Persistence of ﬁrst-line antibiotic-resistant typhoid fever among Pakistani children: a growing concern for regional antimicrobial stewardship

short. A high prevalence of self-medication with antibiotics in the relatively unregulated Pakistani pharmaceutical market, including by sectors of the Karachi population with proﬁcient health literacy (15), is extremely troubling.

As the dissemination of S. Typhi is associated with poor hygiene and inadequate sewage systems infection is far more likely to affect people in low-income nations. While people of any age may contract TF the disproportionately high incidence in children suggests active community transmission. The actual burden of disease by country remains uncertain because many cases are unrecognized, particularly in young children who may present symptoms of a non-specific illness (2,5).
In recent years there has been an alarming rise in worldwide rates of antimicrobial resistance by pathogenic enteric bacteria, largely attributed to poor stewardship leading to the misuse of once highly-effective drugs. Multidrug-resistant (MDR) S. Typhi, defined as resistance to the three first-line antibiotics used to treat TF -ampicillin, chloramphenicol and cotrimoxazole, appeared in the 1970s and is now widespread globally. This is becoming extensively drug-resistant (XDR) S. Typhi (defined as MDR plus resistance to fluoroquinolones and third-generation cephalosporins), mainly through acquiring plasmids conferring antibiotic resistance via bacterial conjugation (commonly associated with the H-58 haplotype) (6,7). When an S. Typhi strain develops resistance by acquiring a promiscuous plasmid or undergoing genetic mutation consistent changes occur in the reported incidence of susceptibility to that antibiotic. Hence, thorough and continuous surveillance is a prerequisite to tracking the extent of resistance among S. Typhi strains and to gaining a better understanding of the factors involved in disease severity (8).
In Pakistan, the southeast province of Sindh is one of two, along with Punjab, that is most affected by TF . Approximately 1,000 TF cases per 100,000 children have been reported annually over several years in Karachi, the country's most populous city and provincial capital of Sindh, located on the Arabian Sea coast (9). We have recently shown evidence of multidrug resistance in S. Typhi isolated from children living in a poverty-stricken slum district of Karachi where water quality and standards of sanitation are both unsatisfactory (7). This first report of the emergence of confirmed cases of MDR S. Typhi from the only public hospital in its largest neighborhood identifies a grave public health concern. The rise in prevalence of MDR and, in some instances, XDR, S. Typhi that has been observed not only in Karachi but also in Hyderabad (6,9), the second-largest city in Sindh and situated 160 Km to the northeast of Karachi, constitutes a major humanitarian crisis. In 2018, of nearly 8,200 confirmed cases of TF in Sindh two-thirds were XDR, of which Karachi accounted for 69% (10).
Addressing ways to arrest the progressive development of antimicrobial drug resistance in Sindh is a public health challenge that should be prioritized if it is to both be contained locally and thus not to become established in other urban centers in other provinces of Pakistan. An elementary first step is the implementation of a regular and effective nationwide surveillance mechanism to enable clinical cases caused by MDR/XDR S. Typhi to be detected with reasonable accuracy. Moreover, a concerted and consolidated effort should be made to restrict ready access to non-prescribed antibiotics among the Microbes Infect Chemother, 2022, v.2, 1-3, e1301 Persistence of first-line antibiotic-resistant typhoid fever among Pakistani children: a growing concern for regional antimicrobial stewardship general public in South Asian and South East Asian countries through unregulated 'over the counter' pharmacy sales and black market trade (6,7). Not only does this widespread availability provide a natural selection pressure for antimicrobial resistance by S. Typhi and other bacterial pathogens it is evident that a suboptimal dose of antibiotics can reduce the severity of TF symptoms sufficiently to obfuscate or delay a confirmatory diagnosis of infection. Physicians also have a responsibility to limit the inefficient prescription of drugs to treat TF (6).
Since the outbreak of the COVID-19 pandemic at the end of 2019 low-income countries have justifiably refocused already strained public health services resources to the testing and treatment of patients with SARS-CoV-2. As an unfortunate consequence, initiatives to tackle neglected tropical diseases have suffered from reallocation of funds (11). Reviving these programs in Pakistan, including TF surveillance, diagnosis and vaccination, will require industrialized nations to commit generous and sustained aid. Pausing to digest the implications of COVID-19 could exacerbate the problem (12).
The growing resistance of S. Typhi strains to front-line antibiotics severely limits treatment options. In parallel with this challenge to effective therapy, however, a recent advancement in the control of TF is the roll out of a large-scale global vaccination program. This was initiated by the World Health Organization among children starting from six months of age in developing countries, of which Pakistan is at the forefront (13). In order to achieve equity in TF vaccination coverage nationwide, vaccine acceptance and participation of whole communities are needed, as are free-of-cost immunization and blood testing. In parallel to these interventions, another sustainable long-term solution is to take steps towards disease prevention by enhancing sanitation practices and providing clean, filtered water to the public.
Health literacy is relatively underexplored as a concept in Pakistan, and evidence from Karachi suggests that levels are low (14). Even where knowledge of risks is adequate, behavioral responses may fall short. A high prevalence of self-medication with antibiotics in the relatively unregulated Pakistani pharmaceutical market, including by sectors of the Karachi population with proficient health literacy (15), is extremely troubling.