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Bate J, Borrow R, Chisholm J, et al.
AbstractBackgroundChildren with acute lymphoblastic leukaemia (ALL) are at increased risk of invasive pneumococcal disease. This study describes the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13) during and after chemotherapy.MethodsChildren with ALL were allocated to study groups and received a single dose of PCV13: Group 1 - maintenance chemotherapy; Group 2 - end of chemotherapy; Group 3 - 6 months after chemotherapy. A protective vaccine response was defined as at least 10 of 12 serotypes (or greater than 83% of serotypes with data) achieving post-vaccination serotype-specific IgG ≥ 0.35 µg/mL and ≥ 4 fold rise, compared to pre-vaccination at 1 and 12 months.ResultsOne hundred and eighteen children were recruited. Only 12.8% (5/39; 95% CI 4.3% to 27.4%) of patients vaccinated during maintenance (Group 1) achieved a protective response at 1 month post-vaccination and none had a protective response at 12 months. For Group 2 patients, 59.5% (22/37; 95% CI 42.1% to 75.3%) achieved a response at 1 month and 37.9% (11/29; 95% CI 20.7% to 57.7%) maintained immunity at 12 months. For Group 3 patients, 56.8% (21/37; 95% CI 39.5% to 72.9%) achieved a protective response at 1 month and 43.3% (13/30; 95% CI 25.5% to 62.6%) maintained immunity at 12 months.ConclusionThis study demonstrated the earliest time point at which protective immunity can be achieved in children with ALL is on completion of chemotherapy. This is earlier than current recommendations and may improve protection during a period when children are most susceptible to infection.
Kempker, R. R., Alghamdi, W. A., Al-Shaer, M. H., Burch, G., Peloquin, C. A.
Tuberculosis (TB) and hepatitis C virus (HCV) infection are both major public health problems. Despite high rates of co-infection there is scarce literature addressing the convergence of the two diseases. One particularly unexplored area is the potential for simultaneous treatment of TB and HCV which would allow for leveraging an extensive global TB treatment infrastructure to help scale up HCV treatment. We review the drug metabolism of anti-TB and HCV drugs and the known and potential drug-drug interactions between recommended HCV regimens and individual anti-TB drugs. Rifampin is the only anti-TB drug to have been formally studied for potential drug interactions with anti-HCV direct-acting antivirals (DAAs) and existing data precludes these combinations. However, based on known pathways of drug metabolism and enzyme effects, the combination of HCV DAA regimens with all other anti-TB drugs may be feasible. Pharmacokinetic studies are needed next to help move co treatment regimens forward for clinical use among patients coinfected with TB and HCV.
Jacobson D, Lindsey J, Gordon C, et al.
AbstractBackgroundPerinatally HIV-infected (PHIV) children and adolescents with low bone mineral density (BMD) may be at higher risk of osteoporosis and fractures in later life than their uninfected peers. Bisphosphonate therapy has been shown to reduce fractures in adults with osteoporosis, but has not been formally studied in HIV-infected youth.MethodsFifty-two PHIV 11-0.99). No cases of jaw osteonecrosis, atrial fibrillation, or non-healing fractures were reported. Mean increases (95% confidence interval) in LS BMD over 48 weeks were significantly larger on alendronate [20% (14%, 25%)] than placebo [7% (5%, 9%), p
Petraitis, V., Petraitiene, R., Valdez, J. M., Pyrgos, V., Lizak, M. J., Klaunberg, B. A., Kalasauskas, D., Basevicius, A., Bacher, J. D., Benjamin, D. K., Hope, W. W., Walsh, T. J.
Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.
Belveyre, T., Guerci, P., Pape, E., Thilly, N., Hosseini, K., Brunaud, L., Gambier, N., Meistelman, C., Losser, M.-R., Birckener, J., Scala-Bertola, J., Novy, E.
Background: The optimal dose of cefoxitin for antibiotic prophylaxis in obese patients remains uncertain. We evaluated the adequacy of a 4-gram dosing regimen of cefoxitin against the most frequent pathogens that infect patients undergoing bariatric surgery.Methods: This observational prospective study included obese patients who required bariatric surgery and a 4-gram dose of cefoxitin as an antibiotic prophylaxis. Serum concentrations were measured during surgery (incision, wound closure and in case of reinjection). The pharmacokinetic/pharmacodynamic (PK/PD) target was to obtain free cefoxitin concentrations above 4x MIC, from incision to wound closure (100% fT>4xMIC). The targeted MIC was based on the worst-case scenario (the highest ECOFF value of Staphylococcus aureus, Enterobacteriaceae and anaerobic bacteria). The secondary outcomes were the factors related to underdosage.Results: Two hundred patients were included. The mean age of the patients was 46 (±12) years-old, and the mean BMI was 45.8 (±6.9) kg/m2. Bypass surgery was the preferred technique (84%). The percentages of patients who met the PK/PD target (100% fT>4xMIC) of cefoxitin were 37.3%, 1.1% and 0% for S. aureus, Enterobacteriaceae and anaerobic bacteria, respectively. BMIs below 50 kg/m2 (OR 0.29, 95% CI [0.11-0.75], P = 0.0107) and a shorter duration of surgery (OR 0.97, 95% CI [0.95-0.99], P = 0.004) were associated with reaching the target concentrations.Conclusions: In obese patients undergoing bariatric surgery, a regimen of 4 grams of cefoxitin led to an inadequate coverage for most common pathogens. A longer surgery duration and BMI over 50 kg/m2 increase the risk of underdosage.
Nagy, T. A., Quintana, J. L. J., Reens, A. L., Crooks, A. L., Detweiler, C. S.
Salmonella enterica are natural bacterial pathogens of humans and animals that cause systemic infection or gastroenteritis. During systemic infection, Salmonella generally reside within professional phagocytes, typically macrophages, whereas gastroenteritis is caused by infection of epithelial cells. We are only beginning to understand which host pathways contribute to Salmonella survival in particular cell types. We therefore sought to identify compounds that perturb Salmonella-host interactions using a chemical genetics approach. We found one small molecule, D61, that reduces Salmonella load in cell-line and primary macrophages but has no effect on Salmonella growth in epithelial cells or rich medium. We determined that in macrophages D61 induces LC3II, a marker of the autophagy pathway, and promotes aggregation of LC3II near Salmonella. We found that D61 antibacterial activity depends on the VPS34 complex and on ATG5. D61 also reduced Salmonella load in the spleens and livers of infected mice. Lastly, we demonstrate that D61 antibacterial activity in macrophages is synergistic with the antibiotic chloramphenicol, but that this synergy is largely independent of the known autophagy-stimulating activity of chloramphenicol. Thus, a small molecule has anti-bacterial activity specifically in macrophages and mice based on the promotion of bacterial degradation by autophagy.Importance Autophagy is a conserved cellular response to metabolic stress and to invading pathogens. For many pathogens, including Salmonella, autophagy can play a detrimental or beneficial role during infection depending on the cellular context. We combined chemical genetics with single cell analyses and murine infection to dissect host-pathogen interactions. We identified a small molecule that reduces bacterial load in macrophages by increasing autophagic flux. This compound also reduces bacterial colonization of tissues in infected mice. These observations demonstrate the potential therapeutic utility of stimulating autophagy in cells and animals to curb infection.
Goff D, Kullar R.
What can antimicrobial stewardship programs (ASPs) learn from a handshake? A handshake represents bringing people together, including adversaries, conveying trust, respect, balance, and equality. In the work environment, people often base their initial opinions of others off this gesture, so a handshake could be your secret weapon . J. Cohen describes the “perfect” handshake as one that gives colleagues the idea that you are trustworthy, confident, driven, and prepared.
Robinson-Papp J, Gensler G, Navis A, et al.
AbstractBackgroundCognitive dysfunction in HIV has decreased, but milder forms of HIV-associated neurocognitive disorders (HAND) persist along with motor dysfunction. The HIV Motor Scale (HMS) is a validated tool which captures motor abnormalities on routine neurologic examination, and which is associated with cognitive impairment in HIV. In this study, we applied a modified HMS (MHMS) to a nationwide cohort of people with longstanding HIV to characterize and understand the factors contributing to motor dysfunction.MethodsThe National NeuroAIDS Tissue Consortium (NNTC) is a nationwide longitudinal cohort study. Participants undergo regular assessments including neurological examination, neuropsychological testing and immunovirologic data collection. Data from examinations were used to calculate the MHMS score which was then correlated with history of AIDS-related CNS disorders (ARCD; e.g. prior CNS opportunistic infection), cerebrovascular disease (CVD) and HIV-associated neurocognitive disorder (HAND).ResultsSixty-nine percent of participants showed an abnormality on the MHMS, with 27% classified as severe. Results did not vary based on demographic or immunologic variables. The most common abnormalities seen were gait (54%) followed by coordination (39%) and strength (25%), and these commonly co-occurred. CVD (p=0.02), history of ARCD (p=0.001), and HAND (p=0.001) were all associated with higher (i.e. worse) HMS in univariate analyses; CVD and ARCD persisted in multivariate analyses. CVD was also marginally associated with symptomatic HAND.ConclusionsComplex motor dysfunction remains common in HIV and is associated with CVD, ARCD and to a lesser extent HAND. Future studies are needed to understand the longitudinal trajectory of HIV-associated motor dysfunction, its neural substrates and impact on quality of life.
Sviridov, Dmitri; Mukhamedova, Nigora; Makarov, Alexander A.; Adzhubei, Alexei; Bukrinsky, Michael
Combination anti-retroviral therapy (cART) has dramatically changed the outcome of HIV infection, turning it from a death sentence to a manageable chronic disease. However, co-morbidities accompanying HIV infection, such as metabolic and cardio-vascular diseases, as well as cognitive impairment, persist despite successful virus control by cART and pose considerable challenges to clinical management of people living with HIV (PLWH). These co-morbidities involve a number of pathological processes affecting a variety of different tissues and cells, making it challenging to identify a common cause(s) that would link these different diseases to HIV infection. In this article, we will present evidence that impairment of cellular cholesterol metabolism may be a common factor driving pathogenesis of HIV-associated co-morbidities. Potential implications for therapeutic approaches are discussed.
Correspondence to Dr. Michael Bukrinsky, GWU SMHS, 2300 Eye St. NW, Washington, DC 20037, USA. E-mail: firstname.lastname@example.org
Received 24 June, 2019
Revised 9 August, 2019
Accepted 9 September, 2019
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0
Copyright © 2019 Wolters Kluwer Health, Inc.
Persistent symptoms attributed to Lyme borreliosis often include self-reported cognitive impairment. However, it remains unclear whether these symptoms can be substantiated by objective cognitive testing.
For this observational study, cognitive performance was assessed in 280 adults with persistent symptoms attributed to Lyme borreliosis (as part of baseline data collected for the Dutch PLEASE study). Cognitive testing covered the five major domains: episodic memory, working memory / attention, verbal fluency, information-processing speed and executive function. Patients’ profiles of test scores were compared to a large age-, education- and sex-adjusted normative sample using multivariate normative comparison. Performance validity was assessed to detect suboptimal effort, and questionnaires were administered to measure self-reported cognitive complaints, fatigue, anxiety, depressive symptoms and several other psychological factors.
Of 280 patients, one was excluded as the test battery could not be completed. Of the remaining 279 patients, 239 (85.4%) displayed sufficient performance validity. Patients with insufficient performance validity felt significantly more helpless and physically fatigued, and less orientated. Furthermore, they had a lower education level and less often paid work. Of the total study cohort 5.7% (n = 16) performed in the impaired range. Among the 239 patients who displayed sufficient performance validity, 2.9% (n = 7) were classified as cognitively impaired. No association between subjective cognitive symptoms and objective impairment was found.
Only a small percentage of patients with borreliosis-attributed persistent symptoms have objective cognitive impairment. Performance validity should be taken into account in neuropsychological examinations of these patients. Self-report questionnaires are insufficiently valid to diagnose cognitive impairment.
ClinicalTrials.gov NCT01207739. Registered 23 September 2010.
Chen, I. H., Kidd, J. M., Abdelraouf, K., Nicolau, D. P.
Cefiderocol is a novel siderophore cephalosporin that utilizes bacterial ferric iron transports to cross the outer membrane. Cefiderocol shows high stability against all classes of β-lactamases, rendering it extremely potent against carbapenem- and multidrug-resistant Gram-negative organisms. Using a neutropenic murine thigh model, we compared the efficacies of human-simulated exposures of cefiderocol (2 g Q8H 3 h infusion) and ceftazidime (2 g Q8H 2 h infusion) against Stenotrophomonas maltophilia, an emerging opportunistic Gram-negative organism associated with serious and often fatal nosocomial infections. Twenty-four S. maltophilia isolates were studied, including isolates resistant to ceftazidime, trimethoprim-sulfate, and/or levofloxacin. The thighs were inoculated with bacterial suspensions of 108 CFU/mL and the human-simulated regimens were administered over 24 h. Efficacy was measured as the change in log10CFU/thigh at 24 h compared with 0 h controls. Cefiderocol human-simulated exposure demonstrated potent bacterial killing; mean bacterial reduction at 24 h was -2.67 ± 0.68 log10CFU/thigh with ≥ 2 log-reduction achieved in 21 isolates (87.5%) and ≥ 1 log-reduction achieved in the remaining three isolates (12.5%). In comparison, ceftazidime human-simulated exposure produced mean bacterial reduction of -1.38 ± 1.49 log10CFU/thigh among 10 ceftazidime-susceptible isolates and mean bacterial growth of 0.64 ± 0.79 log10CFU/thigh among 14 ceftazidime-non-susceptible isolates. While ceftazidime showed modest efficacy against most susceptible isolates, humanized cefiderocol exposures resulted in remarkable in vivo activity against all S. maltophilia isolates examined, inclusive of ceftazidime-non-susceptible isolates. The potent in vitro and in vivo activity of cefiderocol supports the development of this novel compound for managing S. maltophilia infections.
Chen, C., Wu, X.-T., He, Q., Chen, L., Cui, C.-Y., Zhang, Y., Chen, S.-H., Liao, X.-P., Liu, Y.-H., Sun, J.
Recently, a novel plasmid-mediated tigecycline resistance mechanism, Tet(X4), has raised a global antimicrobial resistance concern (1, 2)....
Janefrancis Ijeoma Duru, Samuel Usman, Opeyemi Adeosun, Katherine V. Stamidis and Lydia Bologna
The Northern states were the epicenter of the wild poliovirus outbreak in Nigeria in 2016. To raise immunization coverage, particularly of polio, the Polio Eradication Initiative (PEI) in Nigeria introduced the use of nongovernmental organizations and volunteer community mobilizers (VCMs) through the CORE Group Polio Project (CGPP). The CGPP has been contributing to Nigeria’s polio eradication efforts since 2013. This article explores the contributions of the 2,130 VCMs deployed in 31 participating local government areas in the five implementing CGPP states from 2014 to 2017 to increase awareness, understanding, and acceptance of polio immunization. Data for the study were collected from primary and secondary sources using five collection methods: a survey of VCM supervisors, focus group discussions with VCMs and their supervisors, key in-depth interviews with community stakeholders, case studies of specific best practices of VCMs, and a review of documents and records. A review of the data shows that the VCMs received comprehensive training on the importance of the PEI, routine immunization, Acute Flaccid Paralysis (AFP) surveillance, social mobilization and community engagement, use of behavior change communication tools, and interpersonal communication skills. According to the data collected, the VCMs used the following innovative strategies to ensure high vaccination coverage: house-to-house mobilization, community dialogues, compound meetings, community health camps, and tracking of non-compliant families, missed children, and dropouts. The involvement of VCMs in Nigeria’s PEI efforts has been a pivotal contribution to reductions in the number of households rejecting polio immunization, the proportion of families with missed children, the proportion of families that were non-compliant, and the number of polio cases.
Ly K, Miniño A, Liu S, et al.
AbstractBackgroundHepatitis C virus (HCV)-associated mortality is well-documented nationally, but examination across regions and jurisdictions may inform healthcare planning.MethodsTo document HCV-associated deaths sub-nationally, we calculated age-adjusted HCV-associated death rates, compared death rate ratios (DRR) for ten US regions, 50 states, and District of Columbia (DC) with the national rate and described rate changes between 2016 and 2017 to determine variability. We examined mean age at HCV-associated death and rates and proportions by sex, race/ethnicity, and birth year.ResultsIn 2017, there were 17,253 HCV-associated deaths, representing 4.13 (95% CI, 4.07-4.20) deaths/100,000 standard population, a significant 6.56% rate decline from 4.42 in 2016. Age-adjusted death rates significantly surpassed the US rate for the following jurisdictions: Oklahoma, DC, Oregon, New Mexico, Louisiana, Texas, Colorado, California, Kentucky, Tennessee, Arizona, and Washington (DRR, 2.87, 2.77, 2.24, 1.62, 1.57, 1.46, 1.36, 1.35, 1.35, 1.35, 1.32, 1.32, respectively) (P
Kordalewska, M., Lee, A., Zhao, Y., Perlin, D. S.
Accurate and rapid assessment of Candida auris antifungal drug resistance is crucial for effective infection prevention and control actions, and patient management. Here, performance of a molecular diagnostic platform, enabling rapid identification of FKS1 and ERG11 mutations conferring echinocandin and azole resistance, respectively, was evaluated on a panel of clinical skin swabs. Gene sequencing and antifungal susceptibility testing were used as "gold standard". All swabs were correctly categorized as harboring wild-type or mutant C. auris.
Mergenhagen K, Starr K, Wattengel B, et al.
AbstractBackgroundTreatment of suspected methicillin-resistant Staphylococcus aureus (MRSA) is a cornerstone of many antibiotic regimens; however, antibiotics are associated with toxicity. The Department of Veterans Affairs (VA) hospitals screen each patient on admission and transfer for MRSA nares colonization. The objective of this study was to determine the negative predictive value (NPV) of MRSA screening in the determinization of subsequent positive clinical culture for MRSA. High NPVs with MRSA nares screening maybe used as a stewardship tool for de-escalation as well as avoidance of anti-MRSA therapy.MethodsThis was a retrospective cohort study across VA medical centers nationwide from January 1, 2007 to January 1, 2018. Data from patients with MRSA nares screening upon admission or transfer were obtained from the VA Corporate Data Warehouse. Subsequent clinical cultures within 7 days of the nares swab were evaluated for presence of MRSA. Sensitivity, specificity, positive predictive values (PPVs), and NPVs were calculated for the entire cohort, as well as subgroups for specific culture sites.ResultsThis cohort yielded 561,325 clinical cultures from a variety of anatomical sites. The sensitivity and specificity for positive MRSA clinical culture were 67.4% and 81.2%, respectively. The NPV of MRSA nares screening for ruling out MRSA infection was 96.5%. The NPV for bloodstream infections was 96.5%, for intra-abdominal cultures was 98.6%, for respiratory cultures was 96.1%, for wound cultures was 93.1%, and for cultures from the urinary system was 99.2%.ConclusionGiven the high NPVs, MRSA nares screening may be a powerful stewardship tool for de-escalation and avoidance of empirical anti-MRSA therapy.
Rock C, Maragakis L.
Berthaud, R., Benaboud, S., Hirt, D., Genuini, M., Oualha, M., Castelle, M., Briand, C., Artru, S., Norsa, L., Boyer, O., Foissac, F., Bouazza, N., Treluyer, J.-M.
Methicillin-resistant staphylococcal infections are a global burden. Area under the serum concentration-time curve to minimum inhibitory concentration (AUC/MIC) ratio is the pharmacokinetic (PK) parameter that best predicts vancomycin efficacy. Its therapeutic range is narrow, difficult to achieve because of a wide intersubject variability, especially in children, and is not routinely targeted since the AUC is rarely available. We investigated if an early Bayesian dose adjustment would increase the rate of vancomycin target attainment, in the first 24 hours of treatment (H24), in children.We conducted a single-centre randomized controlled trial in 4 pediatric departments of Necker-Enfants Malades hospital (Paris, France). Patients aged 3 months to 17 years for whom intravenous vancomycin was started were eligible and randomized in a 1:1 ratio: routine care were compared with an early vancomycin therapeutic drug monitoring (3h after treatment initiation) followed by an early Bayesian dose adjustment using a previously published population-based PK model that included age, bodyweight and serum creatinine as covariates. The primary outcome was the proportion of patients of each group achieving vancomycin therapeutic range at H24, defined by AUC0-24/MIC≥400 and AUC0-24 ≤800mg-h/L.Ninety-nine patients were enrolled: 49 were randomized to the Bayesian group and 50 to the control group. Modified intention-to-treat analysis included 82 patients: 85% of Bayesian group patients achieved H24 vancomycin target versus 57% of control group patients (p=0.007) with no difference regarding iatrogenic events. Early Bayesian dose adjustment increased the proportion of children achieving vancomycin target at H24, which may improve clinical outcomes of methicillin-resistant staphylococcal infections.
Clancy, C. J., Nguyen, M. H.
New antibiotics with activity against carbapenem-resistant Enterobacteriaceae (CRE) improve outcomes of CRE-infected patients. However, companies developing these drugs have faced financial difficulties. Sales of ceftazidime-avibactam, meropenem-vaborbactam and plazomicin in the United States (US) totaled $101 million from February 2018-January 2019. We estimate the current annual US market for new anti-CRE antibiotics is $289 million (range: $169-$439 million). Without new antibiotic development models and/or reimbursement reform, the majority of anti-CRE drugs will be commercially inviable.
Anthony Kisanga, Bausumo Abiuda, Peter Walyaula, Lee Losey and Omongot Samson
This article describes the functionality and effectiveness of a community-based acute flaccid paralysis (AFP) surveillance system designed and implemented by the CORE Group Polio Project (CGPP) in conflict-affected and inaccessible areas of South Sudan between October 2015 and September 2017. The findings are based on interviews with key informants and focus group discussions as well as data from the CGPP and the management information system of the WHO. Through the implementing partners, the CGPP identified and built the capacity of the community-based surveillance (CBS) system, a system consisting of county supervisors, payam (sub-county) assistants, and community key informants. This structure played a critical role in the identification and reporting of AFP cases. The CGPP also established partnerships with other key players–local and international–to reach greater numbers of people, particularly displaced populations. Evaluation findings show an increase from 0.0% to 56.4% of cases reported through the CBS system between January 2016 and June 2017, and 80.0% of the cases reported within WHO standards of 24–48 hours were through the CBS system, whereas 20.0% were through the facility-based system. The CBS system also recorded an increase from 36.0% in 2014 to 92.0% in December 2016 for the number of counties that were reporting AFP. A CBS system is, therefore, a valuable complement to facility-based surveillance in insecure environments or where the population has limited access to facilities. Community-based surveillance systems also have the potential to identify cases of other infectious diseases of public health importance.
Hand, foot and mouth disease (HFMD) is a rising public health problem and has attracted considerable attention worldwide. The purpose of this study was to develop an optimal model with meteorological factors to predict the epidemic of HFMD.
Two types of methods, back propagation neural networks (BP) and auto-regressive integrated moving average (ARIMA), were employed to develop forecasting models, based on the monthly HFMD incidences and meteorological factors during 2009–2016 in Jiangsu province, China. Root mean square error (RMSE) and mean absolute percentage error (MAPE) were employed to select model and evaluate the performance of the models.
Four models were constructed. The multivariate BP model was constructed using the HFMD incidences lagged from 1 to 4 months, mean temperature, rainfall and their one order lagged terms as inputs. The other BP model was fitted just using the lagged HFMD incidences as inputs. The univariate ARIMA model was specified as ARIMA (1,0,1)(1,1,0)12 (AIC = 1132.12, BIC = 1440.43). And the multivariate ARIMAX with one order lagged temperature as external predictor was fitted based on this ARIMA model (AIC = 1132.37, BIC = 1142.76). The multivariate BP model performed the best in both model fitting stage and prospective forecasting stage, with a MAPE no more than 20%. The performance of the multivariate ARIMAX model was similar to that of the univariate ARIMA model. Both performed much worse than the two BP models, with a high MAPE near to 40%.
The multivariate BP model effectively integrated the autocorrelation of the HFMD incidence series. Meanwhile, it also comprehensively combined the climatic variables and their hysteresis effects. The introduction of the climate terms significantly improved the prediction accuracy of the BP model. This model could be an ideal method to predict the epidemic level of HFMD, which is of great importance for the public health authorities.
Alamiri, F., Riesbeck, K., Hakansson, A. P.
HAMLET is a protein-lipid complex derived from human milk that was first described for its tumoricidal activity. Later studies showed that HAMLET also has direct bactericidal activity against select species of bacteria, with highest activity against Streptococcus pneumoniae. Additionally, HAMLET in combination with various antimicrobial agents can make a broader range of antibiotic-resistant bacterial species sensitive to antibiotics. Here, we show that HAMLET has direct antibacterial activity not only against pneumococci, but also against Streptococcus pyogenes (GAS) and Streptococcus agalactiae (GBS). Analogous to pneumococci, HAMLET-treatment of GAS and GBS resulted in depolarization of the bacterial membrane followed by membrane permeabilization and death that could be inhibited by calcium and sodium transport inhibitors. Treatment of clinical antibiotic-resistant isolates of S. pneumoniae, GAS, and GBS with sublethal concentrations of HAMLET in combination with antibiotics decreased the minimal inhibitory concentrations of the respective antibiotic into the sensitive range. This effect could also be blocked by ion transport inhibitors, suggesting that HAMLET's bactericidal and combination treatment effects used similar mechanisms. Finally, we show that HAMLET potentiated the effects of erythromycin against erythromycin-resistant bacteria more effectively than it potentiated killing by penicillin G of bacteria resistant to penicillin G. These results show for the first time that HAMLET effectively kills three different species of pathogenic Streptococci using similar mechanisms and also potentiate the activity of macrolides and lincosamides more effectively than combination treatment with beta-lactams. These findings suggest a potential therapeutic role for HAMLET in repurposing antibiotics currently causing treatment failures in patients.
Bidaud, A. L., Botterel, F., Chowdhary, A., Dannaoui, E.
Candida auris is an emerging, multidrug resistant pathogen, responsible for invasive hospital-acquired infections. Flucytosine is an effective anti-Candida drug, but which cannot be used as a monotherapy because of the risk of development of resistant mutants during treatment. It is therefore noteworthy to test possible combinations with flucytosine that may have a synergistic interaction. In this study, we determined the in vitro interaction between flucytosine and amphotericin B, micafungin, or voriconazole. These combinations have been tested against 15 C. auris isolates. The MIC range (Gmean) of flucytosine, amphotericin B, micafungin and voriconazole were 0.125 to 1 μg/mL (0.42 μg/ml), 0.25 to 1 μg/ml (0.66 μg/ml), 0.125 to 0.5 μg/ml (0.3 μg/ml) and 0.03 to 4 μg/ml (1.05 μg/ml), respectively. When tested in combination, indifferent interactions were mostly observed with fractional inhibitory concentration index values from 0.5 to 1, 0.31 to 1.01 and 0.5 to 1.06 for the combination of flucytosine with amphotericin B, micafungin and voriconazole, respectively. A synergy was observed for the strain CBS 10913 from Japan. No antagonism was observed for any combination. Combination of flucytosine with amphotericin B or micafungin may be relevant for the treatment of C. auris infections.
Intestinal schistosomiasis is highly endemic in Tanzania and mass drug administration (MDA) using praziquantel is the mainstay of the control program. However, the MDA program covers only school aged children and does not include neither adult individuals nor other public health measures. The Ijinga schistosomiasis project examines the impact of an intensified treatment protocol with praziquantel MDA in combination with additional public health interventions. It aims to investigate the feasibility of eliminating intestinal schistosomiasis in a highly endemic African setting using an integrated community-based approach. In preparation of this project, we report about baseline data on S.mansoni prevalence, intensity of infection, related hepatosplenic morbidities and their associated factors.
A cross sectional study was conducted among 930 individuals aged 1–95 years living at Ijinga Island, north-western Tanzania in September 2016. Single stool and urine samples were collected from each study participant and processed using Kato Katz (KK) technique and point-of-care Circulating Cathodic (POC-CCA) antigen test for detection of S.mansoni eggs and antigen respectively. Ultrasonographical examination for S.mansoni hepatosplenic morbidities was done to all participants. For statistical analyses Fisher’s exact test, chi-square test, student-t-test, ANOVA and linear regression were used where applicable.
Overall based on KK technique and POC-CCA test, 68.9% (95%CI: 65.8–71.8) and 94.5% (95%CI: 92.8–95.8) were infected with S.mansoni. The overall geometrical mean eggs per gram (GMepg) of faeces was 85.7epg (95%CI: 77.5–94.8). A total of 27.1, 31.2 and 51.9% of the study participants had periportal fibrosis (PPF-grade C-F), splenomegaly and hepatomegaly. Risk factors for PPF were being male (aRR = 1.08, 95%CI: 1.02–1.16, P
White N, Mendo-Lopez R, Papamichael K, et al.
AbstractBackgroundTo optimize utility of laboratory testing for Clostridiodes difficile infection (CDI), the 2017 Infectious Diseases Society of America-Society for Healthcare Epidemiology of America (IDSA-SHEA) clinical practice guidelines recommend excluding patients from stool testing for C. difficile if they have received laxatives within the preceding 48 hours. Sparse data support this recommendation.MethodsPatients with new-onset diarrhea (≥3 bowel movements in any 24 hour period in the 48 hours before stool collection) and a positive stool C. difficile nucleic acid amplification test (NAAT) were enrolled. Laxative use within 48 hours prior to stool testing, severity of illness (defined by four distinct scoring methods), and clinical outcomes were recorded.Results209 patients with CDI were studied, 65 of whom had received laxatives. There were no significant differences in the proportion of patients meeting severe CDI criteria by four severity scoring methods, in patients receiving versus not receiving laxatives (66.2% vs 56.3%, respectively, p = 0.224) by IDSA-SHEA, the primary scoring system. Similar rates of serious outcomes attributable to CDI, including death, ICU admission, and colectomy, were observed in the laxative and no laxative groups.ConclusionOur study found similar rates of severe CDI and serious CDI-attributable clinical outcomes in CDI-diagnosed patients who did or did not receive laxatives. Precluding recent laxative users from CDI testing, as proposed by the IDSA-SHEA guideline, carries a potential for harm due to delayed diagnosis and treatment.
Henry B. Perry, Roma Solomon, Filimona Bisrat, Lisa Hilmi, Katherine V. Stamidis, Robert Steinglass, William Weiss, Lee Losey and Ellyn Ogden
Despite numerous setbacks, the Global Polio Eradication Initiative has implemented various community strategies with potential application for other global health issues. This article reviews strategies implemented by the CORE Group Polio Project (CGPP), including pursuit of the missed child, microplanning, independent campaign monitoring, using community health workers and community mobilizers to build community engagement, community-based surveillance, development of the capacity to respond to other health needs, targeting geographic areas at high risk, the secretariat model for non-governmental organization collaboration, and registration of vital events. These strategies have the potential for contributing to the reduction of child and maternal mortality in hard-to-reach, underserved populations around the world. Community-based surveillance as developed by the CGPP also has potential for improving global health security, now a global health priority.
Pincus N, Bachta K, Ozer E, et al.
AbstractBackgroundAntimicrobial resistance (AMR) is a major challenge in the treatment of infections caused by Pseudomonas aeruginosa. Highly drug-resistant infections are disproportionally caused by a small subset of globally distributed P. aeruginosa sequence types (STs), termed “high-risk clones." We noted that clonal complex (CC) 446 (which includes STs 298 and 446) isolates were repeatedly cultured at one medical center and asked whether this lineage might constitute an emerging high-risk clone.MethodsWe searched P. aeruginosa genomes from collections available from several institutions and from a public database for the presence of CC446 isolates. We determined antibacterial susceptibility using microbroth dilution and examined genome sequences to characterize the population structure of CC446 and investigate the genetic basis of AMR.ResultsCC446 was globally distributed over 5 continents. CC446 isolates demonstrated high rates of AMR with 51.9% (28/54) being multi-drug resistant (MDR) and 53.6% of these (15/28) being extensively drug resistant (XDR). Phylogenetic analysis revealed that most MDR/XDR isolates belonged to a subclade of ST298 (designated ST298*) of which 100% (21/21) were MDR and 61.9% (13/21) were XDR. XDR ST298* was identified repeatedly and consistently at a single academic medical center from 2001-2017. These isolates harbored a large plasmid that carries a novel antibiotic resistance integron.ConclusionsCC446 isolates are globally distributed with multiple occurrences of high AMR. The subclade ST298* is responsible for a prolonged epidemic (≥16 years) of XDR infections at an academic medical center. These findings indicate that CC446 is an emerging high-risk clone deserving further surveillance.
Zimmerman F, Karameh H, Ben-Chetrit E, et al.
AbstractBackgroundBlood culture contamination leads to unnecessary interventions and costs. It may be caused by bacteria in deep skin structures unsusceptible to surface decontamination. This study was designed to test whether diversion of blood obtained at venipuncture into a lithium-heparin tube prior to aspiration of blood culture reduces contamination.MethodsThe order of blood draws for biochemistry and blood cultures was randomized. Following standard disinfection and venipuncture, blood was either aspirated into a sterile lithium-heparin tube before blood culture bottles (diversion group) or blood cultures first and then lithium-heparin tube (control group). All study personnel were blinded with the exception of the phlebotomist.ResultsAfter exclusions, 970 blood culture/biochemistry sets were analysed. Contamination occurred in 24/480 (5.0%) control versus 10/490 (2.0%) diversion group cultures (p=0.01). True pathogens were identified in 26/480 (5.4%) control versus 18/490 (3.7%) diversion cultures (p=0.22). Despite randomization, demographic differences were apparent between the two groups. A post-hoc analysis of 637 cultures from 610 medical patients admitted from home neutralized demographic differences. Culture contamination remained more frequent in the control versus diversion group (17/312, 5% versus 7/325, 2%, p=0.03). Fewer diversion group patients were admitted to hospital (control: 200/299 – 66.9% versus diversion: 182/311 – 58.5%, p=0.03), and length of stay was shorter (control: 30 hours, interquartile range 6-122, versus diversion: 22, range 5-97, p=0.02).ConclusionsUse of lithium-heparin tubes for diversion prior to obtaining blood cultures lead to a 60% decrease in contamination. This technique is easy and cheap and might decrease overall hospital length of stay.Clinical Trials Registration: NCT03966534
Martinello M, Yee J, Bartlett S, et al.
AbstractBackgroundMicro-elimination of HCV among people living with HIV may be feasible in Australia, given unrestricted access to direct-acting antiviral (DAA) therapy from 2016. Our aim was to evaluate progress towards elimination goals within HIV/HCV co-infected adults in Australia following universal DAA access.MethodsThe CEASE prospective cohort study enrolled HIV/HCV positive adults, irrespective of viremic status, from 14 primary and tertiary clinics in Australia. Annual and cumulative HCV treatment uptake, outcome, and HCV RNA prevalence were evaluated, with follow-up through May 2018 (median follow-up: 2.63 years). Factors associated with DAA uptake were analysed.ResultsBetween July 2014 and March 2017, 402 HIV/HCV antibody-positive participants were enrolled (95% male [80% gay and bisexual men,], 13% cirrhosis, 80% history of injecting drug use [39% current injecting]). Following universal DAA access, annual HCV treatment uptake in those eligible increased from 7% and 11% per year in 2014 and 2015, respectively, to 80% in 2016. By 2018, cumulative HCV treatment uptake in those ever eligible for treatment was 91% (336/371). HCV viremic prevalence declined from 82% (95%CI 78%, 86%) in 2014 to 8% (95%CI 6%, 12%) in 2018. Reinfection was reported in only five participants for a reinfection incidence of 0.81 per 100-person years (95% CI 0.34, 1.94).ConclusionsHigh uptake and effectiveness of unrestricted DAA therapy in Australia has permitted rapid treatment scale-up, with a dramatic reduction in HCV infection burden and low reinfection rate among people living with HIV, suggesting that micro-elimination is feasible.
Acinetobacter baumannii is an increasingly worrying organism in the healthcare setting, due to its multidrug resistance and persistence. Prolonged hospitalisation, immunocompromised patients and excessive antibiotic exposure all contribute to increasing the risk of A. baumannii infections, which makes cancer patients a significant risk group. This study aims to investigate the dissemination of A. baumannii at the National Cancer Institute (NCI) in Cairo – Egypt.
All bacterial isolates were typed using Multi-locus Sequence Typing (MLST) to characterise the epidemiology of isolates. The intrinsic OXA-51-like, and the acquired carbapanemases OXA-23, − 24/40, − 58, NDM, IMP, and VIM were also amplified and sequenced to genetically identify mechanisms of carbapenem resistance.
MLST results show a high degree of multi-clonal dissemination, with 18 different Sequence Types (STs) identified, including 5 novel. The majority of isolates belonged to International Clone (IC) 2, and carbapenem resistance was detected in 93% of isolates and mediated by blaOXA-23, blaOXA-58, blaNDM-1 and blaVIM-1. We also report the presence of a resistant ST732 (OXA-378) which has been previously identified in migratory birds.
Multiple highly resistant clones were identified in a Cancer hospital in Cairo. It is vital that clinicians and healthcare workers are aware of the population of A. baumannii present in order to have appropriate treatment and infection control practices.
Wamae, K., Okanda, D., Ndwiga, L., Osoti, V., Kimenyi, K. M., Abdi, A. I., Bejon, P., Sutherland, C., Ochola-Oyier, L. I.
Antimalarial drug resistance is a substantial impediment to malaria control. The spread of resistance has been described using genetic markers which are important epidemiological tools. We carried out a temporal analysis of changes in allele frequencies of 12 drug resistance markers over two decades of changing antimalarial drug policy in Kenya. We did not detect any of the validated kelch 13 (k13) artemisinin resistance markers, nonetheless, a single k13 allele, K189T, was maintained at a stable high frequency (>10%) over time. There was a distinct shift from chloroquine resistant transporter (crt)-76, multi-drug resistant gene 1 (mdr1)-86 and mdr1-1246 chloroquine (CQ) resistance alleles to a 99% prevalence of CQ sensitive alleles in the population, following the withdrawal of CQ from routine use. In contrast, the dihydropteroate synthetase (dhps) double mutant (437G and 540E) associated with sulfadoxine-pyrimethamine (SP) resistance was maintained at a high frequency (>75%), after a change from SP to artemisinin combination therapies (ACTs). The novel cysteine desulfurase (nfs) K65 allele, implicated in resistance to lumefantrine in a West African study, showed a gradual significant decline in allele frequency pre- and post-ACT introduction (from 38% to 20%), suggesting evidence of directional selection in Kenya, potentially not due to lumefantrine. The high frequency of CQ-sensitive parasites circulating in the population suggests that the re-introduction of CQ in combination therapy for the treatment of malaria can be considered in the future. However, the risk of a re-emergence of CQ resistant parasites circulating below detectable levels or being reintroduced from other regions remains.
Whether past history of solid stage I/II inactive cancer has an impact on 28-day mortality of sepsis remains unclear. We aimed to determine the impact of history of stage I or II solid tumor malignancy in complete remission the last 3 years on sepsis outcome.
Using the database of the Hellenic Sepsis Study Group from 1553 patients with sepsis admitted in the ICU, 83 patients with sepsis by Sepsis-3 definition with past-history of stage I/II inactive solid malignancy the last 3 years were depicted. A comparator group of 83 patients fully matched for age, severity, type of infection and comorbidities was selected by propensity score matching.
Mortality after 28 days was 37.3% in the comparator group and 54.2% in the solid tumor stage I/II group (odds ratio for death 1.98; p: 0.030). Following step-wise forward Cox regression analysis, septic shock (hazard ratio 1.80), acute renal injury (hazard ratio 2.06), history of coronary heart disease (hazard ratio 0.36) and history of stage I/II solid tumor malignancy (hazard ratio 1.79) were the only independent variables associated with 28-day mortality. Serum levels of procalcitonin and of soluble urokinase plasminogen activator receptor were similar between the two groups of comparisons.
Past history of stage I/II solid malignancy is an independent risk factor for unfavorable outcome from sepsis the first 28 days.
Jade Feller, Brian.C. Lund, Eli.N. Perencevich, Bruce Alexander, Brett Heintz, Brice Beck, Rajeshwari Nair, Michihiko Goto, Daniel.J. Livorsi
Antimicrobial stewardship programs have focused on reducing inappropriate inpatient antimicrobial prescribing, but several small studies have found a large portion of antimicrobial exposure occurs immediately after hospital discharge. In this study, we describe the prescribing of oral antimicrobials at hospital discharge across an integrated national healthcare system. At the hospital-level, we also compare total inpatient antimicrobial use and post-discharge oral antimicrobial use.
Ahmed Arale, Mercy Lutukai, Somane Mohamed, Lydia Bologna and Katherine V. Stamidis
In 2013, the outbreak of wild poliovirus (WPV) in the Horn of Africa (HOA) triggered an aggressive, coordinated national and regional response to interrupt continued transmission. Kenya, Somalia, Ethiopia, South Sudan, and other HOA countries share a range of complex factors that enabled the outbreak: porous and sparsely populated borders, insecurity due to armed conflicts, and weak health systems with persistently under-resourced health facilities resulting in low-quality care and low levels of immunization coverage in mobile populations. Consequently, the continued risk of WPV importation demanded cross-border and intersectoral collaboration. Assessing and addressing persistent communication gaps at the subnational levels were necessary to gain traction for improved immunization coverage and surveillance activities. This article describes a systematic approach to institutionalizing processes of dialogue and facilitation that can provide for a sustainable and effective joint cross-border health platform between Kenya and Somalia. It examines an operational model called the Cross-Border Health Initiative (CBHI) to support joint intercountry collaboration and coordination efforts. To evaluate progress of the CBHI, the authors used data from population coverage surveys for routine immunization and supplemental immunization activities (for polio), from acute flaccid paralysis (AFP) surveillance, and from plans developed by border districts and border health facilities. The project-trained community health volunteers have been a critical link between the hard-to-reach communities and the health facilities as well as an excellent resource to support understaffed health facilities. The authors conclude that the CBHI has been effective in bolstering immunization coverage, disease surveillance, and rapid outbreak response in border areas. The CBHI has the potential to address other public health threats that transcend borders.
Schriever C, Danziger L.
Clostridioides (Clostridium) difficile infections (CDI) have continued to increase over the past decades, representing a significant cause of healthcare morbidity and mortality. While courses of metronidazole and oral vancomycin typically sufficed, an increase in treatment failures as well as recurrences demanded reevaluation of the efficacy of these agents. Present guidelines set forth by the Infectious Disease Society of America (IDSA) in 2018 state metronidazole is no longer considered an appropriate first-line therapy for initial treatment of CDI in adult patients, as treatment with either oral vancomycin or fidaxomicin have demonstrated superiority . Adding to the complexity of treatment are recurrent or refractory infections, occurring in up to 25% of initial treatments . Although repeated treatment with same or different agent has been effective in many patients, numerous cases of treatment failure have been reported in those refractory to standard therapies . Refractory, or recurrent cases, also known as recurrent C. difficile infections (rCDI), are defined as more than 2 CDI episodes. Management of patients with rCDI episodes has proved challenging for clinicians. Numerous investigators have evaluated how to effectively “break the cycles” of recurrence through the use of antimicrobial tapers, as well as sequential therapy with rifaximin following a treatment course of vancomycin [3–6]. Although some of these trials have demonstrated success, numerous questions remain unanswered including, what is the best management strategy for rCDI?
Samodelov, S. L., Visentin, M., Gai, Z., Häusler, S., Kullak-Ublick, G. A.
The polymixin colistin represents a last resort antibiotic for multidrug resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimise long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule 1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a cis-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in ex vivo glucose uptake when compared to BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy.
Bold T, Cheng M, Marty F.
Many gaps in the burden of resistant pathogens exist in endemic areas of low- and middle-income economies, especially those endemic for carbapenem resistance. The aim of this study is to evaluate risk factors for carbapenem-resistance, to estimate the association between carbapenem-resistance and all-cause 30-day mortality and to examine whether mortality is mediated by inappropriate therapy.
A case-control and a cohort study were conducted in one tertiary-care hospital in Medellín, Colombia from 2014 to 2015. Phenotypic and genotypic characterization of isolates was performed. In the case-control study, cases were defined as patients infected with carbapenem-resistant K. pneumoniae (CRKP) and controls as patients infected with carbapenem-susceptible K. pneumoniae (CSKP). A risk factor analysis was conducted using logistic regression models. In the cohort study, the exposed group was defined as patients infected with CRKP and the non-exposed group as patients infected with CSKP. A survival analysis using an accelerated failure time model with a lognormal distribution was performed to estimate the association between carbapenem resistance and all-cause 30-day-mortality and to examine whether mortality is mediated by inappropriate therapy.
A total of 338 patients were enrolled; 49 were infected with CRKP and 289 with CSKP. Among CRKP isolates CG258 (n = 29), ST25 (n = 5) and ST307 (n = 4) were detected. Of importance, every day of meropenem (OR 1.18, 95%CI 1.10–1.28) and cefepime (OR 1.22, 95%CI 1.03–1.49) use increase the risk of carbapenem resistance. Additional risk factors were previous use of ciprofloxacin (OR 2.37, 95%CI 1.00–5.35) and urinary catheter (OR 2.60, 95%CI 1.25–5.37). Furthermore, a significant lower survival time was estimated for patients infected with CRKP compared to CSKP (Relative Times 0.44, 95%CI 0.24–0.82). The strength of association was reduced when appropriate therapy was included in the model (RT = 0.81 95%CI 0.48–1.37).
Short antibiotic courses had the potential to reduce the selection and transmission of CRKP. A high burden in mortality occurred in patients infected with CRKP in a KPC endemic setting and CRKP leads to increased mortality via inappropriate antibiotic treatment. Furthermore, dissemination of recognized hypervirulent clones could add to the list of challenges for antibiotic resistance control.
Snow, D. M., Riling, K., Kimbler, A., Espinoza, Y., Wong, D., Pham, K., Martinez, Z., Kraus, C. N., Conrad, F., Garcia-Rodriguez, C., Cobb, R. R., Marks, J. D., Tomic, M. T.
Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as Tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A-G), which differ between 35% to 68% in amino acid sequence, necessitates the development of serotype specific countermeasures. We present results of a Phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (mAbs), each binding to non-overlapping epitopes on BoNT serotypes C and D resulting in potent toxin neutralization in rodents. This first-in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults (NCT03046550). Three cohorts of eight healthy subjects received a single intravenous dose of NTM-1634 or placebo at 0.33 mg/kg, 0.66 mg/kg or 1 mg/kg. Follow-up examinations and pharmacokinetic evaluations were continued up to 121 days post-infusion. Subjects were monitored using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetic parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well-tolerated with the expected half-lives for human mAbs and with minimal anti-drug antibodies detected over the dose ranges and duration of the study.
Iwanowski, P., Bhatia, A., Gupta, M., Patel, A., Chavan, R., Yeole, R., Friedland, D.
Nafithromycin (WCK 4873), a novel lactone-ketolide, was administered to healthy adult subjects in 2 randomized, double-blind, placebo-controlled, Phase 1 studies. In the first-in-human study, single-ascending oral doses of nafithromycin (100 to 1200 mg) were administered to subjects under fasted or fed condition, with effects of food on bioavailability of nafithromycin studied at the dose levels of 400 and 800 mg. In the second study, multiple-ascending oral doses of 600, 800, or 1000 mg of nafithromycin were administered once daily for 7 days under a fed condition. Nafithromycin was generally well tolerated at all doses. No serious or severe adverse events were observed. The mean maximum plasma concentration (Cmax) ranged from 0.099 to 1.742 mg/L, and the area under the concentration-time curve from time zero to time t (AUC0–t) ranged from 0.54 to 22.53 h⋅mg/L. Nafithromycin plasma AUC0-t increased approximately 1.2-fold under fed compared to fasted condition. In the multiple-dose study, the Day 7 nafithromycin Cmax ranged from 1.340 to 2.987 mg/L and the AUC over the final dosing interval (AUC0-24) ranged from 13.48 to 43.46 h⋅mg/L. The steady state was achieved after 3 days for the 600 mg and 800 mg dose cohorts and after 4 days for the 1000 mg cohort. Under both single- and multiple-dosing regimens, plasma exposure to nafithromycin appeared to increase more than dose-proportionally. Nafithromycin showed moderate accumulation on Day 7 of dosing. The human pharmacokinetic profile, safety and tolerability data support further development of nafithromycin.
Wangrangsimakul T, Phuklia W, Newton P, et al.
AbstractScrub typhus, a neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi, is a major cause of fever across the Asia Pacific region with over a billion people at risk. Treatment with antibiotics such as doxycycline or chloramphenicol are effective for the majority of patients. In the 1990s, reports from northern Thailand raised a troubling observation; some scrub typhus patients responded poorly to doxycycline, which investigators attributed to doxycycline resistance. Despite the controversial nature of these reports, independent verification was neglected with subsequent studies speculating on the role of doxycycline resistance in contributing to failure of treatment or prophylaxis. In this review, we have outlined the evidence for drug-resistant Orientia tsutsugamushi, assessed the evidence for doxycycline resistance and highlight more recent findings unsupportive of doxycycline resistance. We conclude that doxycycline resistance is a misconception, with treatment outcome likely to be determined by other bacterial, host and pharmacological factors.
Hidalgo, L., de Been, M., Rogers, M. R. C., Schürch, A. C., Scharringa, J., van der Zee, A., Bonten, M. J. M., Fluit, A. C.
Objectives. A large OXA-48 outbreak in the Netherlands involved the spread of OXA-48producing Enterobacteriaceae among at least 118 patients, suggesting horizontal transfer of this resistance gene through one or more plasmids. Elucidating transmission dynamics of resistance plasmids is hampered by the low resolution of classic typing methods. This study aimed to investigate the molecular epidemiology of plasmids carrying OXA-48 carbapenemase using a next-generation sequencing approach.Methods. A total of 68 OXA-48-producing Enterobacteriaceae isolated from the hospital outbreak, as well as 22 non-outbreak related OXA-48-producing Enterobacteriaceae from the Netherlands, Libya and Turkey were selected. Plasmids were sequenced using the Illumina Miseq platform, and read sets were assembled and analysed.Results. In all plasmids blaOXA-48 was embedded in transposon Tn1999.2 and located on a ca. 62 kb IncL/M conjugative plasmid in 14 different species. There were a maximum of 2 SNPs (single nucleotide polymorphisms) between the core sequence alignment of all plasmids. Closely related sequence variants of this plasmid were detected in non-outbreak isolates from the Netherlands and other countries. Thirty-one of 89 OXA-48-producing isolates also harboured blaCTX-M-15, which was not located on the blaOXA-48-carrying plasmid. Sequencing of four plasmids harbouring blaCTX-M15 revealed extensive plasmid heterogeneity.Conclusions. A ca. 62 kb plasmid was responsible for the OXA-48 outbreak in a Dutch hospital. Our findings provide strong evidence for both within-host inter-species and between host dissemination of plasmid-based OXA-48 during a nosocomial outbreak. These findings exemplify the complex epidemiology of carbapenemase producing Enterobacteriaceae (CPE).
MacBrayne C, Williams M, Levek C, et al.
AbstractBackgroundChildren’s Hospital Colorado created a unique method of antimicrobial stewardship, called handshake stewardship, that effectively decreased hospital anti-infective use and costs in its pilot year (2013). Handshake stewardship is distinguished by: (1) the lack of prior authorization; (2) a review of all prescribed anti-infectives; (3) a shared review by the physician and the pharmacist; and (4) a daily, rounding-based, in-person approach to supporting providers. We sought to reevaluate the outcomes of the program after 5 years of experience, totaling 8 years of data.MethodsWe retrospectively measured anti-infective (antibiotic, antiviral, antifungal) use hospital-wide by unit and by drug for an 8-year period spanning October 2010 to October 2018. Aggregated monthly use was measured in days of therapy per thousand patient days (DOT/1000 PD). The percentage of children admitted ever receiving an anti-infective was also measured, as well as severity-adjusted mortality, readmissions, and lengths of stay.ResultsHospital-wide mean anti-infective use significantly decreased, from 891 (95% confidence interval [CI] 859–923) in the pre-implementation phase to 655 (95% CI 637–694) DOT/1000 PD in post-implementation Year 5; in a segmented regression time series analysis, this was a rate of -2.6 DOT/1000 PD (95% CI -4.8 to -0.4). This is largely attributable to decreased antibacterial use, from 704 (95% CI 686–722) to 544 (95% CI 525 –562) DOT/1000 PD. The percentage of children ever receiving an anti-infective during admission likewise declined, from 65% to 52% (95% CI 49–54). There were no detrimental effects on severity adjusted mortality, readmissions, or lengths of stay.ConclusionsThe handshake method is an effective and sustainable approach to stewardship.
Miranda C, Bark C.
The head of occupational health calls to say you must see Dr. Charlie M, a 35-year-old transplant physician, first thing in the morning; he has a cough and a chest X-ray with an upper lobe cavity. You know Dr. M, having both moved from the Philippines for residency. He reports a cough for 1 month—fairly unremarkable but recently noted some blood. He has always had a positive purified protein derivative (PPD) since residency but declined isoniazid (INH) at that time as he said, “the risks-benefits did not make sense for what I thought was probably a reaction to my vaccine.” The fear is palpable and understood, a sputum is collected, and you call the lab to expedite processing. Charlie leaves to go home, and occupational health then pages. You confirm their fears; tuberculosis (TB) is the most likely diagnosis, and they ask you to come meet on the transplant floor where Dr. M had been attending last week. The lab calls; the smear is positive, and you agree with the decision to start the high risk exposed patients on INH prophylaxis. Doctors and nurses start explaining to exhausted patients and their worried family members why their sick immunocompromised loved ones who are already on multiple medications must take an additional medication with potential hepatotoxicity to avoid developing active tuberculosis. Media relations then pages; they need you to review the press release. You call Charlie; he will come back tomorrow morning with his wife, 2-year-old daughter, and 3-month-old son. He cries and you reassure him that his patients and family will be OK because TB is preventable.
Kalligeros, M., Karageorgos, S. A., Shehadeh, F., Zacharioudakis, I. M., Mylonakis, E.
Concomitant use of vancomycin plus piperacillin/tazobactam (TZP) has been associated with increased risk of acute kidney injury (AKI) in hospitalized adults. In this systematic review and meta-analysis, we searched PubMed and EMBASE for pediatric studies examining this hypothesis, with reference to vancomycin monotherapy or in combination with another beta-lactam antibiotic. Out of 1381 non-duplicate studies, 10 met our inclusion criteria. We performed a random effects meta-analysis, based on crude odds ratios, and we accounted for both quality of included studies and publication bias. In primary analysis, concomitant vancomycin and TZP use yielded a statistically significant association with the development of AKI. More specifically, children with AKI had higher odds to have been exposed to vancomycin plus TZP, in comparison with vancomycin monotherapy (OR 8.15; 95% CI: 3.49-18.99), or vancomycin plus any other beta-lactam antibiotic (OR 3.48; 95% CI: 2.71-4.46). Based on the results of the Newcastle Ottawa Scale quality assessment, a secondary analysis including only higher quality studies (6 out of 10 studies) yielded again higher odds of exposure to vancomycin plus TZP, compared to vancomycin plus another beta-lactam antibiotic (OR 3.76; 95% CI: 2.56-5.51). Notably, even after controlling for possible publication bias our results remained statistically significant (OR 3.09; 95% CI: 2.30-4.14). In conclusion, the concomitant use of vancomycin and TZP could be associated with AKI development and the clinical significance of this potential association needs to be studied further in the pediatric population.
Samuel Usman, Lydia Bologna and Katherine V. Stamidis
In North East Nigeria, anti-immunization rumors and sentiments have negatively impacted the country’s polio eradication efforts. Since 2014, the CORE Group Partners Project (CGPP) has leveraged local-level strategies to help change prevailing attitudes and behaviors by improving immunization acceptability in some of the most difficult settlements in Nigeria’s states at highest risk for polio. The CGPP’s communication model in Nigeria, in part, emphasizes the need to counter suspicion and address myths and misunderstandings by convening community dialogs and compound meetings, both of which serve as safe spaces for open discussion primarily aimed at addressing non-compliance. In the communities in Kaduna, Katsina, Kano, Borno, and Yobe states located in the CGPP implementation areas, there has been a consistent reduction in the number of missed children and consistent improvement in polio immunization uptake, providing evidence of the effectiveness of the CGPP communication model. The last case of wild poliovirus in Nigeria was detected in August 2016. Since Nigeria has gone more than 3 years without a case of wild poliovirus, the CGPP communication model promises to remain highly relevant in sustaining the community’s awareness about immunizations that will be required to keep the population coverage of polio immunization high and, by extension, the herd immunity required to maintain zero transmission of poliovirus in Nigeria. This article describes the various strategies used to address noncompliance and provides examples of community engagement in Yobe state, which is one of the project’s largest implementation areas.
Andrew Chimpololo and Vanessa Burrowes
Seventy-five percent of children aged 12–23 months in Malawi have received all eight basic vaccinations—still leaving many children at risk. The Malawi Expanded Program on Immunization comprehensive Multi-Year Plan 2016–2020 reveals several challenges impeding immunization and disease surveillance efforts, such as the fact that non-governmental health organizations (NGHOs) and communities are minimally included in the planning, implementation, and monitoring of these activities. This article examines the extent to which NGHOs are promoting the use of social mobilization (SM) and community mobilizers (CMs) for sharing health information related to the eradication of polio, the importance of routine immunization, and the control of measles and neonatal tetanus. Data collection involved document analysis and interviews with 11 organizations in Malawi whose work contributes to the eradication of polio and control of measles and neonatal tetanus. Content analysis was used to analyze the qualitative data, whereas descriptive statistics were used to analyze the quantitative data. Non-governmental health organizations use a variety of approaches for SM, including mass media campaigns (radio and printed booklets), local skits and dramas, and home visits. Most NGHOs use training workshops and opinion leaders to impart knowledge and skills to CMs on immunization to eradicate polio and to control measles and neonatal tetanus. Major challenges faced by the NGHOs include negative attitudes toward campaigns and demotivation of CMs due to lack of financial incentives. The article concludes with a discussion of approaches to strengthen SM and the role of CMs by NGHOs.
Lepak, A. J., Zhao, M., Andes, D. R.
WCK 5222 is a combination of cefepime and the novel β-lactam enhancer (BLE) zidebactam. Zidebactam has a dual mechanism of action involving high-affinity penicillin binding protein (PBP) 2 binding as well as inhibition of Ambler class A, and C, enzymes. In the current study, we evaluated the effect of zidebactam on the cefepime pharmacodynamic target time above MIC (T>MIC) exposure required for efficacy against a diverse group of carbapenem-resistant Enterobacteriaceae (CRE) secondary to MBL-production. Plasma and ELF pharmacokinetic (PK) studies were performed for both cefepime (6.25, 25, and 100 mg/kg) and zidebactam (3.125, 12.5, and 50 mg/kg) after subcutaneous administration to mice. Only total drug was considered as protein binding is MIC. The results were modelled to evaluate the relationship between cefepime T>MIC, when zidebactam was co-administered, and therapeutic effect. The results revealed a strong association between T>MIC and effect (R2 0.82). Net stasis in organism burden occurred at cefepime T>MIC exposures of only 18%. A 1-log kill endpoint was demonstrated for the group of organisms at approximately 31% T>MIC. These target exposures for stasis and 1-log kill are much lower than previously observed cephalosporin monotherapy PK/PD targets.
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