Connolly, K. L., Eakin, A. E., Gomez, C., Osborn, B. L., Unemo, M., Jerse, A. E.

There is a pressing need for drug development for gonorrhea. Here we describe pharmacokinetics/pharmacodynamics (PK/PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. PK determined in uninfected mice displayed a clear dose response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESCS strain FA1090 were 5 mg/kg (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (time of free drug above the MIC, fTMIC) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against the ESCR strain H041. However, fractionation (TIDq8h) of a 120 mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤ 50% of mice with therapeutic times estimated from single-dose PK data, of 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships in mice reflected that observed in humans with in vivo efficacy against an ESCS strain requiring doses that yielded an fTMIC in excess of 20-24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCR strain and were useful in designing effective dosing regimens.…

Melchers, M. J., Teague, J., Warn, P., Hansen, J., Bernardini, F., Wach, A., Obrecht, D., Dale, G. E., Mouton, J. W.

Murepavadin (POL7080) represents the first member of a novel class of outer membrane protein targeting antibiotics. It specifically interacts with LptD and inhibits LPS transport. Murepavadin is being developed for the treatment of serious infections by Pseudomonas aeruginosa. We determined the plasma protein binding, the pharmacokinetics of murepavadin in plasma and ELF (pulmonary) in infected animals as well as determining the exposure response relationship. Treatment of CD-1® neutropenic mice was started 2 h after infection using murepavadin at different dosing frequencies for 24h, and the number of CFU per lung was determined. The maximum effect model was used to fit the dose-response and the Pharmacodynamic: index (PDI)-response to determine the PDI values resulting in a static and 1-log kill. Using R2 as an indicator of the best fit, the fAUC/MIC correlated best with efficacy. The mean AUC required to provide a static effect was 36.83 mg.h/L (fAUC = 8.25 mg.h/L) and to provide a 1-log reduction was 44.0 mg.h/L (fAUC = 9.86 mg.h/L). The mean static fAUC/MIC was determined to be 27.78 and that for a 1-log reduction was 39.85. These data may serve to determine doses in humans that are likely to be efficacious.…

Khin Thu Zar Htwe, Clyde Dapat, Yugo Shobugawa, Takashi Odagiri, Akinobu Hibino, Hiroki Kondo, Ren Yagami, Takehiko Saito, Nobuhiro Takemae, Tsutomu Tamura, Hisami Watanabe, Yadanar Kyaw, Nay Lin, Yi Yi Myint, Htay Htay Tin, Win Thein, Latt Latt Kyaw, Pan Ei Soe, Makoto Naito, Hassan Zaraket, Hiroshi Suzuki, Takashi Abe, Reiko Saito

by Khin Thu Zar Htwe, Clyde Dapat, Yugo Shobugawa, Takashi Odagiri, Akinobu Hibino, Hiroki Kondo, Ren Yagami, Takehiko Saito, Nobuhiro Takemae, Tsutomu Tamura, Hisami Watanabe, Yadanar Kyaw, Nay Lin, Yi Yi Myint, Htay Htay Tin, Win Thein, Latt Latt Kyaw, Pan Ei Soe, Makoto Naito, Hassan Zaraket, Hiroshi Suzuki, Takashi Abe, Reiko Saito We investigated the circulation patterns of human influenza A and B viruses in Myanmar between 2010 and 2015 by analyzing full HA genes. Upper respiratory tract specimens were collected from patients with symptoms of influenza-like illness. A total of 2,860 respiratory samples were screened by influenza rapid diagnostic test, of which 1,577 (55.1%) and 810 (28.3%) were positive for influenza A and B, respectively. Of the 1,010 specimens that were positive for virus isolation, 370 (36.6%) were A(H1N1)pdm09, 327 (32.4%) were A(H3N2), 130 (12.9%) B(Victoria), and 183 (18.1%) were B(Yamagata) viruses. Our data showed that influenza epidemics mainly occurred during the rainy season in Myanmar. Our three study sites, Yangon, Pyinmana, and Pyin Oo Lwin had similar seasonality and circulating type and subtype of influenza in a given year. Moreover, viruses circulating in Myanmar during the study period were closely related genetically to those detected in Thailand, India, and China. Phylogeographic analysis showed that A(H1N1)pdm09 viruses in Myanmar originated from Europe and migrated to other countries via Japan. Similarly, A(H3N2) viruses in Myanmar originated from Europe, and disseminated to the various countries via Australia. In addition, Myanmar plays a key role in reseeding of influenza B viruses to Southeast Asia and East Asia as well as Europe and Africa. Thus, we concluded that influenza virus in Myanmar has a strong link to neighboring Asian countries, Europe and Oceania.

Rubin R.

This Medical News story is an interview with Megan Ranney, MD, MPH, one of the leading voices in the “This Is Our Lane” movement, which discusses the role of physicians and other health-care professionals in addressing firearm violence as a public health issue.

Galea S.

In this Viewpoint, Sandro Galea acknowledges reasons physicians have traditionally been hesitant to speak out publicly on matters of politics and public health, and reviews how shifting roles and means of communication are forcing practitioners to reconsider that hesitancy and engage in controversies of public health concern, such as gun violence.

Abstract Background Tuberculosis (TB) remains a major public health concern on a global scale, especially in developing nations. So far, no formal guidelines are available for the diagnosis and treatment of tuberculosis pleurisy. The diagnosis of TB is worsened by the immense difficulty in differential determination of tuberculosis pleural effusion (TPE) and malignant pleural effusion (MPE). The purpose of this investigation is to assess the differential diagnostic efficiencies of the pleural IFN-γ release assay (IGRA) and widely-used biochemical parameters in the distinction analysis of TPE and MPE. Methods A cohort of 222 patients with pleural effusion was examined, comprising of 143 TPE and 58 MPE patients. The patients were examined with IGRA, and the widely-used biomarkers in the pleural effusion and peripheral blood. Results Our results show that the TPE patients have significantly higher M. tuberculosis (Mtb) antigen-specific IFN-γ responses to ESAT-6 protein and peptide pool in the blood compared to MPE patients. TPE patients were also shown to have enriched Mtb antigen-specific IFN-γ responses in pleural effusion than in peripheral blood. Among the widely-used biomarkers, the adenosine deaminase (ADA) and carcinoembryonic antigen (CEA) in pleural effusion were better biomarkers with high sensitivity and specificity to discriminate TPE and MPE. In addition, pleural IGRA could not be affected by the pleural adhesion, and the applications of the pleural IGRA together with ADA and CEA provide a promising approach for the TPE and MPE differential identification. Conclusions Our study proposes that the integration of pleural IGRA and ADA, CEA detection could add to more effective diagnosis stratagems in the discernment between TPE and MPE.…

Gamage D, Mach O, Ginige S, et al.

AbstractBackgroundIn July 2016, Sri Lanka replaced one intramuscular dose of inactivated poliovirus vaccine (IPV) with two doses of intradermal fractional IPV (fIPV) in its routine immunization schedule. We carried out a survey of seroprevalence of anti-polio antibodies in children who received two fIPV doses and compared it with those who received one full IPV dose.MethodsChildren born between March and December 2016 were randomly selected from three Sri Lankan districts (Colombo, Badulla, Anuradhapura). Sera were collected and tested for presence of neutralizing antibodies to poliovirus types 1, 2, and 3.ResultsSeroprevalence of anti-polio antibodies was 100% in all districts for poliovirus type 1 (PV1) and PV3; it ranged between 90–93% for PV2 in children who received one full IPV dose and between 78–100% in those receiving two fIPV doses (p=0.217). Median reciprocal titers of anti-PV2 antibodies were similar in those who received full IPV vs fIPV (1:64 vs 1:45 respectively; p=0.110).InterpretationOur study demonstrated that Sri Lanka not only succeeded in maintaining very high primary immunization coverage but that it is feasible for a national immunization program to implement fIPV immunization and achieve high coverage with intradermal application. The seroprevalence of anti-PV2 antibodies did not decrease after the introduction of fIPV.

Li, S.-C., Ye, Q., Xu, H., Zhang, L., Wang, Y.

Background: Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize dosing strategy in order to improve therapeutic efficacy.Methods: We performed a prospective pharmacokinetic study of pediatric patients aged 0-12 years. The population pharmacokinetic model was developed using NONMEM program. Goodness-of-fit plots, nonparametric bootstrap, normalized prediction distribution errors and visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model.Results: The pharmacokinetic data from 112 pediatric patients aged from 0.03 to 11.9 years were analysed. The pharmacokinetics could be best described by a one compartment model with first order elimination along with body weight and estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg q8h would lead to a high risk of underdosing for children in the presence of bacteria with MIC of ≥ 2 mg/L. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them.Conclusion: The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.…

S. Tekin, S. Keske, S. Alan, A. Batirel, C. Karakoc, N. Tasdelen-Fisgin, S. Simsek-Yavuz, B. Işler, M. Aydin, M. Kapmaz, F. Yilmaz-Karadag, O. Ergonul

Tobin, Stacey C

No abstract available…

Abriham Zegeye, Getnet Dessie, Fasil Wagnew, Alemu Gebrie, Sheikh Mohammed Shariful Islam, Bekele Tesfaye, Dessalegn Kiross

by Abriham Zegeye, Getnet Dessie, Fasil Wagnew, Alemu Gebrie, Sheikh Mohammed Shariful Islam, Bekele Tesfaye, Dessalegn Kiross Background Tuberculosis is a global public health problem. One of the overarching dilemmas and challenges facing most tuberculosis program is non-adherence to treatment. However, in Ethiopia there are few studies with variable and inconsistent findings regarding non-adherence to treatment for tuberculosis. Methods This systematic review and meta-analysis was conducted to determine the prevalence of non-adherence to tuberculosis treatment and its determinants in Ethiopia. Biomedical databases including PubMed, Google Scholar, Science Direct, HINARI, EMBASE and Cochrane Library were systematically and comprehensively searched. To estimate the pooled prevalence, studies reporting the prevalence of adherence or non-adherence to tuberculosis treatment and its determinants were included. Data were extracted using a standardized data extraction tool prepared in Microsoft Excel and transferred to STATA/se version-14 statistical software for further analyses. To assess heterogeneity, the Cochrane Q test statistics and I2 test were performed. Since the included studies exhibited high heterogeneity, a random effects model meta- analysis was used to estimate the pooled prevalence of non-adherence to tuberculosis treatment. Finally, the association between determinant factors and non-adherence to tuberculosis treatment was assessed. Results The result of 13 studies revealed that the pooled prevalence of non-adherence to tuberculosis treatment in Ethiopia was found to be 21.29% (95% CI: 15.75, 26.68). In the subgroup analysis, the highest prevalence was observed in Southern Nations and Nationalities of Ethiopia, 23.61% (95% CI: 21.05, 26.17) whereas the lowest prevalence was observed in Amhara region, 10.0% (95% CI: 6.48, 13.17.0;). Forgetfulness (OR = 3.22, 95% CI = 2.28, 4.53), fear side effect of the drugs (OR = 1.93, 95% CI = 1.37, 2.74), waiting time ≥ 1 hour during service (OR = 4.88, 95% CI = 3.44, 6.91) and feeling distance to health institution is long (OR = 5.35, 95% CI = 4.00, 7.16) were found to be determinants of non-adherence to tuberculosis treatment. Conclusion In this meta-analysis, the pooled prevalence of non-adherence to tuberculosis treatment in Ethiopia was high. Forgetfulness, fear of side effect of the drugs, long waiting time (≥1 hour) during service and feeling distance to health institution is long were the main risk factors for non-adherence to tuberculosis treatment in Ethiopia. Early monitoring of the side effects and other reasons which account for missing medication may increase medication adherence in patients with tuberculosis in Ethiopia.…

Abstract Background Clostridium difficile (C. difficile) is a main cause of antibiotic-associated diarrhoea in humans. Several studies have been performed to reveal the prevalence rate of C. difficile in cats and dogs. However, little is known about the epidemiology of C. difficile in healthy pets in China. This study aimed to assess the burden of C. difficile shedding by healthy dogs and cats in China. Furthermore, the genetic diversity and antimicrobial susceptibility patterns of the recovered isolates were determined. Methods A total of 175 faecal samples were collected from 146 healthy dogs and 29 cats. C. difficile strains were isolated and identified from the feces of these pets. The characterized C. difficile strains were typed by multilocus sequence typing (MLST), and the MICs of the isolates were determined against ampicillin, clindamycin, tetracycline, moxifloxacin, chloramphenicol, cefoxitin, metronidazole and vancomycin by the agar dilution method. Results Overall, 3 faecal samples (1.7%) were C. difficile culture positive. One sample (0.7%) from a dog was C. difficile culture positive, while two cats (7.0%) yielded positive cultures. The prevalence rate differed significantly between cats and dogs. These isolates were typed into 3 MLST genotypes and were susceptible to chloramphenicol, tetracycline, metronidazole and moxifloxacin and resistant to ampicillin, clindamycin and cefoxitin. Notably, one strain, D141–1, which was resistant to three kinds of antibiotics and carried toxin genes, was recovered in the faeces of a healthy dog. Conclusion Our results suggest that common pets may be a source of pathogenic C. difficile, indicating that household transmission of C. difficile from pets to humans can not be excluded.…

Stephanie D. Davis

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 190-198, January 15, 2019. …

Branche, Angela; Neeser, Olivia; Mueller, Beat; Schuetz, Philipp

Purpose of review There is convincing evidence linking antibiotic-stewardship efforts which include the infection marker procalcitonin (PCT) to more rational use of antibiotics with improvements in side-effects and clinical outcomes. This is particularly true in the setting of respiratory infection and sepsis. Yet, some recent trials have shown no benefit of PCT-guided care. Our aim was to discuss the benefits and limitations of using PCT for early infection recognition, severity assessment and therapeutic decisions in individual patients based on most the recent study data. Recent findings Current evidence from randomized trials, and meta-analyses of these trials, indicates that PCT-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side-effects, which translates into improved survival of patients with respiratory infections and sepsis. Notably, initial PCT levels have been found to be helpful in defining the risk for bacterial infection in the context of a low pretest probability for bacterial infections (i.e., patients with bronchitis or chronic bastructive pulmonary disease exacerbation). Monitoring of repeated PCT measurements over time has also been found helpful for estimating recovery from bacterial infection and prognosis in higher risk situations (i.e., pneumonia or sepsis) and results in early and safe discontinuation of antibiotic therapy. Some trials, however, did not find a strong effect of PCT guidance which may be explained by low protocol adherence, assessment using only a single rather than repeat PCT levels and lower antibiotic exposure in control group patients. Using PCT in the right patient population, with high-sensitivity assays and with adequate training of physicians is important to increase protocol adherence and reduce antibiotic exposure. Summary Inclusion of PCT into antibiotic stewardship algorithms has the potential to improve the diagnostic and therapeutic management of patients presenting with respiratory illnesses and sepsis, and holds great promise to mitigate the global bacterial resistance crisis and move from a default position of standardized care to more personalized treatment decisions. Correspondence to Philipp Schuetz, MD, MPH, Department of Internal Medicine, Kantonsspital Aarau, Aarau, Switzerland. Tel: +41 0 79 365 10 06; fax: +41 0 62 838 9524; e-mail: Philipp.Schuetz@unibas.ch Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Newsum, Astrid M.; Kooij, Katherine W.; Boyd, Anders; Smit, Colette; Wit, Ferdinand W.N.M.; van der Meer, Jan T.M.; Prins, Maria; Reiss, Peter; van der Valk, Marc; on behalf of the MOSAIC study group, ATHENA observational HIV cohort and NVHB-SHM hepatitis working group

Background: Whether continued, accelerated liver fibrosis progression occurs following acute hepatitis C virus infection (AHCVI) in HIV-positive MSM is unknown. Design and methods: HIV-positive MSM from the AIDS Therapy Evaluation in the Netherlands and MSM Observational Study for Acute Infection with Hepatitis C-cohorts with primary AHCVI and at least one fibrosis-4 (FIB-4) measurement less than 2 years before and 1 year after estimated AHCVI were included. Mixed-effect linear models were used to evaluate (time-updated) determinants of FIB-4 levels over time. Determinants of transitioning to and from FIB-4 of 1.45 or less and more than 1.45 were examined using multistate Markov models. Results: Of 313 MSM, median FIB-4 measurements per individual was 12 (interquartile range  = 8–18) and median follow-up following AHCVI was 3.5 years (interquartile range = 1.9–5.6). FIB-4 measurements averaged at 1.00 [95% confidence interval (CI) = 0.95–1.05] before AHCVI, 1.31 (95% CI = 1.25–1.38) during the first year of AHCVI and 1.10 (95% CI = 1.05–1.15) more than 1 year after AHCVI. Mean FIB-4 more than 1 year after AHCVI was higher for chronically infected patients compared with those successfully treated (P = 0.007). Overall FIB-4 scores were significantly higher with older age, lower CD4+ cell count, longer duration from HIV-diagnosis or AHCVI, and nonresponse to HCV-treatment. At the end of follow-up, 60 (19.2%) and eight MSM (2.6%) had FIB-4 between 1.45–3.25 and at least 3.25, respectively. Older age, lower CD4+-cell count and detectable HIV-RNA were significantly associated with higher rates of progression to FIB-4 more than 1.45, whereas older age, longer duration from HIV-diagnosis and nonresponse to HCV-treatment were significantly associated with lower rates of regression to FIB-4 of 1.45 or less. Conclusion: In this population of HIV-positive MSM, FIB-4 scores were higher during the first year of AHCVI, but FIB-4 at least 3.25 was uncommon by the end of follow-up. Well controlled HIV-infection appears to attenuate FIB-4 progression. Correspondence to Astrid M. Newsum, Department of Infectious Diseases Research and Prevention, Public Health Service of Amsterdam, PO Box 2200, 1000CE Amsterdam, The Netherlands. Tel: +31 0 20 555 5436; e-mail: anewsum@ggd.amsterdam.nl Received 16 October, 2018 Revised 17 December, 2018 Accepted 18 December, 2018 Copyright © 2019 Wolters Kluwer Health, Inc.

Abstract Background Clostridium difficile infection (CDI) is an important cause of diarrhea and continues to be a major burden within healthcare institutions and in the community. For a small subset of patients with frequently relapsing CDI who do not have access to fecal microbiota transplantation (FMT), or fail FMT, there are no clear treatment recommendations. We review our experience with prolonged oral vancomycin for secondary prophylaxis of relapsing CDI. Methods We performed a retrospective chart review of cases from the C. difficile consultation service at our institution since 2013. The service had three primary physicians providing consultations and performing over 1000 FMTs over the five-year period. Patients with relapsing CDI who were not candidates for FMT, refused, or relapsed after FMT were treated with vancomycin, followed by long-term oral vancomycin at a dose of 125 mg once daily. Results Twenty patients received at least 8 weeks of once-daily oral vancomycin for prophylaxis of relapsing CDI. Patients had a median age of 80 years, and experienced a median of four episodes of CDI prior to long-term vancomycin. Most were female and 75% had received FMT. Only a single case of C. difficile relapse occurred while on long-term vancomycin during 200 patient-months of follow-up. Amongst those who stopped long-term vancomycin, 31% relapsed within 6 weeks. No adverse events were observed. Conclusions For elderly patients with frequently relapsing C. difficile, prolonged vancomycin once daily at a dose of 125 mg orally was effective in preventing further relapse. Vancomycin secondary prophylaxis may be considered in patients who have failed FMT, or in cases where FMT is not available.…

Bednasz, C. J., Venuto, C. S., Ma, Q., Daar, E. S., Sax, P. E., Fischl, M., Collier, A. C., Smith, K. Y., Tierney, C., Acosta, E. P., Mager, D. E., Morse, G. D., on behalf of the AIDS Clinical Trials Group Study A5202 Team

Introduction AIDS Clinical Trial Group A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine, or abacavir/lamivudine in treatment-naïve adults living with HIV-1, evaluating efficacy, safety and tolerability. We report an analysis on the contribution of participant characteristics to the disposition of tenofovir plasma concentrations.Methods Tenofovir concentration data from a total of 817 individuals (88%) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of inter-individual variability (IIV), and a proportional and mixed error model was assessed for residual variability.Results The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka), and a proportional residual variability model was selected. Final mean parameter estimates were: ka = 2.87 hr-1, CL/F = 37.2 L/hr, apparent volumes of the central and peripheral compartments = 127 and 646 L, and apparent inter-compartmental clearance = 107 L/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/r or efavirenz were significantly associated with CL/F (p < 0.001).Conclusion Race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naïve adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations, and suggests that examining pre-exposure prophylaxis regimens and TFV exposure in different race/ethnicity groups be considered.…

Faiza Khalid

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 136-138, January 15, 2019. …

James G. Bedford, Meredith O’Keeffe, Patrick C. Reading, Linda M. Wakim

by James G. Bedford, Meredith O’Keeffe, Patrick C. Reading, Linda M. Wakim Interferon-induced transmembrane protein 3 (IFITM3) is a potent antiviral protein that enhances cellular resistance to a variety of pathogens, including influenza virus. Classically defined as an interferon-stimulated gene, expression of IFITM3 on cells is rapidly up-regulated in response to type I and II interferon. Here we found that IFITM3 is rapidly up-regulated by T cells following their activation and this occurred independently of type I and II interferon and the interferon regulatory factors 3 and 7. Up-regulation of IFITM3 on effector T cells protected these cells from virus infection and imparted a survival advantage at sites of virus infection. Our results show that IFITM3 expression on effector T cells is crucial for these cells to mediate their effector function and highlights an interferon independent pathway for the induction of IFITM3 which, if targeted, could be an effective approach to harness the activity of IFITM3 for infection prevention.

Andonov A, Robbins M, Borlang J, et al.

AbstractHepatitis E virus (HEV) is a major public health concern in developing countries where the primary transmission is via contaminated water. Zoonotic HEV cases have been increasingly described in Europe, Japan and the United States with pigs representing the main animal reservoir of infection. We report an unusual acute hepatitis infection in a previously healthy man caused by a rat hepatitis E virus with a considerably divergent genomic sequence compared to other rat HEV strains. It is possible that rat HEV is an under recognized cause of hepatitis infection and further studies are necessary to elucidate its potential risk and mode of transmission.

Abstract Background Rotavirus vaccine was introduced in Kenya immunization program in July 2014. Pre-vaccine disease burden estimates are important for assessing vaccine impact. Methods Children with acute gastroenteritis (AGE) (≥3 loose stools and/or ≥ 1 episode of unexplained vomiting followed by loose stool within a 24-h period), hospitalized in Siaya County Referral Hospital (SCRH) from January 2010 through December 2013 were enrolled. Stool specimens were tested for rotavirus (RV) using an enzyme immunoassay (EIA). Hospitalization rates were calculated using person-years of observation (PYO) from the Health Demographic Surveillance System (HDSS) as a denominator, while adjusting for healthcare utilization at household level and proportion of stool specimen collected from patients who met the case definition at the surveillance hospital. Mortality rates were calculated using PYO as the denominator and number of deaths estimated using total deaths in the HDSS, proportion of deaths attributed to diarrhoea by verbal autopsy (VA) and percent positive for rotavirus AGE (RVAGE) hospitalizations. Results Of 7760 all-cause hospitalizations among children

Abstract Background After allogeneic haematopoietic stem cell transplantation (allo-HSCT), Hepatitis B virus reactivation (HBVr) can be observed in patients with previous resolved Hepatitis B virus (HBV) infections. Nephrotic syndrome (NS) is the main clinical manifestation of HBsAg-positive glomerulonephritis. However, the development of HBVr combined with NS after allo-HSCT is uncommon. Case presentation We presented a case of a 47-year-old female with acute myelogenous leukemia who underwent HLA-identical sibling allo-HSCT and achieved leukemia free survival. She had pretransplant serological markers of a resolved HBV infection (HBsAg-negative, anti-HBc and anti-HBs positive). However, she developed HBVr combined with nephrotic syndrome (NS) 16 months after HSCT. Her histological renal lesion was mesangial proliferative glomerulonephritis. IgA+, IgM+, and C1q deposits but not HBV antigens (HBsAg and HBcAg) were identified in her renal biopsy material. Long-term entecavir and immunosuppression resulted in decrease of HBV virus replication, amelioration of proteinuria and stabilisation of renal function. Conclusions Entecavir combined with immunosuppression has efficacy in the treatment of HBVr combined with NS after allo-HSCT, but long course of treatment is needed. Closely monitoring and antiviral prophylaxis might be necessary for allo-HSCT recipients to prevent reactivation of resolved HBV infection and its related complications.…

Zhou, R., Yang, G., Guo, X., Zhou, Q., Lei, J., Shi, Y.

Cleavage of amyloid precursor protein (APP) by the intramembrane protease -secretase is linked to Alzheimer’s disease. We report an atomic structure of human -secretase in complex with a transmembrane APP fragment at 2.6-Å resolution. The transmembrane helix (TM) of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of -secretase). A hybrid β-sheet, which is formed by a β-strand from APP and two β-strands from PS1, guides -secretase to the scissile peptide bond of APP between its TM and β-strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of -secretase bound to Notch, reveal contrasting features of substrate binding, which may be exploited toward design of substrate-specific inhibitors.…

Marais B, van Toorn R, Figaji T, et al.

Jennifer L. Larson-Casey

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 251-252, January 15, 2019. …

Seppo T. Rinne

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 249-250, January 15, 2019. …

Ubaldo Mushabe Bahemuka, Andrew Abaasa, Eugene Ruzagira, Christina Lindan, Matt A. Price, Anatoli Kamali, Pat Fast

by Ubaldo Mushabe Bahemuka, Andrew Abaasa, Eugene Ruzagira, Christina Lindan, Matt A. Price, Anatoli Kamali, Pat Fast Introduction People living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda. Methods HIV high risk, sero-negative adults (18–49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 30–40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models. Results A total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years of observation. Dropout was associated with being female (aRR = 1.56, 95% confidence interval [CI] 1.12–2.18), being 18–24 years (aRR = 1.64; 95% CI 1.03–2.60) or being 25–34 years (aRR = 1.63; 95% CI 1.04–2.55) compared to being 35+ years; having no education (aRR = 2.02; 95% CI: 1.23–3.31); living in the community for less than one year (aRR = 2.22; 95% CI: 1.46–3.38), or 1–5 years (aRR = 1.68; 95% CI: 1.16–2.45), compared to more than five years. Conclusions Our results suggest that individuals from fishing communities can be recruited and retained in longitudinal studies; however, intensified participant tracing may be necessary for women, younger volunteers, those who are less educated and new residents.…

Tamma PD, Miller MA, Cosgrove SE.

This Viewpoint summarizes recommendations from the Agency for Healthcare Research and Quality for improving antibiotic use and safety that encourages clinicians to ask if antibiotics are necessary, and to use testing and deliberate judgment to decide which ones, for how long, and if coverage can be narrowed or the drugs stopped altogether.

Ana Martínez, Núria Soldevila, Arantxa Romero-Tamarit, Núria Torner, Pere Godoy, Cristina Rius, Mireia Jané, Àngela Domínguez, and the Surveillance of Hospitalized Cases of Severe Influenza in Catalonia Working Group

by Ana Martínez, Núria Soldevila, Arantxa Romero-Tamarit, Núria Torner, Pere Godoy, Cristina Rius, Mireia Jané, Àngela Domínguez, and the Surveillance of Hospitalized Cases of Severe Influenza in Catalonia Working Group Seasonal influenza is a cause of hospitalization, especially in people with underlying disease or extreme age, and its severity may differ depending on the types and subtypes of circulating viruses. We investigated the factors associated with ICU admission or death in hospitalized patients with severe laboratory-confirmed influenza according to the viral type and subtype. An observational epidemiological study was carried out in patients aged ≥18 years from 12 Catalan hospitals between 2010 and 2016. For each reported case we collected demographic, virological and clinical characteristics. A mixed-effects logistic regression model was used to estimate crude and adjusted ORs. 1726 hospitalized patients were included: 595 (34.5%) were admitted to the ICU and 224 (13.0%) died. Lower ICU admission was associated with age ≥75 years in all influenza types and subtypes and with age 65–74 years for type A. In contrast, the 65–74 and ≥75 years age groups were associated with an increased risk of death in all types and subtypes, especially for type B (aOR 27.42, 95% CI: 4.95–151.93 and 15.96; 95% CI: 3.01–84.68). The comorbidity most closely associated with severe outcomes was immune deficiency, which was associated with death for type B (aOR 9.02, 95% CI: 3.05–26.69) and subtype A(H1N1)pdm09 (aOR 3.16, 95% CI: 1.77–5.66). Older age was a differential factor for ICU admission and death: it was associated with lower ICU admission but a risk factor for death. The comorbidity with the closest association with death was immune deficiency, mainly in influenza type B patients.

Shuaiqi Guo, Tyler D.R. Vance, Corey A. Stevens, Ilja Voets, Peter L. Davies

Gram-negative bacteria produce repeats-in-toxin adhesion proteins (RTX adhesins) to facilitate microbial adhesion. These large, multidomain proteins share a common architecture comprised of four regions. First to emerge from the bacterium, C terminal end leading, is the RTX export sequence that directs the protein through the type 1 secretion system (T1SS). This is followed by the ligand-binding region responsible for host adhesion and cohesion, which contains diverse ligand-binding domains. These serve a zip code function to direct bacteria to a particular environmental niche.

Sarah E. Barker, Ian R. Bricknell, Julia Covello, Sarah Purcell, Mark D. Fast, William Wolters, Deborah A. Bouchard

by Sarah E. Barker, Ian R. Bricknell, Julia Covello, Sarah Purcell, Mark D. Fast, William Wolters, Deborah A. Bouchard The role of parasitic sea lice (Siphonostomatoida; Caligidae), especially Lepeophtheirus salmonis, in the epidemiology of Infectious Salmon Anemia Virus (ISAv) has long been suspected. The epidemiological studies conducted during the 1998 major Infectious Salmon Anaemia (ISA) outbreak in Scotland demonstrated a strong correlation between sea lice presence and ISAv positive sites or subsequent clinical outbreaks of ISA. The question posed from this observation was “do sea lice infestations on Atlantic salmon make them more susceptible to viral infections?” This study investigated the role that sea lice infestations have on the severity of ISAv infections and disease mortality in experimental populations of farmed Atlantic salmon (Salmo salar). A series of experiments was carried out that investigated the potential of sea lice to modify the outcome of an ISAv infection. Experimental populations of Atlantic salmon were established that had: no lice and no ISAv, a single infection with either ISAv or lice and a co-infection with lice then ISAV. The results were quite clear, the process of infestation by the parasite prior to ISAv exposure significantly increased the mortality and death rates of Atlantic salmon, when compared to uninfected controls and ISAv infected groups only. This was consistent over two source strains of Atlantic salmon (Pennobscot and Saint John River), but the severity and timing was altered. Immunological responses were also consistent in that pro-inflammatory genes were induced in lice only and co-infected fish, whereas the anti-viral response, Mx, MH class I β, Galectin 9 and TRIM 16, 25 genes were down-regulated by lice infection prior to and shortly after co-infection with ISAv. It is concluded that the sea lice settlement on Atlantic salmon and the parasite’s subsequent manipulation of the host’s immune system, which increases parasite settlement success, also increased susceptibility to ISAv.

Scott M. Landfear, Dan Zilberstein

Kinetoplastid parasites such as trypanosomes and Leishmania must adapt to their environments to survive within their hosts, yet they do not express many of the well established families of signal transduction receptors. Evidence suggests that other membrane proteins, including transporters and channels, play central roles in environmental sensing in these parasites.

Harel Z, McArthur E, Hladunewich M, et al.

This study uses Canadian administrative health databases to estimate gestational age–specific serum creatinine levels before, during, and after pregnancy among women without antecedent kidney disease.

Monika Szymańska-Czerwińska, Agnieszka Jodełko, Kinga Zaręba-Marchewka, Krzysztof Niemczuk

by Monika Szymańska-Czerwińska, Agnieszka Jodełko, Kinga Zaręba-Marchewka, Krzysztof Niemczuk Q fever is a worldwide zoonotic disease reported in humans and many animal species including cattle. The aims of this study were to evaluate the prevalence of Coxiella (C.) burnetii shedding in Polish dairy cattle herds and to identify the pathogen’s genotypes and sequence types (STs) using multiple-locus variable number tandem repeat analysis (MLVA) and multispacer sequence typing (MST) methods. The presence of C. burnetii DNA was detected using a commercial real-time PCR kit, targeting the IS1111 element. Overall, 1,439 samples from 279 herds were tested including: 897 individual milk specimens, 101 bulk tank milk samples, 409 genital tract swabs and 32 placentas. Furthermore, 30 consumer milk samples, including 10 from vending machines and 77 dairy products were also analyzed. C. burnetii shedding was confirmed in 31.54% of tested cattle herds as well as in 69.16% of consumer milk and dairy products. Among real-time PCR–positive samples, 49 specimens obtained from 49 cattle herds and 8 samples of purchased dairy products were selected for genotyping. Overall, five previously known MLVA genotypes (I, J, BG, BE, and NM) and three new ones (proposed as PL1, PL2, and PL3) were identified. Two MST sequence types were recorded: ST16 and a novel sequence (ST61). The new genotypes and sequence types need further research particularly into their pathogenicity to humans.

Tomich, A. D., Klontz, E. H., Deredge, D., Barnard, J. P., McElheny, C. L., Eshbach, M. L., Weisz, O. A., Wintrode, P., Doi, Y., Sundberg, E. J., Sluis-Cremer, N.

The spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active against Escherichia coli, including multidrug-resistant strains. However, many other Gram-negative pathogens, including the "priority pathogens" Klebsiella pneumoniae and Pseudomonas aeruginosa, are inherently resistant to FOM due to the chromosomally-encoded fosA gene, which directs expression of a metal-dependent glutathione S-transferase (FosA) that metabolizes FOM. In this study, we describe the discovery and biochemical and structural characterization of 3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one (ANY1), a small molecule active site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains.…

Suwanbongkot, C., Langohr, I. M., Harris, E. K., Dittmar, W., Christofferson, R. C., Macaluso, K. R.

Tick vectors are capable of transmitting several rickettsial species to vertebrate hosts resulting in varying levels of disease. Studies have demonstrated the transmissibility of both rickettsial pathogens and novel Rickettsia species or strains with unknown pathogenicity to vertebrate hosts during tick bloodmeal acquisition; however, the quantitative nature of transmission remains unknown. We tested the hypothesis that if infection severity is a function of rickettsial load delivered during tick transmission, then a more virulent SFG Rickettsia species is transmitted at greater levels during tick feeding. Using Rickettsia parkeri- or Candidatus Rickettsia andeanae-infected Amblyomma maculatum cohorts, a qPCR assay was employed to quantify rickettsiae in tick salivary glands, saliva, and in the vertebrate hosts at the tick attachment site over the duration of tick feeding. Compared to Ca. R. andeanae, significantly greater R. parkeri were present in tick saliva, salivary glands, and in the vertebrate hosts at the feeding site during tick feeding. Microscopy demonstrated the presence of both rickettsial species in tick salivary glands, and immunohistochemistry analysis of the attachment site identified localized R. parkeri, but not Ca. R. andeanae, in the vertebrate host. Lesions were also distinct and more severe in the R. parkeri exposed vertebrate hosts compared to Ca. R. andeanae exposed animals. The specific factors that contribute to the generation of a sustained rickettsial infection and subsequent disease are yet to be elucidated, but the results of this study suggest that rickettsial load in ticks and during transmission may be an important element.…

Claire McBrien

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 131-133, January 15, 2019. …

Manali Mukherjee

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 158-170, January 15, 2019. …

Atkins H.

Multiple sclerosis (MS) is an autoimmune disease that results from breakdown of immunological tolerance toward the central nervous system. The early course of MS is commonly characterized by repeated acute episodes of focal inflammation within the central nervous system causing neurologic events called relapses, characterized by the development of neurological disabilities and gadolinium-enhancing and demyelinating lesions on magnetic resonance imaging (MRI) scans. As the acute inflammation resolves over the course of several weeks, neurologic symptoms may partially or completely resolve. Over time, these acute inflammatory events tend to occur less frequently, and patients experience progression, an accumulation of long-lasting disabilities from the consequences of repeated damage to the central nervous system. The time from diagnosis to onset of progressive disabilities varies, but having many relapses shortly after disease onset with early appearance of disabilities or large numbers of lesions on MRI portend a poor prognosis.

Nils Große Hokamp

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page e3-e4, January 15, 2019. …

Song, Y.-J., Wang, K.-L., Shen, Y.-L., Gao, J., Li, T., Zhu, Y.-B., Li, C.-C., He, L.-H., Zhou, Q.-X., Zhao, N.-L., Zhao, C., Yang, J., Huang, Q., Mu, X.-Y., Li, H., Dou, D.-F., Liu, C., He, J.-H., Sun, B., Bao, R.

Biofilm formation is a critical determinant in the pathopoiesis of Pseudomonas aeruginosa. It could significantly increase bacterial resistance to drugs and host defense. Thus, inhibiting biofilm matrix production could be regarded as a promising attempt to prevent colonization of P. aeruginosa and the subsequent infection. PpgL, a periplasmic gluconolactonase, has been reported to be involved in P. aeruginosa QS system regulation. However, the detailed function and catalysis mechanism remain elusive. Here the crystal structure of PpgL is exhibited in this current study, along with biochemical analysis, revealing that PpgL is a typical β-propeller enzyme with unique metal-independent lactone hydrolysis activity. Consequently, comparative analysis of seven-bladed propeller lactone catalyzing enzymes and mutagenesis studies identify the critical sites which contribute to the diverse catalytic and substrate-recognition functions. In addition, the reduced biofilm formation and attenuated invasion phenotype resulting from deletion of ppgl confirm the importance of PpgL in P. aeruginosa pathogenesis. These results suggest that PpgL is a potential target for developing new agents against the diseases caused by P. aeruginosa.…

Sanja Matic Petrovic, Milena Radunovic, Milena Barac, Jovana Kuzmanovic Pficer, Dusan Pavlica, Valentina Arsic Arsenijevic, Ana Pucar

by Sanja Matic Petrovic, Milena Radunovic, Milena Barac, Jovana Kuzmanovic Pficer, Dusan Pavlica, Valentina Arsic Arsenijevic, Ana Pucar Objectives The aim of this cross-sectional observational study was to compare the prevalence of different oral Candida spp. in patients with Type 2 Diabetes and chronic periodontitis in two oral sites: dorsal surface of the tongue and subgingival area. In order to determine subgingival areas as potential reservoirs of yeasts, this study aimed to find differences in the yeasts’ detection between the dorsum of the tongue, as the oral site most commonly inhabited with microorganisms, and subgingival samples. Additionally, potential predictors for the yeasts prevalence were determined. Material and methods Subjects (N = 146) were divided into four groups: group A- healthy individuals without periodontitis, group B- healthy individuals with chronic periodontitis, group C- Type 2 Diabetes patients with good glycoregulation and Chronic periodontitis and group D- Type 2 Diabetes patients with poor glycoregulation and Chronic periodontitis. Samples were obtained from the tongue by swabbing. Subgingival plaque samples were taken by paper points and periodontal curette. Isolation and identification of different Candida spp. was done using ChromAgar medium. In addition, germ-tube production and carbohydrate assimilation tests were performed. Results The prevalence of Candida spp. was higher in diabetics with poor glycoregulation. The most frequently isolated species was Candida albicans followed by Candida glabrata and Candida tropicalis. In 15.6% of cases, Candida spp. was present in the subgingival area while absent on the tongue. Multivariate regression model showed that HbA1c was Candida spp. predictor for both locations. Conclusions Our results confirmed that there are Candida spp. carriers among subjects with clinically healthy oral mucosa. Also, this study identified subgingival areas as potential reservoirs of these pathogenic species. Glycoregulation has been recognized as a positive predictor factor of Candida spp.…

Daniel J. Gottlieb

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 140-141, January 15, 2019. …

Meri R. J. Varkila, Alinda G. Vos, Roos E. Barth, Hugo A. Tempelman, Walter L. J. Devillé, Roel A. Coutinho, Diederick E. Grobbee, Kerstin Klipstein-Grobusch

by Meri R. J. Varkila, Alinda G. Vos, Roos E. Barth, Hugo A. Tempelman, Walter L. J. Devillé, Roel A. Coutinho, Diederick E. Grobbee, Kerstin Klipstein-Grobusch Objectives HIV infection has been associated with an impaired lung function in high-income countries, but the association between HIV infection and pulmonary function in Sub-Saharan Africa remains unclear. This study aims to investigate the relation between HIV infection and pulmonary function in a rural African population. Methods A cross-sectional study was conducted among HIV-positive and HIV-negative adults in a rural area in South Africa, as part of the Ndlovu Cohort Study. A respiratory questionnaire and post-bronchodilator spirometry were performed. Multivariable regression analysis was used to investigate whether HIV was independently associated with a decrease in post-bronchodilator FEV1/FVC ratio considering age, sex, body mass index, respiratory risk factors and a history of a pulmonary infection (tuberculosis (TB) or a pneumonia). Possible mediation by a history of pulmonary infection was tested by removing this variable from the final model. Results Two hundred and one consecutive participants were enrolled in the study in 2016, 84 (41.8%) were HIV-positive (82.1% on ART). The median age was 38 (IQR 29–51) years. Following multivariable analysis HIV was not significantly associated to a decline in post-bronchodilator FEV1/FVC ratio (β -0.017, p 0.18). However, upon removal of a history of a pulmonary infection from the final model HIV was significantly related to post-bronchodilator FEV1/FVC ratio, β -0.026, p 0.03. Conclusions Pulmonary function is affected by HIV infection which most likely results from co-infection with TB or other pneumonia. Further research should focus on the influence of a pulmonary infection, most notably TB, on pulmonary function, especially as the incidence of TB is high in HIV infection.…

Laine Monsey, Lyle G. Best, Jianhui Zhu, Susan DeCroo, Matthew Z. Anderson

by Laine Monsey, Lyle G. Best, Jianhui Zhu, Susan DeCroo, Matthew Z. Anderson Cardiovascular disease (CVD) is an important contributor to morbidity and mortality in American Indian communities. The Strong Heart Study (SHS) was initiated in response to the need for population based estimates of cardiovascular disease in American Indians. Previous studies within SHS have identified correlations between heart disease and deficiencies in mannose binding lectin (MBL), a motif recognition molecule of the innate immune system. MBL mediates the immune response to invading pathogens including Chlamydia pneumoniae (Cp), which has also been associated with the development and progression of CVD. However, a link between MBL2 genotype and Cp in contributing to heart disease has not been established. To address this, SHS collected baseline Cp antibody titers (IgA and IgG) and MBL2 genotypes for common functional variants from 553 individuals among twelve participating tribes. A single nucleotide polymorphism (SNP) in the promoter, designated X/Y, correlated significantly with increased Cp IgG titer levels, whereas another promoter SNP (H/L) did not significantly influence antibody levels to Cp. Two variants within exon 1 of MBL2, the A and B alleles, also displayed significant association with Cp antibody titers. Some MBL2 genotypes were absent from the population, suggesting linkage disequilibrium may be operating within the SHS cohort. Additional factors, such as increasing age and socioeconomic status, were also associated with increased Cp IgG antibody titers. This study demonstrates that MBL2 genotype associates with immune reactivity to C. pneumoniae in the SHS cohort. Thus, MBL2 may contribute to the progression of cardiovascular disease (CVD) among American Indians indirectly through pathogen interactions in addition to its previously defined roles.

Evangelia Akoumianaki

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 149-157, January 15, 2019. …

Chia-Ying Wu, Shu-Ling Yu, Yung-Tsung Chen, Yi-Hsuan Chen, Pei-Wen Hsiao, Yen-Hung Chow, Juine-Ruey Chen

by Chia-Ying Wu, Shu-Ling Yu, Yung-Tsung Chen, Yi-Hsuan Chen, Pei-Wen Hsiao, Yen-Hung Chow, Juine-Ruey Chen Enterovirus 71 (EV71) has emerged as a neurological virus causing life-threatening diseases in young children and infants. Although EV71 vaccines in development have presented promising results in several clinical trials, the identified key antigen for improving the broad protective efficacy of EV71 vaccines has not been well investigated. In this report, we show that different multiplicities of infection (MOIs) of the B4(E59) virus significantly affect EV71 vaccine production in a serum-free microcarrier bioreactor system. The antigens produced from high MOIs of 10−1 and 10−2 exhibited higher yield and more infectious full particle (FP) contents in the EV71 vaccines than those produced with low MOIs of 10−4 and 10−6, leading to better cross-neutralizing efficacy. The C4(E36) neutralization results showed that only antisera raised from EV71 FPs provided substantial neutralizing titers against C4(E36), whereas empty particles (EPs) of EV71 conferred no efficacy. Competitive ELISA showed that anti-FP mainly binds to FPs and that 20% of antibodies bind to EPs, whereas most anti-EP binds EPs, with only 10% antibodies binding to FPs. VP1-adsorbed anti-FP lost most of the virus neutralization efficiency, suggesting that the VP1 subunit of FP is the major immunogenic antigen determining the ability of the EV71 vaccine to elicit cross-neutralizing antibodies against EV71 virus subtypes. These findings demonstrate that the high-MOI production approach is significantly correlated with FP productivity, thereby improving the cross-neutralization efficacy of an EV71 vaccine and providing the basis for a better vaccine design against widespread EV71 viruses.

Hye Ryun Kim

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 243-246, January 15, 2019. …

Del Giacomo, Paola; Losito, Angela Raffaella; Tumbarello, Mario

Purpose of review Skin and soft tissue infections (SSTIs) with a wide spectrum of disease severity ranging from uncomplicated to potentially lethal are still a leading cause of morbidity and mortality. The burden of carbapenem-resistant gram-negative bacteria (CR-GNB) in SSTIs is increasing. Luckily, the armamentarium of drugs available is recently expanding as well. The present review looks at data on the role CR-GNB in SSTIs and on the old and new drugs available for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), Pseudomonas, and Acinetobacter. Recent findings The most recent information concern the availability of new antibiotics that, even if no specific clinical trials on complicated SSTIs (cSSTIs) have been performed, may play a role in clinical practice also for the treatment of cSSTIs caused by CR-GNB. Ceftolozane-tazobactam has been found to be a good option for CR Pseudomonas infections including SSTIs. Ceftazidime-avibactam is approved for several indications, including aerobic GNB infections with limited treatment options. Meropenem–vaborbactam therapy has been associated with decreased mortality in infections caused by CRE. Eravacycline has the potential to become useful for the treatment of CR Acinetobacter for which the treatment options are limited. Summary In the carbapenem resistance era, the physicians goal should be to stratify patients according to risk factors for CR-GNB causing SSTIs in order to minimize inappropriate initial therapies. Some recently approved drugs seem destined to become the backbone of target therapy in patients with severe infections caused by susceptible CR-GNB strains. Prompt diagnosis of cSSTIs is crucial and, when feasible, surgical debridement as source control is essential as well. Correspondence to Prof. Mario Tumbarello, Istituto Malattie Infettive, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Roma, Italy. Tel: +39 06 30155373; fax: +39 06 3054519; e-mail: mario.tumbarello@unicatt.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Perez-Varela, M., Corral, J., Aranda, J., Barbe, J.

While the relationship between Acinetobacter baumannii efflux pumps and antimicrobial resistance is well-documented, less is known about the involvement of these proteins in the pathogenicity of this nosocomial pathogen. In previous work, we identified the AbaQ MFS efflux pump and demonstrated its participation in the motility and virulence of A. baumannii. In the present study, we examined the role in these processes of A. baumannii transporters belonging to different superfamilies of efflux pumps. Genes encoding known or putative permeases belonging to efflux pump superfamilies other than MFS were selected and the corresponding knockouts constructed. The antimicrobial susceptibilities of these mutants were consistent with previously reported data. In mutants of A. baumannii strain ATCC 17978 carrying inactivated genes encoding the efflux pumps A1S_2736 (RND), A1S_3371 (MATE) and A1S_0710 (SMR) as well as the newly described ABC permeases A1S_1242 and A1S_2622, both surface-associated motility and virulence were reduced compared to the parental strain. However, inactivation of the genes encoding the known ABC permeases A1S_0536 and A1S_1535, the newly identified putative ABC permeases A1S_0027 and A1S_1057, or the PACE transporters A1S_1503 and A1S_2063 had no effects on bacterial motility or virulence. Our results demonstrate the involvement of antimicrobial transporters belonging at least to five of the six known efflux pump superfamilies in both surface-associated motility and virulence in A. baumannii ATCC 17978.…