Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Global antimicrobial-resistance drivers: an ecological country-level study at the human-animal interface.

BACKGROUND: Antimicrobial resistance (AMR) is a pressing, holistic, and multisectoral challenge facing contemporary global health. In this study we assessed the associations between socioeconomic, anthropogenic, and environmental indicators and country-level rates of AMR in humans and food-producing animals. METHODS: In this modelling study, we obtained data on Carbapenem-resistant Acinetobacter baumanii and Pseudomonas aeruginosa, third generation cephalosporins-resistant Escherichia coli and Klebsiella pneumoniae, oxacillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium AMR in humans and food-producing animals from publicly available sources, including WHO, World Bank, and Center for Disease Dynamics Economics and Policy. AMR in food-producing animals presented a combined prevalence of AMR exposure in cattle, pigs, and chickens. We used multivariable ß regression models to determine the adjusted association between human and food-producing animal AMR rates and an array of ecological country-level indicators. Human AMR rates were classified according to the WHO priority pathogens list and antibiotic-bacterium pairs. FINDINGS: Significant associations were identified between animal antimicrobial consumption and AMR in food-producing animals (OR 1·05 [95% CI 1·01-1·10]; p=0·013), and between human antimicrobial consumption and AMR specifically in WHO critical priority (1·06 [1·00-1·12]; p=0·035) and high priority (1·22 [1·09-1·37]; p<0·0001) pathogens. Bidirectional associations were also found: animal antibiotic consumption was positively linked with resistance in critical priority human pathogens (1·07 [1·01-1·13]; p=0·020) and human antibiotic consumption was positively linked with animal AMR (1·05 [1·01-1·09]; p=0·010). Carbapenem-resistant Acinetobacter baumanii, third generation cephalosporins-resistant Escherichia coli, and oxacillin-resistant Staphylococcus aureus all had significant associations with animal antibiotic consumption. Analyses also suggested significant roles of socioeconomics, including governance on AMR rates in humans and animals. INTERPRETATION: Reduced rates of antibiotic consumption alone will not be sufficient to combat the rising worldwide prevalence of AMR. Control methods should focus on poverty reduction and aim to prevent AMR transmission across different One Health domains while accounting for domain-specific risk factors. The levelling up of livestock surveillance systems to better match those reporting on human AMR, and, strengthening all surveillance efforts, particularly in low-income and middle-income countries, are pressing priorities. FUNDING: None.

Pharmacokinetics of TKM-130803 in Sierra Leonean patients with Ebola virus disease: plasma concentrations exceed target levels, with drug accumulation in the most severe patients.

BACKGROUND: TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored. METHODS: Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04-0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL). FINDINGS: Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p<0·025 both siRNAs). INTERPRETATION: TKM-130803 was circulating in molar excess of circulating virus; a level considered needed for efficacy. Given extremely high viral loads it seems likely that the patients died because they were physiologically beyond the point of no return. Subjects who died exhibited some indication of impaired drug clearance, justifying caution in dosing strategies for such patients. This analysis has given a useful insight into the pharmacokinetics of the siRNA in the disease state and illustrates the value of designing PKPD studies into future clinical trials in epidemic situations. FUNDING: This work was supported by the Wellcome Trust of Great Britain (grant number 106491/Z/14/Z and 097997/Z/11/A) and by the EU FP7 project PREPARE (602525). The PHE laboratory was funded by the UK Department for International Development. The funders had no role in trial design, data collection or analysis. The views expressed are those of the authors and not necessarily those of Public Health England, the Department of Health, or the EU. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429.

Antimicrobial susceptibility of uropathogens isolated from Cambodian children.

BACKGROUND: Bacterial resistance to commonly used antimicrobials is an increasing problem in Asia but information concerning the antimicrobial susceptibility of bacteria causing urinary tract infections (UTIs) in children is limited. METHODS: This was a 5-year retrospective study of children with suspected UTI attending a paediatric hospital in north-west Cambodia. Urines with a positive culture containing a single organism with a count of >10(5) colony-forming units (CFU)/ml were considered diagnostic of infection. The organism was identified and the resistance pattern (using CLSI guidelines) and presence of an extended-spectrum ß-lactamase (ESBL) phenotype was determined. RESULTS: In total, there were 217 episodes of infection, 210 (97%) with Gram-negative bacteria. Escherichia coli was the most common infecting isolate with high levels of resistance to most oral antibiotics, except nitrofurantoin. Nearly half of the E. coli (44%) were extended-spectrum cephalosporin (ESC)-resistant with the proportion increasing significantly over the 5-year period. ESC-resistant E. coli were more likely to be multi-drug-resistant and 91% demonstrated an ESBL phenotype. CONCLUSION: The data highlight the importance of microbiological surveillance of UTIs in children, particularly in areas where there are known to be multiply resistant organisms.

Clinically and microbiologically derived azithromycin susceptibility breakpoints for Salmonella enterica serovars Typhi and Paratyphi A.

Azithromycin is an effective treatment for uncomplicated infections with Salmonella enterica serovar Typhi and serovar Paratyphi A (enteric fever), but there are no clinically validated MIC and disk zone size interpretative guidelines. We studied individual patient data from three randomized controlled trials (RCTs) of antimicrobial treatment in enteric fever in Vietnam, with azithromycin used in one treatment arm, to determine the relationship between azithromycin treatment response and the azithromycin MIC of the infecting isolate. We additionally compared the azithromycin MIC and the disk susceptibility zone sizes of 1,640 S. Typhi and S. Paratyphi A clinical isolates collected from seven Asian countries. In the RCTs, 214 patients who were treated with azithromycin at a dose of 10 to 20 mg/ml for 5 to 7 days were analyzed. Treatment was successful in 195 of 214 (91%) patients, with no significant difference in response (cure rate, fever clearance time) with MICs ranging from 4 to 16 µg/ml. The proportion of Asian enteric fever isolates with an MIC of ≤ 16 µg/ml was 1,452/1,460 (99.5%; 95% confidence interval [CI], 98.9 to 99.7) for S. Typhi and 207/240 (86.3%; 95% CI, 81.2 to 90.3) (P < 0.001) for S. Paratyphi A. A zone size of ≥ 13 mm to a 5-µg azithromycin disk identified S. Typhi isolates with an MIC of ≤ 16 µg/ml with a sensitivity of 99.7%. An azithromycin MIC of ≤ 16 µg/ml or disk inhibition zone size of ≥ 13 mm enabled the detection of susceptible S. Typhi isolates that respond to azithromycin treatment. Further work is needed to define the response to treatment in S. Typhi isolates with an azithromycin MIC of >16 µg/ml and to determine MIC and disk breakpoints for S. Paratyphi A.