Infectious Disease

Infectious Disease Publications

Lieberman MT, Van Tyne D, Dzink-Fox JA, Ma EJ, Gilmore MS, Fox JG. Long-term colonization dynamics of Enterococcus faecalis in implanted devices in research macaques. Appl Environ Microbiol 2018;Abstract
Enterococcus faecalis is a common opportunistic pathogen that colonizes cephalic recording chambers (CRCs) of macaques used in cognitive neuroscience research. We previously characterized 15 strains isolated from macaques at our institution in 2011. The goal of this study was to examine how a 2014 protocol change prohibiting antimicrobials within CRCs affected colonizing strains. We collected 20 isolates from 10 macaques between 2013-2017 for comparison to four previously characterized 2011 isolates with respect to sequence type (ST) distribution, antimicrobial resistance, biofilm formation, and changes in genes that might confer a survival advantage. ST4 and ST55 were predominant among 2011 isolates, whereas the less antimicrobial-resistant lineage ST48 emerged to dominance after 2013. Two macaques remained colonized by ST4 and ST55 strains for five and four years, respectively. While the antimicrobial resistance and virulence factors identified in these ST4 and ST55 strains remained relatively stable, we detected an increase in biofilm formation ability over time in both isolates. We also found that ST48 strains were typically robust biofilm formers, which could explain why this ST increased in prevalence. Finally, we identified mutations in the DNA mismatch repair genes and in separate ST55 and ST4 strains, and confirmed that strains bearing these mutations displayed a hypermutator phenotype. The presence of a hypermutator phenotype may complicate future antimicrobial treatment for clinically relevant infections in macaques. is a common cause of healthcare-associated infections in humans, largely due to its ability persist in the hospital environment, colonize patients, acquire antimicrobial resistance, and form biofilms. Understanding how enterococci evolve in healthcare settings provides insight into factors affecting enterococcal survival and persistence. Macaques used in neuroscience research have long-term cranial implants that, despite best practices, often become colonized by This provides a unique opportunity to non-invasively examine the evolution of enterococci on a long-term indwelling device. We collected strains from cephalic implants over a seven-year period and characterized sequence type, antimicrobial resistance, virulence factors, biofilm production and hypermutator phenotypes. Improved antimicrobial stewardship allowed a less-antimicrobial-resistant strain to predominate at the implant interface, potentially improving antimicrobial treatment outcomes if future clinical infections occur. Biofilm formation appears to play an important role in persistence of associated with these implants.
Chen L, Fu T, Gu H, Jie Y, Sun Z, Jiang D, Yu J, Zhu X, Xu J, Hong J. Trends in dacryocystitis in China: A STROBE-compliant article. Medicine (Baltimore) 2018;97(26):e11318.Abstract
The aim of the study was to review the distribution, current trends, and microbiological characteristics of bacterial pathogens isolated from dacryocystitis patients in China during the last 15 years.This is a retrospective multiple-center noncomparative case series. The medical records of 15,452 consecutive patients from 7 cities diagnosed as having dacryocystitis between 2002 and 2016 were reviewed. The patients' demographics, microbiological data, and antibiotic sensitivity were reviewed and analyzed.A total of 3344 lacrimal sac content cultures were taken (21.6%) during the study period. A pathogen was identified in 1996 samples (59.7%), with bacterial isolates accounting for 1902 of the positive cultures (95.3%). Gram-positive isolates, gram-negative isolates, and anaerobic bacteria were found in 1218 (61.0%), 607 (30.4%), and 285 (14.3%) samples, respectively. An increase in gram-positive isolates over the study duration was found (P = .003). The predominant isolates were coagulase negative Staphylococci (485, 25.5%), Staphylococcus aureus (186, 9.8%), Pseudomonas aeruginosa (184, 9.7%), and Haemophilus influenzae (152, 9.0%). There was a trend toward increasing resistance to erythromycin from 10.5% during the first 5 years of the study to 20.7% during the last 5 years (P < .001). Antimicrobial susceptibility testing showed that gatifloxacin was the most effective drug against most of gram-positive, gram-negative, and anaerobic bacteria.The microbial culture rate of dacryocystitis in China is low. There was an increase in the percentage of gram-positive bacteria over time. The sensitivity of gram-positive isolates to tested antibiotics is relatively low compared with that of gram-negative isolates. Our data show that the empiric use of fourth-generation fluoroquinolones in refractory dacryocystitis may be justified.
Lee JY, Lee JS, Materne EC, Rajala R, Ismail AM, Seto D, Dyer DW, Rajaiya J, Chodosh J. Bacterial RecA Protein Promotes Adenoviral Recombination during Infection. mSphere 2018;3(3)Abstract
Adenovirus infections in humans are common and sometimes lethal. Adenovirus-derived vectors are also commonly chosen for gene therapy in human clinical trials. We have shown in previous work that homologous recombination between adenoviral genomes of human adenovirus species D (HAdV-D), the largest and fastest growing HAdV species, is responsible for the rapid evolution of this species. Because adenovirus infection initiates in mucosal epithelia, particularly at the gastrointestinal, respiratory, genitourinary, and ocular surfaces, we sought to determine a possible role for mucosal microbiota in adenovirus genome diversity. By analysis of known recombination hot spots across 38 human adenovirus genomes in species D (HAdV-D), we identified nucleotide sequence motifs similar to bacterial Chi sequences, which facilitate homologous recombination in the presence of bacterial Rec enzymes. These motifs, referred to here as Chi, were identified immediately 5' to the sequence encoding penton base hypervariable loop 2, which expresses the arginine-glycine-aspartate moiety critical to adenoviral cellular entry. Coinfection with two HAdV-Ds in the presence of an lysate increased recombination; this was blocked in a RecA mutant strain, DH5α, or upon RecA depletion. Recombination increased in the presence of lysate despite a general reduction in viral replication. RecA colocalized with viral DNA in HAdV-D-infected cell nuclei and was shown to bind specifically to Chi sequences. These results indicate that adenoviruses may repurpose bacterial recombination machinery, a sharing of evolutionary mechanisms across a diverse microbiota, and unique example of viral commensalism. Adenoviruses are common human mucosal pathogens of the gastrointestinal, respiratory, and genitourinary tracts and ocular surface. Here, we report finding Chi-like sequences in adenovirus recombination hot spots. Adenovirus coinfection in the presence of bacterial RecA protein facilitated homologous recombination between viruses. Genetic recombination led to evolution of an important external feature on the adenoviral capsid, namely, the penton base protein hypervariable loop 2, which contains the arginine-glycine-aspartic acid motif critical to viral internalization. We speculate that free Rec proteins present in gastrointestinal secretions upon bacterial cell death facilitate the evolution of human adenoviruses through homologous recombination, an example of viral commensalism and the complexity of virus-host interactions, including regional microbiota.
Dabul ANG, Avaca-Crusca JS, Van Tyne D, Gilmore MS, Camargo ILBC. Resistance in In Vitro Selected Tigecycline-Resistant Methicillin-Resistant Staphylococcus aureus Sequence Type 5 Is Driven by Mutations in mepR and mepA Genes. Microb Drug Resist 2018;24(5):519-526.Abstract
A tigecycline-susceptible (TGC-S) Sequence Type (ST) 5 clinical methicillin-resistant Staphylococcus aureus (MRSA) strain was cultured in escalating levels of tigecycline, yielding mutants eightfold more resistant. Their genomes were sequenced to identify genetic alterations, resulting in resistance. Alterations in rpsJ, commonly related to tigecycline resistance, were also investigated. Tigecycline resistance was mediated by loss-of-function mutations in the transcriptional repressor mepR, resulting in derepression of the efflux pump mepA. Increased levels of resistance were obtained by successive mutations in mepA itself. No alterations in RpsJ were observed in selected strains, but we observed a K57M substitution, previously correlated with resistance, among TGC-S clinical strains. Thus, the pathway to tigecycline resistance in CC5 MRSA in vitro appears to be derepression of mep operon as the result of mepR loss-of-function mutation, followed by alterations in MepA efflux pump. This shows that other evolutionary pathways, besides mutation of rpsJ, are available for evolving tigecycline resistance in CC5 MRSA.
Sié A, Diarra A, Millogo O, Zongo A, Lebas E, Bärnighausen T, Chodosh J, Porco TC, Deiner MS, Lietman TM, Keenan JD, Oldenburg CE. Seasonal and Temporal Trends in Childhood Conjunctivitis in Burkina Faso. Am J Trop Med Hyg 2018;Abstract
Acute conjunctivitis follows a seasonal pattern. Although its clinical course is typically self-limited, conjunctivitis epidemics incur a substantial economic burden because of missed school and work days. This study investigated seasonal and temporal trends of childhood conjunctivitis in the entire country of Burkina Faso from 2013 to 2016, using routine monthly surveillance from 2,444 government health facilities. A total of 783,314 cases were reported over the 4-year period. Conjunctivitis followed a seasonal pattern throughout the country, with a peak in April. A nationwide conjunctivitis outbreak with a peak in September 2016 was noted ( < 0.001), with an excess number of cases first detected in June 2016. Nationwide passive surveillance was able to detect an epidemic 3 months before its peak, which may aide in allocation of resources for containment and mitigation of transmission in future outbreaks.
Johnston T, Van Tyne D, Chen RF, Fawzi NL, Kwon B, Kelso MJ, Gilmore MS, Mylonakis E. Propyl-5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC): a new bacteriostatic agent against methicillin-resistant Staphylococcus aureus. Sci Rep 2018;8(1):7062.Abstract
The emergence of Staphylococcus aureus strains resistant to 'last resort' antibiotics compels the development of new antimicrobials against this important human pathogen. We found that propyl 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) shows bacteriostatic activity against S. aureus (MIC = 4 μg/ml) and rescues Caenorhabditis elegans from S. aureus infection. Whole-genome sequencing of S. aureus mutants resistant to the compound, along with screening of a S. aureus promoter-lux reporter array, were used to explore possible mechanisms of action. All mutants resistant to HMPC acquired missense mutations at distinct codon positions in the global transcriptional regulator mgrA, followed by secondary mutations in the phosphatidylglycerol lysyltransferase fmtC/mprF. The S. aureus promoter-lux array treated with HMPC displayed a luminescence profile that was unique but showed similarity to DNA-damaging agents and/or DNA replication inhibitors. Overall, HMPC is a new anti-staphylococcal compound that appears to act via an unknown mechanism linked to the global transcriptional regulator MgrA.
Kim W, Zhu W, Hendricks GL, Van Tyne D, Steele AD, Keohane CE, Fricke N, Conery AL, Shen S, Pan W, Lee K, Rajamuthiah R, Fuchs BB, Vlahovska PM, Wuest WM, Gilmore MS, Gao H, Ausubel FM, Mylonakis E. A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 2018;556(7699):103-107.Abstract
A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.
Deiner MS, McLeod SD, Chodosh J, Oldenburg CE, Fathy CA, Lietman TM, Porco TC. Clinical Age-Specific Seasonal Conjunctivitis Patterns and Their Online Detection in Twitter, Blog, Forum, and Comment Social Media Posts. Invest Ophthalmol Vis Sci 2018;59(2):910-920.Abstract
Purpose: We sought to determine whether big data from social media might reveal seasonal trends of conjunctivitis, most forms of which are nonreportable. Methods: Social media posts (from Twitter, and from online forums and blogs) were classified by age and by conjunctivitis type (allergic or infectious) using Boolean and machine learning methods. Based on spline smoothing, we estimated the circular mean occurrence time (a measure of central tendency for occurrence) and the circular variance (a measure of uniformity of occurrence throughout the year, providing an index of seasonality). Clinical records from a large tertiary care provider were analyzed in a similar way for comparison. Results: Social media posts machine-coded as being related to infectious conjunctivitis showed similar times of occurrence and degree of seasonality to clinical infectious cases, and likewise for machine-coded allergic conjunctivitis posts compared to clinical allergic cases. Allergic conjunctivitis showed a distinctively different seasonal pattern than infectious conjunctivitis, with a mean occurrence time later in the spring. Infectious conjunctivitis for children showed markedly greater seasonality than for adults, though the occurrence times were similar; no such difference for allergic conjunctivitis was seen. Conclusions: Social media posts broadly track the seasonal occurrence of allergic and infectious conjunctivitis, and may be a useful supplement for epidemiologic monitoring.
Lebreton F, Valentino MD, Schaufler K, Earl AM, Cattoir V, Gilmore MS. Transferable vancomycin resistance in clade B commensal-type Enterococcus faecium. J Antimicrob Chemother 2018;73(6):1479-1486.Abstract
Objectives: Vancomycin-resistant Enterococcus faecium is a leading cause of MDR hospital infection. Two genetically definable populations of E. faecium have been identified: hospital-adapted MDR isolates (clade A) and vancomycin-susceptible commensal strains (clade B). VanN-type vancomycin resistance was identified in two isolates of E. faecium recovered from blood and faeces of an immunocompromised patient. To understand the genomic context in which VanN occurred in the hospitalized patient, the risk it posed for transmission in the hospital and its origins, it was of interest to determine where these strains placed within the E. faecium population structure. Methods: We obtained the genome sequence of the VanN isolates and performed comparative and functional genomics of the chromosome and plasmid content. Results: We show that, in these strains, VanN occurs in a genetic background that clusters with clade B E. faecium, which is highly unusual. We characterized the chromosome and the conjugative plasmid that carries VanN resistance in these strains, pUV24. This plasmid exhibits signatures of in-host selection on the vanN operon regulatory system, which are associated with a constitutive expression of vancomycin resistance. VanN resistance in clade B strains may go undetected by current methods. Conclusions: We report a case of vancomycin resistance in a commensal lineage of E. faecium responsible for an atypical bacteraemia in an immunocompromised patient. A reservoir of transferable glycopeptide resistance in the community could pose a concern for public health.
Zhang S, Lebreton F, Mansfield MJ, Miyashita S-I, Zhang J, Schwartzman JA, Tao L, Masuyer G, Martínez-Carranza M, Stenmark Pål, Gilmore MS, Doxey AC, Dong M. Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium. Cell Host Microbe 2018;23(2):169-176.e6.Abstract
Botulinum neurotoxins (BoNTs), produced by various Clostridium strains, are a family of potent bacterial toxins and potential bioterrorism agents. Here we report that an Enterococcus faecium strain isolated from cow feces carries a BoNT-like toxin, designated BoNT/En. It cleaves both VAMP2 and SNAP-25, proteins that mediate synaptic vesicle exocytosis in neurons, at sites distinct from known BoNT cleavage sites on these two proteins. Comparative genomic analysis determines that the E. faecium strain carrying BoNT/En is a commensal type and that the BoNT/En gene is located within a typical BoNT gene cluster on a 206 kb putatively conjugative plasmid. Although the host species targeted by BoNT/En remains to be determined, these findings establish an extended member of BoNTs and demonstrate the capability of E. faecium, a commensal organism ubiquitous in humans and animals and a leading cause of hospital-acquired multi-drug-resistant (MDR) infections, to horizontally acquire, and possibly disseminate, a unique BoNT gene cluster.
Ebrahimiadib N, Hernandez M, Modjtahedi BS, Roohipoor RC, Foster SC. Atopy in Patients With Ocular Cicatricial Pemphigoid. Cornea 2018;37(4):436-441.Abstract
PURPOSE: To evaluate the presence of atopy in patients with ocular cicatricial pemphigoid (OCP). METHOD: Patient encounters between August 2005 and November 2016 at the Massachusetts Eye Research and Surgery Institute (MERSI) were searched to identify those with biopsy-proven OCP who had concurrent evidence of atopy. RESULTS: There were 230 patients with biopsy-proven OCP. Thirty-three of them were found to have clinical symptoms of atopy (asthma, hay fever, and eczema) and of these, 23 had evidence of atopy in their conjunctival biopsy specimens. All patients were administered immunomodulatory therapy for treatment of their OCP with 20 patients requiring additional antiallergy treatment to control residual atopic ocular symptoms. Among patients who used antiallergy medications, 80% showed improvement in residual symptoms. Rituximab and/or intravenous immunoglobulin is a preferred OCP medication for patients with OCP with some evidence of atopy. CONCLUSIONS: Clinicians should consider the coexistence of atopy in patients with OCP, especially in those with persistent symptoms after initiation of immunomodulatory therapy.
Nascimento H, Viana-Niero C, Nogueira CL, Martins Bispo PJ, Pinto F, de Paula Pereira Uzam C, Matsumoto CK, Oliveira Machado AM, Leão SC, Höfling-Lima AL, de Freitas D. Identification of the Infection Source of an Outbreak of Mycobacterium Chelonae Keratitis After Laser in Situ Keratomileusis. Cornea 2018;37(1):116-122.Abstract
PURPOSE: Nontuberculous mycobacteria keratitis is a rare but challenging complication of laser in situ keratomileusis (LASIK). This study was conducted to determine the source(s) of infection in a cluster of cases of keratitis after LASIK and to describe this outbreak and patients' outcomes. METHODS: In this retrospective, case series, single-center study, 86 patients were included who underwent LASIK or photorefractive keratectomy between December 2011 and February 2012. Corneal scrapes from the affected eyes, samples of tap and distilled water, water from the reservoir of the distilling equipment, steamer, and autoclave cassette; antiseptic and anesthetic solutions and surgical instrument imprints were cultivated in liquid and on solid media. Gram-negative bacteria and yeasts were identified using automated systems and mycobacteria by polymerase chain reaction-restriction enzyme analysis of the hsp65 gene (PRA-hsp65) and DNA sequencing. Mycobacterial isolates were typed by pulsed-field gel electrophoresis. The cases and outcomes are described. The main outcome measure was identification of the source(s) of the mycobacterial infections. RESULTS: Eight (15 eyes) of 86 patients (172 eyes) who underwent LASIK developed infections postoperatively; no patients who underwent photorefractive keratectomy developed infections. Mycobacterium chelonae was isolated from 4 eyes. The distilled water collected in the surgical facility contained the same M. chelonae strain isolated from the patients' eyes. Different gram-negative bacteria and yeasts were isolated from samples collected at the clinic but not from the patients' eyes. CONCLUSIONS: Tap water distilled locally in surgical facilities may be a source of infection after ocular surgery and its use should be avoided.
Welsh MA, Taguchi A, Schaefer K, Van Tyne D, Lebreton F, Gilmore MS, Kahne D, Walker S. Identification of a Functionally Unique Family of Penicillin-Binding Proteins. J Am Chem Soc 2017;139(49):17727-17730.Abstract
Penicillin-binding proteins (PBPs) are enzymes involved in the assembly of the bacterial cell wall, a major target for antibiotics. These proteins are classified by mass into high-molecular-weight PBPs, which are transpeptidases that form peptidoglycan cross-links, and low-molecular-weight PBPs, which are typically hydrolases. We report a functionally unique family of low-molecular-weight PBPs that act as transpeptidases rather than hydrolases, but they do not cross-link peptidoglycan. We show that these PBPs can exchange d-amino acids bearing chemical tags or affinity handles into peptidoglycan precursors, including Lipid II, enabling biochemical studies of proteins involved in cell wall assembly. We report that, in two organisms, the PBPs incorporate lysine into cellular peptidoglycan and that, further, the PBPs have the unprecedented ability to transfer the primary ε-amine of lysine to peptidoglycan.
Marmalidou A, Kheirkhah A, Dana R. Conjunctivochalasis: A Systematic Review. Surv Ophthalmol 2017;Abstract
Conjunctivochalasis (CCH) is a conjunctival condition characterized by loose, redundant conjunctival folds, most typically in the inferior bulbar conjunctiva of both eyes. Although CCH is a common cause of ocular irritation and discomfort, especially in the elderly, it is often overlooked in clinical practice. Conjunctivochalasis may be associated with various ocular and non-ocular conditions; however, the most important risk factor is aging. Although often asymptomatic, CCH may cause symptoms related to tear film instability and/or delayed tear clearance. Pathogenesis of CCH remains largely unknown, but may involve different elements such as aged conjunctiva, unstable tear film, mechanical friction, ocular surface inflammation, and delayed tear clearance. Contradictory results have been reported on histopathologic changes in CCH, with some studies showing a normal microscopic structure. For symptomatic CCH, medical treatment may include lubrication and anti-inflammatory medications. For symptomatic patients who fail to respond to medical treatment, a surgical procedure may be considered. Although various surgical procedures have been used for CCH, more often it consists of conjunctival cauterization or excision of the redundant conjunctiva, with or without amniotic membrane transplantation.

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