Pediatric Drug-Resistant Tuberculosis: The Current and Future Prospects for Management and Prevention.

In the continued battle against one of the oldest enemies known to mankind, Mycobacterium tuberculosis (MTB), the emergence of drug resistance to antituberculosis drugs among children poses multiple challenges for early detection and treatment. Molecular diagnostics and newer drugs like bedaquiline and delamanid have strengthened the armamentarium and helped design convenient, safe, and child-friendly therapeutic regimens against drug-resistant tuberculosis (TB). Preventive strategies like treatment of TB infection among children living in close contact with patients with drug-resistant TB and effective vaccines against TB are currently in the investigative stages of development and implementation. In addition to the implementation of recent novel diagnostics and treatment modalities, effective psychosocial and nutritional support, as well as dedicated monitoring for compliance and adverse effects, are crucial determinants for successful treatment outcomes in these children.

Population structure and antimicrobial resistance patterns of Salmonella Typhi and Paratyphi A amid a phased municipal vaccination campaign in Navi Mumbai, India.

We performed whole-genome sequencing of 174 Salmonella Typhi and 54 Salmonella Paratyphi A isolates collected through prospective surveillance in the context of a phased typhoid conjugate vaccine introduction in Navi Mumbai, India. We investigate the temporal and geographical patterns of emergence and spread of antimicrobial resistance. We evaluated the relationship between the spatial distance between households and genetic clustering of isolates. Most isolates were non-susceptible to fluoroquinolones, with nearly 20% containing ≥3 quinolone resistance-determining region mutations. Two H58 isolates carried an IncX3 plasmid containing blaSHV-12, associated with ceftriaxone resistance, suggesting that the ceftriaxone-resistant isolates from India independently evolved on multiple occasions. Among S. Typhi, we identified two main clades circulating (2.2 and 4.3.1 [H58]); 2.2 isolates were closely related following a single introduction around 2007, whereas H58 isolates had been introduced multiple times to the city. Increasing geographic distance between isolates was strongly associated with genetic clustering (odds ratio [OR] = 0.72 per km; 95% credible interval [CrI]: 0.66-0.79). This effect was seen for distances up to 5 km (OR = 0.65 per km; 95% CrI: 0.59-0.73) but not seen for distances beyond 5 km (OR = 1.02 per km; 95% CrI: 0.83-1.26). There was a non-significant reduction in odds of clustering for pairs of isolates in vaccination communities compared with non-vaccination communities or mixed pairs compared with non-vaccination communities. Our findings indicate that S. Typhi was repeatedly introduced into Navi Mumbai and then spread locally, with strong evidence of spatial genetic clustering. In addition to vaccination, local interventions to improve water and sanitation will be critical to interrupt transmission. IMPORTANCE Enteric fever remains a major public health concern in many low- and middle-income countries, as antimicrobial resistance (AMR) continues to emerge. Geographical patterns of typhoidal Salmonella spread, critical to monitoring AMR and planning interventions, are poorly understood. We performed whole-genome sequencing of S. Typhi and S. Paratyphi A isolates collected in Navi Mumbai, India before and after a typhoid conjugate vaccine introduction. From timed phylogenies, we found two dominant circulating lineages of S. Typhi in Navi Mumbai-lineage 2.2, which expanded following a single introduction a decade prior, and 4.3.1 (H58), which had been introduced repeatedly from other parts of India, frequently containing "triple mutations" conferring high-level ciprofloxacin resistance. Using Bayesian hierarchical statistical models, we found that spatial distance between cases was strongly associated with genetic clustering at a fine scale (<5 km). Together, these findings suggest that antimicrobial-resistant S. Typhi frequently flows between cities and then spreads highly locally, which may inform surveillance and prevention strategies.

Harmonization of Amoxicillin Dose, Duration, and Formulation for Acute Childhood Respiratory Infections.

Pediatric guidelines vary in their recommended amoxicillin dosing for common respiratory infections. It would help program delivery if there was harmonization of dosing and formulation of amoxicillin across multiple clinical respiratory infections, considering the pharmacokinetics, common targets, drug resistance, availability, cost effectiveness, and ease of administration. The World Health Organization EML AWaRe Book recommends higher dose amoxicillin given twice daily for five days for all uncomplicated respiratory infections where an antibiotic is indicated. The WHO AWaRe Book amoxicillin dosing guidance can be achieved for infants and older children using only scored 250 mg and 500 mg dispersible tablets (DTs), the WHO recommended child formulation. There is a clear need for wider availability of 250 mg/500 mg dispersible tablets of amoxicillin in both public and private health care sectors, to improve access to essential antibiotics.

Programmatic Effectiveness of a Pediatric Typhoid Conjugate Vaccine Campaign in Navi Mumbai, India.

BACKGROUND: The World Health Organization recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018, the Navi Mumbai Municipal Corporation (NMMC) implemented a typhoid conjugate vaccine (TCV) campaign. The campaign targeted all children aged 9 months through 14 years within NMMC boundaries (approximately 320 000 children) over 2 vaccination phases. The phase 1 campaign occurred from 14 July 2018 through 25 August 2018 (71% coverage, approximately 113 420 children). We evaluated the phase 1 campaign's programmatic effectiveness in reducing typhoid cases at the community level. METHODS: We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai and offered blood cultures to children who presented with fever ≥3 days. We used a cluster-randomized (by administrative boundary) test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched test-positive, culture-confirmed typhoid cases with up to 3 test-negative, culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression. RESULTS: Between 1 September 2018 and 31 March 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (programmatic effectiveness, 56%; 95% confidence interval [CI], 25% to 74%; P = .002). Cases aged ≥5 years were 0.37 times as likely (95% CI, .19 to .70; P = .002) and cases during the first year of surveillance were 0.30 times as likely (95% CI, .14 to .64; P = .002) to live in vaccine campaign communities. CONCLUSIONS: Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever.

Oral Faropenem Sodium - Implications for Antimicrobial Resistance and Treatment Effectiveness.

Rising antimicrobial resistance (AMR) is causing therapeutic failures with antibiotics. Inappropriate use is a contributing factor. One such antibiotic on the radar is faropenem, a broad spectrum antibiotic approved in 2005 in India. Recently, faropenem sodium suspension was approved for use in children. There is a potential danger of overuse due to the convenience of oral administration. Other carbapenems such as meropenem are used parenterally. Overuse of faropenem may promote cross-resistance with other carbapenems making them ineffective.

Lessons from Vaccine-Related Poliovirus in Israel, UK and USA.

Genetic variants of vaccine poliovirus type 2, imported from an unknown source, were detected in waste waters in Jerusalem, London and New York in early 2022. Wild poliovirus type 2 was globally eradicated in 1999, but vaccine virus type 2 continued for 16 more years; routine use of the vaccine was discontinued in 2016 and reintroduced occasionally on purpose. As an unintended consequence, type 2 vaccine virus variants (circulating vaccine-derived polioviruses, cVDPVs) that mimic wild viruses' contagiousness and neurovirulence, have been emerging and spreading. To illustrate, in just the past four years (2018-2021), 2296 children developed cVDPV polio in 35 low-income countries. Many assume that virus transmission is via the faecal-oral route. Sustained virus transmission was documented in London and New York, in spite of high standards of sanitation and hygiene. Here, virus transmission cannot be attributed to faecal contamination of food or drinking water (for faecal-oral transmission). Hence, contagious transmission can only be explained by inhalation of droplets/aerosol containing virus shed in pharyngeal fluids (respiratory transmission), as was the classical teaching of polio epidemiology. If transmission efficiency of VDPV is via the respiratory route where hygiene is good, it stands to reason that it is the same case in countries with poor hygiene, since poor hygiene cannot be a barrier against respiratory transmission. By extrapolation, the extreme transmission efficiency of wild polioviruses must also have been due to their ability to exploit respiratory route transmission. These lessons have implications for global polio eradication. It was as a result of assuming faecal-oral transmission that eradication was attempted with live attenuated oral polio vaccine (OPV), ignoring its safety problems and very low efficacy in low-income countries. Inactivated poliovirus vaccine (IPV) is completely safe and highly efficacious in protecting children against polio, with just three routine doses. Protecting all children from polio must be the interim goal of eradication, until poliovirus circulation dies out under sustained immunisation pressure. OPV should be discontinued under cover of immunity induced by IPV to stop the emergence of new lineages of VDPVs, not only type 2, but also types 1 and 3, to expedite the completion of polio eradication.

Timely use of Covid-19 vaccines could have saved thousands of lives.

Earlier we, TJJ and DD, had written in IJME, that during the pandemic with high case-fatality in those above 65 and younger adults with chronic lung, heart or kidney diseases or diabetes, vaccination must be administered early as a life-saving procedure (1). It was pointed out that protection delayed may be protection denied to drive home the urgency of vaccination for saving lives. At that time, Phase III vaccine trials were in progress and we had adequate data on safety, but efficacy had yet to be measured. Good immunogenicity had already been documented in Phases I and II in which there were no signals of safety problems. Efficacy was "on promise" when we argued for early vaccination of those at risk of death.

Covid-19 vaccine trials and ethics: Protection delayed is protection denied.

The Covid-19 pandemic is raging, taking heavy toll of lives and livelihoods. The need for safe and effective vaccine(s) is urgent. Vaccine research has progressed rapidly and a few vaccine candidates have passed trial Phases 1 and 2, confirming reasonable safety and immunogenicity parameters. They are ready for large scale Phase 3 trials to quantify protective efficacy, if any, and to detect uncommon but serious adverse effects, if any. These developments present unprecedented opportunities and challenges, scientific and ethical. Globally hundreds die every day due to Covid-19, and emergency/compassionate use of vaccine candidates that are ready for Phase 3 trials are likely to save lives. We perceive an ethical imperative to allow such vaccination for those at high risk of death and voluntarily make such informed choice - for them protection delayed will be tantamount to protection denied.

COVID-19 Eradication for Vaccine Equity in Low Income Countries.

The coronavirus disease 2019 (COVID-19) pandemic will transition into endemic phase with perpetual risk of severe disease and high mortality in vulnerable people - the elderly and those with co-morbidities, unless eradicated. Although several vaccines are already available to rich countries, low-income countries face gross vaccine inequity. We propose COVID-19 eradication to address both problems. An eradication program will ensure vaccine equity and international cooperation to establish public health surveillance and high quality laboratory diagnostic services in all countries. Eradication is biologically and technically feasible. We hope the World Health Organization will accept the proposition and design the necessary strategy without delay.

Association of Empiric Antibiotic Regimen Discordance With 30-Day Mortality in Neonatal and Pediatric Bloodstream Infection-A Global Retrospective Cohort Study.

BACKGROUND: While there have been studies in adults reporting discordant empiric antibiotic treatment associated with poor outcomes, this area is relatively unexplored in children and neonates despite evidence of increasing resistance to recommended first-line treatment regimens. METHODS: Patient characteristics, antibiotic treatment, microbiology, and 30-day all-cause outcome from children <18 years with blood-culture-confirmed bacterial bloodstream infections (BSI) were collected anonymously using REDCap™ through the Global Antibiotic Prescribing and Resistance in Neonates and Children network from February 2016 to February 2017. Concordance of early empiric antibiotic treatment was determined using European Committee on Antimicrobial Susceptibility Testing interpretive guidelines. The relationship between concordance of empiric regimen and 30-day mortality was investigated using multivariable regression. RESULTS: Four hundred fifty-two children with blood-culture-positive BSI receiving early empiric antibiotics were reported by 25 hospitals in 19 countries. Sixty percent (273/452) were under the age of 2 years. S. aureus, E. coli, and Klebsiella spp. were the most common isolates, and there were 158 unique empiric regimens prescribed. Fifteen percent (69/452) of patients received a discordant regimen, and 7.7% (35/452) died. Six percent (23/383) of patients with concordant regimen died compared with 17.4% (12/69) of patients with discordant regimen. Adjusting for age, sex, presence of comorbidity, unit type, hospital-acquired infections, and Gram stain, the odds of 30-day mortality were 2.9 (95% confidence interval: 1.2-7.0; P = 0.015) for patients receiving discordant early empiric antibiotics. CONCLUSIONS: Odds of mortality in confirmed pediatric BSI are nearly 3-fold higher for patients receiving a discordant early empiric antibiotic regimen. The impact of improved concordance of early empiric treatment on mortality, particularly in critically ill patients, needs further evaluation.

Preoperative successful thrombectomy and thrombolysis of acute extensive splanchnic venous system and TIPSS thrombosis in a child with Budd-Chiari syndrome-Creating a window to enable living donor liver transplantation.

Preoperative extensive PV thrombosis can pose a technical challenge during liver transplantation surgery. Several strategies adopted to mitigate this problem include creation of a superior mesenteric vein-PV jump graft, use of a polytetrafluoroethylene graft, renoportal anastomosis, or cavoportal hemitransposition. Extensive and diffuse thrombosis of the splanchnic venous system may even necessitate multivisceral transplantation. We describe the case of a pediatric patient with Budd-Chiari syndrome and decompensated cirrhosis, who developed extensive thrombosis of the porto-spleno-mesenteric venous system prior to liver transplantation. We used a combination technique of thrombus aspiration by a novel trans-TIPPS approach followed by thrombolysis. Complete preoperative resolution of the extensive thrombosis was achieved. This allowed the creation of a brief window to enable planned LDLT. In prudently selected patients, performing an early mechanical and chemical thrombolysis of an extensive acute splanchnic venous thrombosis can thus help expedite a planned LDLT.

Influenza.

Influenza continues to baffle humans by its constantly changing nature. The twenty-first century has witnessed considerable advances in the understanding of the influenza viral pathogenesis, its synergy with bacterial infections and diagnostic methods. However, challenges continue: to find a less expensive and more reliable point-of-care test for use in developing countries, to produce more efficacious antiviral drugs, to explore ways to combat emerging antiviral resistance and to develop vaccines that can either be produced in a shorter production time or can overcome the need for annual matching with the circulating influenza strains. Most importantly for India, as a nation that suffered the highest mortality in the influenza pandemic 1918, there is an urgent need to gear up our existing preparedness for the next pandemic which is capable to hit at any moment in time.

The moral dilemma of the polio eradication programme.

During the last five years, globally, cases of polio caused by vaccine viruses have outnumbered those of polio caused by natural (wild) polioviruses, posing a moral dilemma. Public health ethics should ensure the best interests of the community, with equity in sharing benefits and risks irrespective of socioeconomic disparities. Vaccine viruses in oral polio vaccine (OPV) cause vaccine-associated paralytic polio (VAPP), while paralytic polio is also caused by vaccine-derived polioviruses (VDPVs). By its policy of the use of OPV in low and middle-income countries, while rich countries use the safe inactivated polio vaccine (IPV), the Global Polio Eradication Programme has been responsible for social injustice. In 2017 and 2018, there were outbreaks of polio in Syria and Papua New Guinea due to circulating VDPVs, after many years of these countries remaining free of polio due to wild polioviruses. The only ethical way forward for global polio eradication is to replace OPV with IPV in all countries.