefore to climate change. Here, we review how trait-based approaches can synthesise and mechanistically predict the temperature dependence of transmission across vectors, pathogens, and environments. We present 11 pathogens transmitted by 15 different mosquito species - including globally important diseases like malaria, dengue, and Zika - synthesised from previously published studies. Transmission varied strongly and unimodally with temperature, peaking at 23-29ºC and declining to zero below 9-23ºC and above 32-38ºC. Different traits restricted transmission at low versus high temperatures, and temperature effects on transmission varied by both mosquito and parasite species. Temperate pathogens exhibit broader thermal ranges and cooler thermal minima and optima than tropical pathogens. Among tropical pathogens, malaria and Ross River virus had lower thermal optima (25-26ºC) while dengue and Zika viruses had the highest (29ºC) thermal optima. We expect warming to increase transmission below thermal optima but decrease transmission above optima. Key directions for future work include linking mechanistic models to field transmission, combining temperature effects with control measures, incorporating trait variation and temperature variation, and investigating climate adaptation and migration.

Fine-scale spatial and temporal dynamics of kdr haplotypes in Aedes aegypti from Mexico.

BACKGROUND: As resistance to insecticides increases in disease vectors, it has become exceedingly important to monitor populations for susceptibility. Most studies of field populations of Aedes aegypti have largely characterized resistance patterns at the spatial scale of the city or country, which may not be completely informative given that insecticide application occurs at the scale of the house or city block. Phenotypic resistance to pyrethroids dominates in Ae. aegypti, and it has been partially explained by mutations in the voltage-gated sodium channel gene. Here, we assess community-level patterns of four knockdown resistance (kdr) haplotypes (C1534/I1016, F1534/I1016, C1534/V1016 and F1534/V1016) in Ae. aegypti in 24 randomly chosen city blocks from a city in Yucatán State, Mexico, during both the dry and wet season and over two years. RESULTS: Three of the four haplotypes, C1534/I1016, C1534/V1016 and F1534/V1016 were heterogeneous between city blocks at all four sampling time points, and the double mutant haplotype, C1534/I1016, showed a significant increase following the wet season. The F1534/I1016 haplotype was rarely detected, similar to other studies. However, when haplotype frequencies were aggregated to a coarser spatial scale, the differences in space and time were obscured. CONCLUSIONS: Our results provide empirical evidence that the selection of kdr alleles is occurring at fine spatial scales, indicating that future studies should include this scale to better understand evolutionary processes of resistance in natural populations.

Evaluation of Grower-Friendly, Science-Based Sampling Approaches for the Detection of Salmonella in Ponds Used for Irrigation of Fresh Produce.

The recognition that irrigation water sources contribute to preharvest contamination of produce has led to new regulations on testing microbial water quality. To best identify contamination problems, growers who depend on irrigation ponds need guidance on how and where to collect water samples for testing. In this study, we evaluated several sampling strategies to identify Salmonella and Escherichia coli contamination in five ponds used for irrigation on produce farms in southern Georgia. Both Salmonella and E. coli were detected regularly in all the ponds over the 19-month study period, with overall prevalence and concentrations increasing in late summer and early fall. Of 507 water samples, 217 (42.8%) were positive for Salmonella, with a very low geometric mean (GM) concentration of 0.06 most probable number (MPN)/100 mL, and 442 (87.1%) tested positive for E. coli, with a GM of 6.40 MPN/100 mL. We found no significant differences in Salmonella or E. coli detection rates or concentrations between sampling at the bank closest to the pump intake versus sampling from the bank around the pond perimeter, when comparing with results from the pump intake, which we considered our gold standard. However, samples collected from the bank closest to the intake had a greater level of agreement with the intake (Cohen's kappa statistic = 0.53; p < 0.001) than the samples collected around the pond perimeter (kappa = 0.34; p = 0.009). E. coli concentrations were associated with increased odds of Salmonella detection (odds ratio = 1.31; 95% confidence interval = 1.10-1.56). All the ponds would have met the Produce Safety Rule standards for E. coli, although Salmonella was also detected. Results from this study provide important information to growers and regulators about pathogen detection in irrigation ponds and inform best practices for surface water sampling.

Restoration of pyrethroid susceptibility in a highly resistant Aedes aegypti population.

Insecticide resistance has evolved in disease vectors worldwide, creating the urgent need to either develop new control methods or restore insecticide susceptibility to regain use of existing tools. Here we show that phenotypic susceptibility can be restored in a highly resistant field-derived strain of Aedes aegypti in only 10 generations through rearing them in the absence of insecticide.

Larval density mediates knockdown resistance to pyrethroid insecticides in adult Aedes aegypti.

BACKGROUND: Understanding mechanisms driving insecticide resistance in vector populations remains a public health priority. To date, most research has focused on the genetic mechanisms underpinning resistance, yet it is unclear what role environmental drivers may play in shaping phenotypic expression. One of the key environmental drivers of Aedes aegypti mosquito population dynamics is resource-driven intraspecific competition at the larval stage. We experimentally investigated the role of density-dependent larval competition in mediating resistance evolution in Ae. aegypti, using knockdown resistance (kdr) as a marker of genotypic resistance and CDC bottle bioassays to determine phenotype. We reared first-instar larvae from susceptible and pyrethroid-resistant field-derived populations of Ae. aegypti at high and low density and measured the resulting phenotypic resistance and population kdr allele frequencies. RESULTS: At low density, only 48.2% of the resistant population was knocked down, yet at high density, the population was no longer phenotypically resistant - 93% were knocked down when exposed to permethrin, which is considered susceptible according to WHO guidelines. Furthermore, the frequency of the C1534 kdr allele in the resistant population at high density decreased from 0.98 ± 0.04 to 0.69 ± 0.04 in only one generation of selection. CONCLUSIONS: Our results indicate that larval conditions, specifically density, can impact both phenotype and genotype of pyrethroid-resistant populations. Furthermore, phenotypic susceptibility to pyrethroids may be re-established in a resistant population through a gene x environment interaction, a finding that can lead to the development of novel resistance management strategies that capitalize on density-induced costs.