Abstract: 

Antimicrobial resistance (AMR) has emerged as a major public health threat resulting in increased economic and healthcare cost to treat infections with 700,000 annual deaths attributable to resistant infections. Highest burden of AMR is reported in low- and middle-income countries (LMICs) settings like Pakistan. In addition to high rates of AMR, LMICs like Pakistan also bears the highest burdens of infections caused by invasive pathogens. One of the most important pathogens responsible for high morbidity and mortality rates in Pakistan is Streptococcus pneumoniae (S. pneumoniae). It is a gram-positive facultative anaerobe that can cause infection in middle ear (otitis media), lungs (pneumonia), blood (sepsis) and meninges (meningitis). Children, elderly and immunocompromised individuals are the most susceptible to pneumococcal infections. Burden of these infections is distributed disproportionately amongst the geographic regions with 50% of the infections and deaths occurring in four countries including Pakistan. S. pneumoniae has been categorized into 100 serotypes on the basis of differences in chemical composition and structure of its polysaccharide capsule. These serotypes differ in their prevalence, virulence, and disease severity. Pneumococcal strains also vary at a genotypic level with few genotypes-serotypes combinations more resistant than the others. To decrease the burden of pneumococcal infections and AMR in pneumococci, 10-valent pneumococcal conjugate vaccine (PCV10) that protects against 10 pneumococcal serotypes was introduced in Pakistan in 2012. Introduction of PCVs has shown to reduce AMR and burden of infections caused by vaccine serotypes. Since the introduction of PCV10 in Pakistan, no study has reported the impact of vaccination on the pneumococcal population in terms of AMR, serotypes and genotypes distribution. 

Rationale: Antimicrobial resistance transmission and propagation is a multi-dimensional challenge requiring implementation of a multifaceted solution including improved hygiene measures, surveillance of AMR, administration of current vaccines, and development of new vaccines.  With the lack of AMR surveillance networks and reliable data on AMR distribution in Pakistan as well as lack of information on impact of PCV10 on pneumococcal serotypes, genotypes (STs and GPSCs), and AMR in Pakistan, this study fills the aforementioned gaps in knowledge and has following specific aims:

1. To determine patterns of AMR in pathogens isolated from blood and cerebrospinal fluid cultures in Pakistan,

2. To investigate the impact of vaccination on AMR in pneumococcal population using whole-genome sequencing approach, and 

3. To determine sequence heterogeneity of pneumococcal surface protein A, a potential vaccine target, in post-vaccine era in Pakistan.

Publications: 

1. Javaid, N., Sultana, Q., Rasool, K., Gandra, S., Ahmad, F., Chaudhary, S.U. and Mirza, S., 2021. Trends in antimicrobial resistance amongst pathogens isolated from blood and cerebrospinal fluid cultures in Pakistan (2011-2015): A retrospective cross-sectional study. PLoS One, 16(4), p.e0250226.

2. Javaid, N., Olwagen, C., Nzenze, S., Hawkins, P., Gladstone, R., McGee, L., Breiman, R.F., Bentley, S.D., Madhi, S.A. and Lo, S., 2022. Population genomics of pneumococcal carriage in South Africa following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) immunization. Microbial Genomics, 8(6), p.000831.

3. Martinez, P.J., Farhan, A., Mustafa, M., Javaid, N., Darkoh, C., Garrido-Sanabria, E., Fisher-Hoch, S.P., Briles, D.E., Kantarci, A. and Mirza, S., 2019. PspA facilitates evasion of pneumococci from bactericidal activity of neutrophil extracellular traps (NETs). Microbial pathogenesis, 136, p.103653.

4. Ashraf, M.U., Iman, K., Khalid, M.F., Salman, H.M., Shafi, T., Rafi, M., Javaid, N., Hussain, R., Ahmad, F., Shahzad‐Ul‐Hussan, S. and Mirza, S., 2019. Evolution of efficacious pangenotypic hepatitis C virus therapies. Medicinal research reviews, 39(3), pp.1091-1136.

Final Thesis Defence Committee:

Dr. Sultan Sial (Associate Professor, Department of Mathematics) 

Dr. Imran Nisar (Professor) External Thesis Committee Member, Assistant Professor & Vice Chair Research, Department of Pediatrics and Child Health, The Aga Khan University, Pakistan.

Dr. Shaper Mirza (Associate Professor, PhD Supervisor, Department of Life Sciences)

Dr. Safee Ullah Chaudhary (Associate Professor & Department Chair, Thesis Committee Member, Department of Life Sciences)

Dr. Adnan Khan (Associate Professor, Department of Mathematics)