Repurposing antibiotic resistance surveillance data to support treatment of recurrent infections in a remote setting.

In northern Australia, a region with limited access to healthcare and a substantial population living remotely, antibiotic resistance adds to the complexity of treating infections. Focussing on Escherichia coli urinary tract infections (UTIs) and Staphylococcus aureus skin & soft tissue infections (SSTIs) captured by a northern Australian antibiotic resistance surveillance system, we used logistic regression to investigate predictors of a subsequent resistant isolate during the same infection episode. We also investigated predictors of recurrent infection. Our analysis included 98,651 E. coli isolates and 121,755 S. aureus isolates from 70,851 patients between January 2007 and June 2020. Following an initially susceptible E. coli UTI, subsequent recovery of a cefazolin (8%) or ampicillin (13%) -resistant isolate during the same infection episode was more common than a ceftriaxone-resistant isolate (2%). For an initially susceptible S. aureus SSTI, subsequent recovery of a methicillin-resistant isolate (8%) was more common than a trimethoprim-sulfamethoxazole-resistant isolate (2%). For UTIs and SSTIs, prior infection with a resistant pathogen was a strong predictor of both recurrent infection and resistance in future infection episodes. This multi-centre study demonstrates an association between antibiotic resistance and an increased likelihood of recurrent infection. Particularly in remote areas, a patient's past antibiograms should guide current treatment choices since recurrent infection will most likely be at least as resistant as previous infection episodes. Using population-level surveillance data in this way can also help clinicians decide if they should switch antibiotics for patients with ongoing symptoms, while waiting for diagnostic results.

Can non-typeable Haemophilus influenzae carriage surveillance data infer antimicrobial resistance associated with otitis media?

Importance: In remote communities of the Northern Territory, Australia, children experience high rates of otitis media (OM), commonly caused by non-typeable Haemophilus influenzae (NTHi). Few data exist on antibiotic susceptibility of NTHi from OM. Objective: To determine whether population-level nasopharyngeal NTHi antibiotic susceptibility data could inform antibiotic treatment for OM. Methods: NTHi isolates (n = 92) collected from ear discharge between 2003 and 2013 were selected to time- and age-match NTHi isolates from the nasopharyngeal carriage (n = 95). Antimicrobial susceptibility were tested. Phylogenomic trees and a genome-wide association study (GWAS) were performed to determine the similarity of nasopharyngeal and ear isolates at a population level. Results: Among 174 NTHi isolates available for antimicrobial susceptibility testing, 10.3% (18/174) were resistant to ampicillin and 9.2% (16/174) were resistant to trimethoprim-sulfamethoxazole. Small numbers of isolates (≤3) were resistant to tetracycline, chloramphenicol, or amoxicillin-clavulanic acid. There was no statistical difference in the proportion of ampicillin-resistant (P = 0.11) or trimethoprim-sulfamethoxazole-resistant isolates (P = 0.70) between ear discharge and nasopharynx-derived NTHi isolates. Three multi-drug resistant NTHi isolates were identified. Phylogenomic trees showed no clustering of 187 Haemophilus influenzae isolates based on anatomical niche (nasopharynx or ear discharge), and no genetic variations that distinguished NTHi derived from ear discharge and nasopharyngeal carriage were evident in the GWAS. Interpretation: In this population-level study, nasopharyngeal and ear discharge isolates did not represent distinct microbial populations. These results support tracking of population-level nasopharyngeal NTHi antibiotic resistance patterns to inform clinical management of OM in this population.

Disease burden, associated mortality and economic impact of antimicrobial resistant infections in Australia.

Background: The growing spread of antimicrobial resistance (AMR) is accepted as a threat to humans, animals and the environment. This threat is considered to be both country specific and global, with bacteria resistant to antibiotic treatment geographically dispersed. Despite this, we have very few Australian estimates available that use national surveillance data supplemented with measures of risk, to generate reliable and actionable measures of AMR impact. These data are essential to direct policies and programs and support equitable healthcare resource utilisation. Importantly, such data can lead to implementation of programs to improved morbidity and mortality of patients with a resistant infection. Methods: Using data from a previous case-cohort study, we estimated the AMR-associated health and economic impact caused by five hospital-associated AMR pathogens (Enterococcus spp., E. coli, K. pneumoniae, P. aeruginosa and S. aureus) in patients with a bloodstream, urinary tract, or respiratory tract infection in Australia in 2020. We estimated disease burden based on the counterfactual scenario in which all AMR infections were replaced by no infection.We used a population-level simulation model to compute AMR-associated mortality, loss of quality-adjusted life years and costs. Findings: In 2020, there were 1,031 AMR-associated deaths (95% uncertainty interval [UI] 294, 2,615) from the five resistant hospital-associated infections in Australia. The greatest odds of dying were from respiratory infections (ceftazidime-resistant P. aeruginosa) and bloodstream infections, both resulting in high hospital and premature death costs. MRSA bacteraemia contributed the most to hospital costs (measured as bed-days) as patients with this infection resulted in additional 12,818 (95% UI 7246, 19966) hospital bed-days and cost the hospitals an extra $24,366,741 (95%UI $13,774,548, $37,954,686) per year. However, the cost of premature death from five resistant pathogens was $438,543,052, which was by far greater than the total hospital cost ($71,988,858). We estimate a loss of 27,705 quality-adjusted life years due to the five AMR pathogens. Interpretation: These are the first Australian estimates of AMR-associated health and economic impact. Country-level estimates of AMR impact are needed to provide local evidence to better inform programs and health policies to reduce morbidity and mortality associated with infection. The burden in hospital is likely an underestimate of the impact of AMR due to community-associated infections where data are limited, and the AMR burden is high. This should now be the focus of future study in this area. Funding: TMW was supported by the Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE) (grant number GNT1116530) Fellowship.

Contribution of socio-economic factors in the spread of antimicrobial resistant infections in Australian primary healthcare clinics.

OBJECTIVES: To effectively contain antimicrobial-resistant (AMR) infections, we must better understand the social determinates of health that contribute to transmission and spread of infections. METHODS: We used clinical data from patients attending primary healthcare clinics across three jurisdictions of Australia (2007-2019). Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) isolates and their corresponding antibiotic susceptibilities were included. Using multivariable logistic regression analysis, we assessed associations between AMR prevalence and indices of social disadvantage as reported by the Australian Bureau of Statistics (i.e., remoteness, socio-economic disadvantage and average person per household). RESULTS: This study reports 12 years of longitudinal data from 43 448 isolates from a high-burden low-resource setting in Australia. Access to health and social services (as measured by remoteness index) was a risk factor for increased prevalence of third-generation cephalosporin-resistant (3GC) E. coli (odds ratio 5.05; 95% confidence interval 3.19, 8.04) and methicillin-resistant S. aureus (MRSA) (odds ratio 5.72; 95% confidence interval 5.02, 6.54). We did not find a positive correlation of AMR and socio-economic disadvantage or average person per household indices. CONCLUSION: Remoteness is a risk factor for increased prevalence of 3GC-resistant E. coli and MRSA. We demonstrate that traditional disease surveillance systems can be repurposed to capture the broader social drivers of AMR. Access to pathogen-specific and social data early and within the local regional context will fill a significant gap in disease prevention and the global spread of AMR.

The Increased Length of Hospital Stay and Mortality Associated With Community-Associated Infections in Australia.

Background: An increasing proportion of antibiotic-resistant infections are community acquired. However, the burden of community-associated infections (CAIs) and the resulting impact due to resistance have not been well described. Methods: We conducted a multisite, retrospective case-cohort study of all acute care hospital admissions across 134 hospitals in Australia. Patients admitted with a positive culture of 1 of 5 organisms of interest, namely Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium, from January 1, 2012, through December 30, 2016, were included. Data linkage was used to link hospital admissions and pathology data. Patients with a bloodstream infection (BSI), urinary tract infection (UTI), or respiratory tract infection (RTI) were included in the analysis. We compared patients with a resistant and drug-sensitive infection and used regression analyses to derive the difference in length of hospital stay (LOS) and mortality estimates associated with resistance. Results: No statistically significant impact on hospital LOS for patients with resistant CAIs compared with drug-sensitive CAIs was identified. CAI patients with drug-resistant Enterobacteriaceae (E. coli, K. pneumoniae) BSIs were more likely to die in the hospital than those with drug-sensitive Enterobacteriaceae BSIs (odds ratio [OR], 3.28; 95% CI, 1.40-6.92). CAI patients with drug-resistant P. aeruginosa UTIs were more likely to die in the hospital than those with the drug-sensitive counterpart (OR, 2.43; 95% CI, 1.12-4.85). Conclusions: The burden of CAI in the hospital is significant, and antibiotic resistance is adding to associated mortality.

The antimicrobial resistance travel tool, an interactive evidence-based educational tool to limit antimicrobial resistance spread.

BACKGROUND: International travel has been recognized as a risk factor contributing to the spread of antimicrobial resistance (AMR). However, tools focused on AMR in the context of international travel and designed to guide decision-making are limited. We aimed at developing an evidence-based educational tool targeting both healthcare professionals (HCPs) and international travellers to help prevent the spread of AMR. METHODS: A literature review on 12 antimicrobial-resistant bacteria (ARB) listed as critical and high tiers in the WHO Pathogen Priority List covering four key areas was carried out: AMR surveillance data; epidemiological studies reporting ARB prevalence data on carriage in returning travellers; guidance documents reporting indications on screening for ARB in returning travellers and recommendations for ARB prevention for the public. The evidence, catalogued at country-level, provided the content for a series of visualizations that allow assessment of the risk of AMR acquisition through travel. RESULTS: Up to January 2021, the database includes data on: (i) AMR surveillance for 2.018.241 isolates from 86 countries; (ii) ARB prevalence of carriage from 11.679 international travellers and (iii) 15 guidance documents published by major public health agencies. The evidence allowed the development of a consultation scheme for the evaluation of risk factors, prevalence of carriage, proportion and recommendations for screening of AMR. For the public, pre-travel practical measures to minimize the risk of transmission were framed. CONCLUSIONS: This easy-to-use, annually updated, freely accessible AMR travel tool (https://epi-net.eu/travel-tool/overview/), is the first of its kind to be developed. For HCPs, it can provide a valuable resource for teaching and a repository that facilitates a stepwise assessment of the risk of AMR spread and strengthen implementation of optimized infection control measures. Similarly, for travellers, the tool has the potential to raise awareness of AMR and outlines preventive measures that reduce the risk of AMR acquisition and spread.

Antibiotic resistance in uropathogens across northern Australia 2007-20 and impact on treatment guidelines.

BACKGROUND: Urinary tract infections are common and are increasingly resistant to antibiotic therapy. Northern Australia is a sparsely populated region with limited access to healthcare, a relatively high burden of disease, a substantial regional and remote population, and high rates of antibiotic resistance in skin pathogens. OBJECTIVES: To explore trends in antibiotic resistance for common uropathogens Escherichia coli and Klebsiella pneumoniae in northern Australia, and how these relate to current treatment guidelines in the community and hospital settings. METHODS: We used data from an antibiotic resistance surveillance system. We calculated the monthly and yearly percentage of isolates that were resistant in each antibiotic class, by bacterium. We analysed resistance proportions geographically and temporally, stratifying by healthcare setting. Using simple linear regression, we investigated longitudinal trends in monthly resistance proportions and correlation between community and hospital isolates. RESULTS: Our analysis included 177 223 urinary isolates from four pathology providers between 2007 and 2020. Resistance to most studied antibiotics remained <20% (for E. coli and K. pneumoniae, respectively, in 2019: amoxicillin/clavulanate 16%, 5%; cefazolin 17%, 8%; nitrofurantoin 1%, 31%; trimethoprim 36%, 17%; gentamicin 7%, 2%; extended-spectrum cephalosporins 8%, 5%), but many are increasing by 1%-3% (absolute) per year. Patterns of resistance were similar between isolates from community and hospital patients. CONCLUSIONS: Antibiotic resistance in uropathogens is increasing in northern Australia, but treatment guidelines generally remain appropriate for empirical therapy of patients with suspected infection (except trimethoprim in some settings). Our findings demonstrate the importance of local surveillance data (HOTspots) to inform clinical decision making and guidelines.

Championing women working in health across regional and rural Australia - a new dual-mentorship model.

BACKGROUND: Mentoring is a critical component of career development and job satisfaction leading to a healthier workforce and more productive outputs. However, there are limited data on mentorship models in regional areas and in particular for women aspiring to leadership positions. Mentorship programs that leverage off experienced mentors from diverse disciplines have the potential to foster the transfer of knowledge and to positively influence job satisfaction and build capacity within the context of workforce shortage. METHODS: This study describes a dual-mentorship model of professional development for women working in health in regional and rural Australia. We present the framework and describe the evaluation findings from a 12-month pilot program. RESULTS: Both academic and corporate mentors provided diverse perspectives to the mentees during the 12-month period. On average, corporate mentors met with mentees more often, and focused these discussions on strategy and leadership skills whilst academic mentors provided more technical advice regarding academic growth. Mentees reported an improvement in workplace interconnectedness and confidence at the completion of the program. CONCLUSION: We developed a framework for establishing a professional mentorship program that matches women working in regional health with mentors from diverse sectors including business, government, philanthropy and health, to provide a holistic approach to improving career satisfaction, institutional productivity and supporting a diverse workforce in regional or resource-poor settings.

Health and economic burden of antimicrobial-resistant infections in Australian hospitals: a population-based model.

OBJECTIVE: To estimate the additional health and economic burden of antimicrobial-resistant (AMR) infections in Australian hospitals. METHODS: A simulation model based on existing evidence was developed to assess the additional mortality and costs of healthcare-associated AMR Escherichia coli (E. coli), Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, and Staphylococcus aureus infections. SETTING: Australian public hospitals. FINDINGS: Australian hospitals spent an additional AUD$5.8 million (95% uncertainty interval [UI], $2.2-$11.2 million) per year treating ceftriaxone-resistant E.coli bloodstream infections (BSI), and an estimated AUD$5.5 million per year (95% UI, $339,633-$22.7 million) treating MRSA patients. There are no reliable estimates of excess morbidity and mortality from AMR infections in sites other than the blood and in particular for highly prevalent AMR E. coli causing urinary tract infections (UTIs). CONCLUSION: The limited evidence-base of the health impact of resistant infection in UTIs limits economic studies estimating the overall burden of AMR. Such data are increasingly important and are urgently needed to support local clinical practice as well as national and global efforts to curb the spread of AMR.

Using the best available data to estimate the cost of antimicrobial resistance: a systematic review.

Background: Valuation of the economic cost of antimicrobial resistance (AMR) is important for decision making and should be estimated accurately. Highly variable or erroneous estimates may alarm policy makers and hospital administrators to act, but they also create confusion as to what the most reliable estimates are and how these should be assessed. This study aimed to assess the quality of methods used in studies that quantify the costs of AMR and to determine the best available evidence of the incremental cost of these infections. Methods: In this systematic review, we searched PubMed, Embase, Cinahl, Cochrane databases and grey literature sources published between January 2012 and October 2016. Articles reporting the additional burden of Enterococcus spp., Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) resistant versus susceptible infections were sourced. The included studies were broadly classified as reporting oncosts from the healthcare/hospital/hospital charges perspective or societal perspective. Risk of bias was assessed based on three methodological components: (1) adjustment for length of stay prior to infection onset and consideration of time-dependent bias, (2) adjustment for comorbidities or severity of disease, and (3) adjustment for inappropriate antibiotic therapy. Results: Of 1094 identified studies, we identified 12 peer-reviewed articles and two reports that quantified the economic burden of clinically important resistant infections. Two studies used multi-state modelling to account for the timing of infection minimising the risk of time dependent bias and these were considered to generate the best available cost estimates. Studies report an additional CHF 9473 per extended-spectrum beta-lactamases -resistant Enterobacteriaceae bloodstream infections (BSI); additional €3200 per third-generation cephalosporin resistant Enterobacteriaceae BSI; and additional €1600 per methicillin-resistant S. aureus (MRSA) BSI. The remaining studies either partially adjusted or did not consider the timing of infection in their analysis. Conclusions: Implementation of AMR policy and decision-making should be guided only by reliable, unbiased estimates of effect size. Generating these estimates requires a thorough understanding of important biases and their impact on measured outcomes. This will ensure that researchers, clinicians, and other key decision makers concerned with increasing public health threat of AMR are accurately guided by the best available evidence.

Clinical management of drug-resistant bacteria in Australian hospitals: An online survey of doctors' opinions.

BACKGROUND: To gain a better understanding of clinical practice for the treatment of common drug-resistant infections. METHODS: A web-based anonymous survey was developed to gain a better understanding of clinical practice of patients infected with drug-resistant bloodstream infections (BSI). The survey instrument was a questionnaire requesting doctors to provide their opinion on the most likely choice of an antibiotic, dose and route of administration for patients infected with a drug-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Enterococcus faecium. RESULTS: All of the survey participants (n = 28) were hospital-based doctors. Choice of therapy for drug-resistant E. coli and K. pneumoniae was uniform across survey participants. However, optimal treatment of ceftazidime-resistant P. aeruginosa and VRE was less clear. CONCLUSION: The survey adds to the limited body of evidence in this clinical area and can be a useful tool for health economists in determining the additional cost of treating patients with drug-resistant infections.

How much do superbugs cost Australian hospitals? An evidence-based open-access tool.

Drug resistant "superbugs" are on the rise and pose a considerable threat. Little is known of their impact on health outcomes and costs to health services at a country-level. Local and relevant estimates that are realistic and derived with a transparent method can stimulate and inform policy responses. We describe an innovative online open-access tool, ResImpact that provides estimates of the national cost of common drug-resistant infections in Australia. Users are able to modify the proportion of five resistant organisms and be presented with an estimate of the associated healthcare costs. By translating complex economic data into a practical and user-friendly output, policy makers and other health professionals can improve their policy response for the Australian healthcare system.

Letter to the editor in response to estimating the burden of antimicrobial resistance: a systematic literature review.

The systematic review published by Naylor et al. in April 2018 highlights methodological assumptions and biases that occur in studies investigating the burden of antimicrobial resistance (AMR). They note that, due to both the large diversity of statistical approaches and perspectives chosen, the current evidence base of the burden of AMR is highly variable. Certainly, these conclusions are valid and the authors present a very thorough analysis of the currently published literature with a broad array of drug-bug combinations. But readers are left with limited direction of estimating the current best available estimate of the health and economic burden of AMR. Such estimates are desperately needed to inform clinical management and for priority setting activities and initiative to curbing the global threat of AMR.

Epidemiology of sexually transmissible infections in New South Wales: are case notifications enough?

BACKGROUND: Surveillance of sexually transmissible infections (STI)s is important to assess the disease burden in the population and to monitor and evaluate changes in trends over time. Routinely collected surveillance data in New South Wales are reliant on case reporting, which for many infections is an inadequate mechanism for capturing incidence and prevalence. Increasing rates of chlamydia over the past decade have sparked intense debate as to whether the current notification system is optimal and whether the true burden of infection are being measured. This study describes the current surveillance for STIs in New South Wales. METHODS: New South Wales-specific data for the years 2000-2009 were analysed. Notification data were used to examine the rate of the 4 STIs that are notifiable in New South Wales; chlamydia, gonorrhoea, infectious syphilis and HIV notifications. Hospital admissions and chlamydia-associated pelvic inflammatory disease were analysed using admitted patient data. RESULTS: Chlamydia was the most frequently reported of the notifiable STIs in New South Wales. Despite the higher rates of notification compared with other STIs, chlamydia-related hospitalisations contribute less than a 5th of all STI-related hospital admissions. Infectious syphilis contributed to the highest proportion of all STI-related hospitalisations in New South Wales and rates increased from 2000 to 2009. For other STIs such as anogenital herpes and gonorrhoea, hospital admissions remained stable for the same period. CONCLUSIONS: Notifications data for STIs should be complemented with hospital admission and other data sources to better describe STI morbidity. A synthesis of these data sources is needed to improve current surveillance and allow for better comparisons and trend analysis of STIs in New South Wales.

Mycobacterium bovis BCG-specific Th17 cells confer partial protection against Mycobacterium tuberculosis infection in the absence of gamma interferon.

Protective immunity against tuberculosis (TB) requires the integrated response of a network of lymphocytes. Both gamma interferon (IFN-γ)- and interleukin 17 (IL-17)-secreting CD4(+) T cells have been identified in subjects with latent TB infection and during experimental Mycobacterium tuberculosis infection, but the contribution of Th17 cells to protective immunity is unclear. To examine their protective effects in vivo, we transferred mycobacterium-specific IL-17- and IFN-γ-secreting CD4(+) T cells isolated from M. tuberculosis BCG-immunized IL-12p40(-/-) and IFN-γ(-/-) or wild-type mice, respectively, into M. tuberculosis-infected IL-12p40(-/-) or RAG(-/-) mice. In the absence of IL-12 and IL-23, neither IL-17-secreting (Th17) nor IFN-γ-secreting (Th1) BCG-specific T cells expanded or provided protection against M. tuberculosis. In RAG(-/-) recipients with an intact IL-12/IL-23 axis, both Th17 and Th1 cells were activated and induced significant protection against M. tuberculosis. The reduction in the bacterial load following transfer of IFN-γ(-/-) Th17 cells was associated with significant prolongation of survival compared to recipients of naïve IFN-γ(-/-) T cells. This effect was at the cost of an increased inflammatory infiltrate characterized by an excess of neutrophils. Therefore, Th17 cells can provide IFN-γ-independent protection against M. tuberculosis, and this effect may contribute to the early control of M. tuberculosis infection.

Putting science to work for health care reform: how much research is available to support improvements to our hospitals?

OBJECTIVE: To assess how much Australian research is available to inform reform of hospital services. DESIGN: Bibliographic analysis using a MEDLINE search to locate all research publications focused on the organisation and delivery of Australian hospital services for the period 1996 through 2007. MAIN OUTCOME MEASURES: Number of peer-reviewed articles published by year and categorised by: study design (descriptive, methodological, intervention); type of intervention; clinical focus; and funding source. RESULTS: 679 articles on the organisation and delivery of Australian hospital services were published in peer-reviewed journals from 1 January 1996 to 31 December 2007. Of these, 57% were empirical research reports and 43% were commentaries. There were, on average, 32 empirical research articles per annum. Of the empirical research articles, 70% were descriptive, 23% tested an intervention, and 7% were methodological. Research output increased over time with increases in commentary and descriptive research being the main contributors to this trend. The main funding bodies for this research were universities and government departments. CONCLUSION: A small but growing amount of local research is available to support reform of Australian hospital services. To boost the amount of relevant research evidence, we need to: build formal partnerships between researchers, policymakers, clinicians and health service managers; make targeted investment in health systems and services research; and increase the use of routinely collected data for research.

Antigen load governs the differential priming of CD8 T cells in response to the bacille Calmette Guerin vaccine or Mycobacterium tuberculosis infection.

One reason proposed for the failure of Mycobacterium bovis bacille Calmette Guérin (BCG) vaccination to adequately control the spread of tuberculosis is a limited ability of the vaccine to induce effective CD8 T cell responses. However, the relative capacity of the BCG vaccine and virulent Mycobacterium tuberculosis to induce activation of CD8 T cells, and the factors that govern the initial priming of these cells after mycobacterial infection, are poorly characterized. Using a TCR transgenic CD8 T cell transfer model, we demonstrate significant activation of Ag-specific CD8 T cells by BCG, but responses were delayed and of reduced magnitude compared with those following infection with M. tuberculosis. The degree of CD8 T cell activation was critically dependent on the level of antigenic stimulation, as modifying the infectious dose to achieve comparable numbers of BCG or M. tuberculosis in draining lymph nodes led to the same pattern of CD8 T cell responses to both strains. Factors specific to M. tuberculosis infection did not influence the priming of CD8 T cells, as codelivery of M. tuberculosis with BCG did not alter the magnitude of BCG-induced T cell activation. Following transfer to RAG-1(-/-) recipients, BCG and M. tuberculosis-induced CD8 T cells conferred equivalent levels of protection against M. tuberculosis infection. These findings demonstrate that BCG is able to prime functional CD8 T cells, and suggest that effective delivery of Ag to sites of T cell activation by vaccines may be a key requirement for optimal CD8 T cell responses to control mycobacterial infection.