Biology subjects

Grad, Y. H.

Publications and source records attributed to Grad, Y. H..

8 recordsLinked to original sources

bioRxiv2018

Photo-inactivation of Neisseria gonorrhoeae: A paradigm changing approach for combating antibiotic-resistant gonococcal infection

Neisseria gonorrhoeae is the causative pathogen of the sexually transmitted disease gonorrhea, a disease at risk of becoming untreatable due to increasing antibiotic resistance. There is a critical need for the development of new anti-gonococcal therapies. In this study, we investigated the effectiveness of antimicrobial blue light (aBL), an innovative non-antibiotic approach, for the inactivation of antibiotic-resistant N. gonorrhoeae. Our findings indicated that aBL at 405 nm preferentially inactivated antibiotic-resistant N. gonorrhoeae over the vaginal epithelial cells. Furthermore, no genotoxicity of aBL to the vaginal epithelial cells was observed at the exposure for inactivating N. gonorrhoeae. aBL also effectively inactivated N. gonorrhoeae that had invaded into the vaginal epithelial cells. No gonococcal resistance to aBL developed after 15 successive cycles of sub-therapeutic inactivation. Endogenous aBL-active photosensitizing chromophores (porphyrins and flavins) in N. gonorrhoeae were identified and quantified using ultra performance liquid chromatography, with coproporphyrin being the most abundant endogenous porphyrin species. Taken together, aBL at 405 nm represents a potent potential treatment for gonococcal infections.\n\nOne Sentence SummaryaBL selectively inactivated antibiotic-resistant Neisseria gonorrhoeaen over normal vaginal epithelial cells.

microbiology↗

bioRxiv2018

Co-circulating mumps lineages at multiple geographic scales

Despite widespread vaccination, eleven thousand mumps cases were reported in the United States (US) in 2016-17, including hundreds in Massachusetts, primarily in college settings. We generated 203 whole genome mumps virus (MuV) sequences from Massachusetts and 15 other states to understand the dynamics of mumps spread locally and nationally, as well as to search for variants potentially related to vaccination. We observed multiple MuV lineages circulating within Massachusetts during 2016-17, evidence for multiple introductions of the virus to the state, and extensive geographic movement of MuV within the US on short time scales. We found no evidence that variants arising during this outbreak contributed to vaccine escape. Combining epidemiological and genomic data, we observed multiple co-circulating clades within individual universities as well as spillover into the local community. Detailed data from one well-sampled university allowed us to estimate an effective reproductive number within that university significantly greater than one. We also used publicly available small hydrophobic (SH) gene sequences to estimate migration between world regions and to place this outbreak in a global context, but demonstrate that these short sequences, historically used for MuV genotyping, are inadequate for tracing detailed transmission. Our findings suggest continuous, often undetected, circulation of mumps both locally and nationally, and highlight the value of combining genomic and epidemiological data to track viral disease transmission at high resolution.

genomics↗

bioRxiv2018

Antimicrobial exposure in sexual networks drives divergent evolution in modern gonococci

The sexually transmitted pathogen Neisseria gonorrhoeae is regarded as being on the way to becoming an untreatable superbug. Despite its clinical importance, little is known about its emergence and evolution, and how this corresponds with the introduction of antimicrobials. We present a genome-based phylogeographic analysis of 419 gonococcal isolates from across the globe. Results indicate that modern gonococci originated in Europe or Africa as late as the 16thcentury and subsequently disseminated globally. We provide evidence that the modern gonococcal population has been shaped by antimicrobial treatment of sexually transmitted and other infections, leading to the emergence of two major lineages with different evolutionary strategies. The well-described multi-resistant lineage is associated with high rates of homologous recombination and infection in high-risk sexual networks where antimicrobial treatment is frequent. A second, multi-susceptible lineage associated with heterosexual networks, where asymptomatic infection is more common, was also identified, with potential implications for infection control.

genomics↗

bioRxiv2018

Azithromycin resistance through interspecific acquisition of an epistasis dependent efflux pump component and transcriptional regulator in Neisseria gonorrhoeae

Mosaic interspecifically acquired alleles of the multiple transferable resistance (mtr) efflux pump operon correlate with reduced susceptibility to azithromycin in Neisseria gonorrhoeae in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we use population genomics, transformations, and transcriptional analyses to dissect the relationship between variant mtr alleles and azithromycin resistance. We find that the locus encompassing the mtrR transcriptional repressor and the mtrCDE pump is a hotspot of interspecific recombination introducing alleles from N. meningitidis and N. lactamica into N. gonorrhoeae, with multiple rare haplotypes in linkage disequilibrium at mtrD and the mtr promoter region. Transformations demonstrated that resistance is mediated through epistasis between these two loci and that the full length of the mosaic mtrD allele is required. Gene expression profiling revealed the mechanism of resistance in mosaics couples the novel mtrDalleles with promoter mutations enhancing expression of the pump. Overall, our results demonstrate that epistatic interactions at mtr gained from multiple Neisseria has contributed to azithromycin resistance in the gonococcal population.\n\nAUTHOR SUMMARYNeisseria gonorrhoeae is the sexually transmitted bacterial pathogen responsible for over 100 million cases of gonorrhea worldwide each year. The incidence of reduced susceptibility to the macrolide class antibiotic azithromycin has increased in the past decade; however, a large proportion of the genetic basis of resistance to this drug remains unexplained. Recently, resistance has been shown to be highly associated with mosaic alleles of the multiple transferable resistance (mtr) efflux pump, which have been gained via horizontal gene exchange with other Neisseria. However, if and how these alleles caused resistance was unknown. Here, we demonstrate that resistance has been gained through epistasis between mtrD and the mtr promoter region using evidence from both population genomics and experimental genetic manipulation. Epistasis also acts within the mtrD locus alone, requiring the full length of the gene for phenotypic resistance. Transcriptomic profiling indicates that the mechanism of resistance in mosaics is likely derived from both structural changes to mtrD, coupled with promoter mutations that result in regulatory changes to mtrCDE.

microbiology↗

bioRxiv2018

Trends in outpatient antibiotic prescribing practice among US older adults, 2011-2015: an observational study

Structured abstractO_ST_ABSObjectiveC_ST_ABSTo identify temporal trends in outpatient antibiotic use and antibiotic prescribing practice among older adults.\n\nDesignObservational study using United States Medicare administrative claims during 2011-2015. Trends in antibiotic use were estimated using multivariable regression adjusting for beneficiaries demographic and clinical covariates.\n\nSettingMedicare.\n\nParticipants4.6 million Medicare beneficiaries from a nationwide, 20% sample of fee-forservice Medicare beneficiaries [≥]65 years old.\n\nMain outcome measurementsOverall rates of antibiotic prescription claims, rates of appropriate and inappropriate prescribing, rates for each of the most frequently prescribed antibiotics, and rates of antibiotic claims associated with specific diagnoses.\n\nResultsAntibiotic claims fell from 1362.2 to 1361.6 claims per 1,000 beneficiaries per year during 2011-2015, an overall 0.2% decrease (95% CI 0.07-0.32). Inappropriate antibiotic claims fell from 552 to 533 claims per 1,000 beneficiaries, a 4.1% decrease (CI 3.9-4.3). Individual antibiotics had heterogeneous changes in use. For example, azithromycin claims per beneficiary decreased by 18.4% (CI 18.2-18.7) while levofloxacin claims increased by 28.1% (CI 27.5-28.6). Azithromycin use associated with each of the potentially appropriate and inappropriate respiratory diagnoses we considered decreased, while levofloxacin use associated with each of those diagnoses increased.\n\nConclusionAmong US Medicare beneficiaries, overall antibiotic use and inappropriate use declined modestly, but individual drugs experienced divergent changes in use. Trends in drug use across indications were stronger than trends in use for individual indications, suggesting that guidelines and concerns about antibiotic resistance were not major drivers of change in antibiotic use.

epidemiology↗

bioRxiv2017

Vaccine waning and mumps re-emergence in the United States

Following decades of declining mumps incidence amid widespread vaccination, the United States and other high-income countries have experienced a resurgence in mumps cases over the last decade. Outbreaks affecting vaccinated individuals--and communities with high vaccine coverage--have prompted concerns about the effectiveness of the live attenuated vaccine currently in use: it is unclear if immune protection wanes, or if the vaccine protects inadequately against mumps virus lineages currently circulating. Synthesizing data from epidemiological studies, we estimate that vaccine-derived protection wanes at a timescale of 27 (95%CI: 16 to 51) years. After accounting for this waning, we identify no evidence of changes in vaccine effectiveness over time associated with the emergence of heterologous virus genotypes. Moreover, a mathematical model of mumps transmission validates our findings about the central role of vaccine waning in the re-emergence of cases: outbreaks from 2006 to the present among young adults, and outbreaks occurring in the late 1980s and early 1990s among adolescents, align with peaks in the susceptibility of these age groups attributable to loss of vaccine-derived protection. In contrast, evolution of mumps virus strains escaping pressure would be expected to cause a higher proportion of cases among children. Routine use of a third dose at age 18y, or booster dosing throughout adulthood, may enable mumps elimination and should be assessed in clinical trials.\n\nOne Sentence SummaryThe estimated waning rate of vaccine-conferred immunity against mumps predicts observed changes in the age distribution of mumps cases in the United States since 1967.

epidemiology↗

bioRxiv2017

Despite egg-adaptive mutations, the 2012-13 H3N2 influenza vaccine induced comparable antibody titers to the intended strain

BackgroundInfluenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity and mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A/H3N2. Failure to achieve consistently high VE has been attributed both to mismatches between the vaccine and circulating influenza strains and to the vaccine's elicitation of protective immunity in only a subset of the population. The low H3N2 VE in 2012-13 was attributed to egg-adaptive mutations that created antigenic mismatch between the intended (A/Victoria/361/2011) and actual vaccine strain (IVR-165).\n\nMethodsWe investigate the basis of the low VE in 2012-2013 by evaluating whether vaccinated and unvaccinated individuals were infected by different viral strains and assessing the serologic responses to A/Victoria/361/2011 and the IVR-165 vaccine strain in an adult cohort before and after vaccination.\n\nResultsWe found no significant genetic differences between the strains that infected vaccinated and unvaccinated individuals. Vaccination increased titers to A/Victoria/361/2011 as much as to IVR-165. These results are consistent with the hypothesis that vaccination served merely to boost preexisting cross-reactive immune responses, which provided limited protection against infection with the circulating influenza strains.\n\nConclusionsIn contrast to suggestive analyses based on ferret antisera, low H3N2 VE in 2012-13 does not appear to be due to the failure of the egg-adapted strain to induce a response to the intended vaccine strain. Instead, low VE might have been caused by the emergence of anti-genically novel influenza strains and low vaccine immunogenicity in a subset of the population.

epidemiology↗

bioRxiv2017

Impact of rapid susceptibility testing and antibiotic selection strategy on the emergence and spread of antibiotic resistance in gonorrhea

BackgroundIncreasing antibiotic resistance limits treatment options for gonorrhea. We examined the extent to which a hypothetical point-of-care (POC) test reporting antibiotic susceptibility profiles could slow the spread of resistance.\n\nMethodsWe developed a deterministic compartmental model describing gonorrhea transmission in a single-sex population with three antibiotics available to treat infections. Probabilities of resistance emergence on treatment and fitness costs associated with resistance were based on characteristics of ciprofloxacin, azithromycin, and ceftriaxone. We evaluated time to 1% and 5% prevalence of resistant strains among all isolates with: (1) empiric treatment (azithromycin plus ceftriaxone), and treatment guided by POC tests determining susceptibility to (2) ciprofloxacin only and (3) all three antibiotics.\n\nFindingsBased on current gonococcal susceptibility patterns in the United States, the model indicated that continued empiric dual antibiotic treatment without POC testing resulted in >5% of isolates being resistant to both azithromycin and ceftriaxone within 15 years. When either POC test was used in 10% of identified cases, this was delayed by 5 years. The three antibiotic POC test delayed the time to reach 1% prevalence of triply-resistant strains by 6 years, while the ciprofloxacin-only test resulted in no delay. Results were less sensitive to assumptions about fitness costs and test characteristics with increasing test uptake. The main limitation of this study is that we made simplifying assumptions to describe gonorrhea transmission and the emergence and spread of resistance in the population.\n\nConclusionsRapid diagnostics that report antibiotic susceptibility have the potential to extend the usefulness of existing antibiotics for treatment of gonorrhea. Monitoring resistance patterns will be critical with the introduction of such tests.

epidemiology↗