Project 1: Clinical and Molecular Epidemiology of Antimicrobial Resistance in Invasive Bacteria from Nigerian Children.
Project Leader
- Stephen Obaro, MD, PhD
Team
- Bernard Eseoghene Ebruke, MBBS,MSc
- Christian T. Happi, PhD
- Nubwa Medugu, MBBS
- Claude Mambo Muvunyi, MBChB,PhD
- Xu Li, PhD
- Ian C. Michelow, MD, MMed, DTM&H
- Martin Miguel Conda Sheridan, PhD
Within the next decade, invasive bacterial infections are predicted to cause an increase in case fatality rates by an order of magnitude. This is especially true for many parts of Africa where the rate of antimicrobial resistance (AMR) is rampant, although still poorly defined. Therefore, it is imperative to elucidate the epidemiology, clinical sequelae, and mechanisms of AMR as a matter of priority. We propose a comprehensive field-to-laboratory investigation of Nigerian and Rwandan children with serious bacterial infections (SBI). This study will address an urgent unmet need in countries of West and East Africa, which are representative of other resource-limited African countries. Because prescriptions are not uniformly needed for access to antibiotics in many African countries, antimicrobials are frequently used indiscriminately. Furthermore, weak healthcare systems compel patients to use private pharmacies, which are often perceived as “rapid and affordable care”. In reality, they receive inferior care that is devoid of medical and microbiological expertise. These practices have contributed to the emergence of pan-resistant “superbugs” that pose a potentially devastating threat to the world.
Microbiologic diagnostic services in Africa are scarce or non-existent, which allows for the proliferation of multidrug resistant organisms (MDRO) as “silent killers” in people of all ages, both in the community as well as in healthcare settings. Even at places where clinical laboratories do exist, their tests are often rudimentary or inaccurate. Local laboratories do not have the capacity or funding to archive isolates, nor do they have the skills or sophisticated instruments needed to study the determinants of AMR or their clinical correlates. Through support from the Bill & Melinda Gates Foundation (Grant #OPP1034619, PI Obaro) and the National Institute of Allergy and Infectious Diseases (Grant # R01 AI097493, PI Obaro) we previously established a bacterial biorepository antimicrobial susceptibility testing (AST) capacity to address this critical need. Data from 2,750 bacteremia episodes derived from >25,000 Nigerian infected children <5 years, we confirmed that AMR in diverse bacterial strains is widely prevalent in central and northern Nigeria.
In CAMRA Project 1, we will expand this bacterial culture collection by including isolates from children in other locations in Nigeria, West Africa as well as Rwanda, East Africa. Our primary goal is to perform phenotypic and molecular characterization of MDROs, and to correlate MDRO bacteremia with clinical outcomes. Based upon our current surveillance efforts that reveal a preponderance of the NDM-5 carbapenemase in our clinical isolates, we hypothesize that the molecular epidemiology of extended-spectrum β-lactamase (ESBL)-producing organisms and carbapenem-resistant Enterobacteriales (CRE) in Africa are different from those described in Europe and the United States, which has implications for accurate diagnostic testing, effective antimicrobial therapy, risk of mortality, and potential global spread. We will test this hypothesis with the following specific aims:
Specific Aims
Analyze the phenotypic-genotypic profiles of archived Enterobacteriales from Nigeria and Rwanda.
- Characterize the distribution and determinants of AMR among Enterobacteriales and their attributable diseases in Nigeria and Rwanda.
- Determine human, animal, and environmental reservoirs of MDRO.
Project 2: Translating Genomics of AMR into Diagnostics and Therapeutics.
Project Leader
- Stephen Obaro, MD, PhD
Team
- Claude Mambo Muvunyi, MBChB, PhD
- Robert A. Bonomo, MD
- Mohamed Draz, PhD
- Umut Gurkan, PhD
Most infections in Africa present as an undifferentiated acute febrile illness (AFI), and since the prevalence of malaria is high across many regions, antimalarials are often the first line of empiric treatment, although bacteria and other pathogens may be the cause of illness. In children, clinicians often empirically add broad-spectrum antibiotics since serious bacterial infection cannot be confidently excluded given the dearth of microbiology diagnostic services. This indiscriminate use of broad-spectrum antibiotics, while sometimes lifesaving, is an important driver of antimicrobial resistance (AMR) in this setting. In this context, three major epidemiological characteristics in Africa confound the management of AFI in children: 1) the high prevalence of malaria, 2) poor availability and quality of diagnostic services, and 3) sickle cell disease, the most common genetic disorder on the continent, that amplifies the risk of mortality from malaria and bacteremia. In light of the incremental control of malaria over the last decade, the relative contribution of serious bacterial infections (SBI) and multidrug resistant organisms (MDRO) to morbidity and mortality warrants detailed evaluation. Furthermore, bacteremia is the leading cause of hospital admissions and deaths in children in sub-Saharan Africa, especially where children, who are partially immune to malaria, may have asymptomatic parasitemia.
Reliable and affordable microbiology diagnostic services are scarce in Africa; consequently, clinicians in low-income countries lack information on local causes of severe SBI and rely on empirical treatment guided by the World Health Organization (WHO) Integrated Management of Childhood Illnesses guidelines. Although these guidelines are useful, they may not accurately predict the causes of disease, risking poor clinical outcomes, and the promotion of antimicrobial resistance. WHO currently recommends the use of ampicillin and gentamicin for empiric treatment of neonatal sepsis. However, contemporary data on the etiology of SBI in newborns from low- and middle-income countries (LMIC), including Nigeria, have noted a high prevalence of extended-spectrum β-lactamase-producing Enterobacteriales (ESBL-E) and emerging strains of carbapenem-resistant Klebsiella species with case fatality rates in excess of 40%, thus rendering the WHO recommendations ineffective in this setting.
New approaches for prompt detection, prevention, and treatment of early onset neonatal sepsis and SBI in children caused by Enterobacteriales are urgently needed to curb the case fatality rate. There are currently a limited number of antibiotics that have an approved neonatal indication, and reformulation of one of these, such as tobramycin for enhanced bactericidal activity is worth exploring. The primary goal of CAMRA Project 2 is to build on our experience of developing an affordable and accurate portable point-of-care (POC) diagnostic test for malaria and sickle cell disease (Fig. 1) by incorporating tests for inflammatory markers, C-reactive protein (CRP) and procalcitonin (PCT) that have potential for differentiating SBI from malaria and viral infections. In addition, we will expand the diagnostic repertoire to include detection of MDROs through their gene products. We will accomplish our goals of translating clinical and molecular epidemiological studies of AMR into diagnostics and therapeutics with the following specific aims:
Specific Aims
Explore novel antimicrobial combinations for treatment of MDROs.
- Development of inflammatory biomarkers for bloodstream bacterial infection screening.
- Development of a screening tool for prevalent AMR enzymes