Infectious Disease

Infectious Disease Publications

Ebrahimiadib N, Hernandez M, Modjtahedi BS, Roohipoor RC, Foster SC. Atopy in Patients With Ocular Cicatricial Pemphigoid. Cornea 2018;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.
Junk AK, Chen PP, Lin SC, Nouri-Mahdavi K, Radhakrishnan S, Singh K, Chen TC. Disinfection of Tonometers: A Report by the American Academy of Ophthalmology. Ophthalmology 2017;124(12):1867-1875.Abstract
OBJECTIVE: To examine the efficacy of various disinfection methods for reusable tonometer prisms in eye care and to highlight how disinfectants can damage tonometer tips and cause subsequent patient harm. METHODS: Literature searches were conducted last in October 2016 in the PubMed and the Cochrane Library databases for original research investigations. Reviews, non-English language articles, nonophthalmology articles, surveys, and case reports were excluded. RESULTS: The searches initially yielded 64 unique citations. After exclusion criteria were applied, 10 laboratory studies remained for this review. Nine of the 10 studies used tonometer prisms and 1 used steel discs. The infectious agents covered in this assessment include adenovirus 8 and 19, herpes simplex virus (HSV) 1 and 2, human immunodeficiency virus 1, hepatitis C virus, enterovirus 70, and variant Creutzfeldt-Jakob disease. All 4 studies of adenovirus 8 concluded that after sodium hypochlorite (dilute bleach) disinfection, the virus was undetectable, but only 2 of the 4 studies found that 70% isopropyl alcohol (e.g., alcohol wipes or soaks) eradicated all viable virus. All 3 HSV studies concluded that both sodium hypochlorite and 70% isopropyl alcohol eliminated HSV. Ethanol, 70% isopropyl alcohol, dilute bleach, and mechanical cleaning all lack the ability to remove cellular debris completely, which is necessary to prevent prion transmission. Therefore, single-use tonometer tips or disposable tonometer covers should be considered when treating patients with suspected prion disease. Damage to tonometer prisms can be caused by sodium hypochlorite, 70% isopropyl alcohol, 3% hydrogen peroxide, ethyl alcohol, water immersion, ultraviolet light, and heat exposure. Disinfectants can cause tonometer tips to swell and crack by dissolving the glue that holds the hollow tip together. The tonometer tip cracks can irritate the cornea, harbor microbes, or allow disinfectants to enter the interior of the tonometer tip. CONCLUSIONS: Sodium hypochlorite (dilute bleach) offers effective disinfection against adenovirus and HSV, the viruses commonly associated with nosocomial outbreaks in eye care. Tonometer prisms should be examined regularly for signs of damage.
DeFrancesco AS, Masloboeva N, Syed AK, DeLoughery A, Bradshaw N, Li G-W, Gilmore MS, Walker S, Losick R. Genome-wide screen for genes involved in eDNA release during biofilm formation by Staphylococcus aureus. Proc Natl Acad Sci U S A 2017;114(29):E5969-E5978.Abstract
Staphylococcus aureus is a leading cause of both nosocomial and community-acquired infection. Biofilm formation at the site of infection reduces antimicrobial susceptibility and can lead to chronic infection. During biofilm formation, a subset of cells liberate cytoplasmic proteins and DNA, which are repurposed to form the extracellular matrix that binds the remaining cells together in large clusters. Using a strain that forms robust biofilms in vitro during growth under glucose supplementation, we carried out a genome-wide screen for genes involved in the release of extracellular DNA (eDNA). A high-density transposon insertion library was grown under biofilm-inducing conditions, and the relative frequency of insertions was compared between genomic DNA (gDNA) collected from cells in the biofilm and eDNA from the matrix. Transposon insertions into genes encoding functions necessary for eDNA release were identified by reduced representation in the eDNA. On direct testing, mutants of some of these genes exhibited markedly reduced levels of eDNA and a concomitant reduction in cell clustering. Among the genes with robust mutant phenotypes were gdpP, which encodes a phosphodiesterase that degrades the second messenger cyclic-di-AMP, and xdrA, the gene for a transcription factor that, as revealed by RNA-sequencing analysis, influences the expression of multiple genes, including many involved in cell wall homeostasis. Finally, we report that growth in biofilm-inducing medium lowers cyclic-di-AMP levels and does so in a manner that depends on the gdpP phosphodiesterase gene.
Li H, Reksten TR, Ice JA, Kelly JA, Adrianto I, Rasmussen A, Wang S, He B, Grundahl KM, Glenn SB, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta M-L, Brun JG, Gøransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnström M, Cunninghame Graham DS, Patel K, Adler AJ, Farris DA, Brennan MT, Chodosh J, Gopalakrishnan R, Weisman MH, Venuturupalli S, Wallace DJ, Hefner KS, Houston GD, Huang AJW, Hughes PJ, Lewis DM, Radfar L, Vista ES, Edgar CE, Rohrer MD, Stone DU, Vyse TJ, Harley JB, Gaffney PM, James JA, Turner S, Alevizos I, Anaya J-M, Rhodus NL, Segal BM, Montgomery CG, Scofield HR, Kovats S, Mariette X, Rönnblom L, Witte T, Rischmueller M, Wahren-Herlenius M, Omdal R, Jonsson R, Ng W-F, for Registry UKPS's S, Nordmark G, Lessard CJ, Sivils KL. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet 2017;13(6):e1006820.Abstract
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
Inomata T, Ono K, Matsuba T, Shiang T, Di Zazzo A, Nakatani S, Yamaguchi M, Ebihara N, Murakami A. Pre-banking microbial contamination of donor conjunctiva and storage medium for penetrating keratoplasty. Jpn J Ophthalmol 2017;Abstract
PURPOSE: The aims of this study were to investigate the incidence of positive donor tissue cultures before transfer to preservation medium (Optisol™-GS) for penetrating keratoplasty, to verify the efficacy of antibiotics contained in Optisol™-GS by examining the drug susceptibility and to assess the relationship between the results of our microbial assessments as well as donor factors and the incidence of contamination. METHODS: We conducted a retrospective, cross-sectional study using Juntendo Eye Bank records for all corneal transplantations. Two hundred donor conjunctiva harvestings and storage medium (EP-II(®)) cultures were performed between July 2008 and June 2011. We analyzed the associations between donor factors (age, gender, history of cataract surgery, death-to-preservation interval, cause of death) and contamination rates using multivariate analysis by the generalized estimating equation model. RESULTS: We obtained positive bacterial cultures from 154 of the 200 eyes (77.0%). The isolated bacteria were indigenous, such as coagulase-negative Staphylococci, Corynebacterium sp., and methicillin-resistant Staphylococcus aureus (MRSA). There was significant resistance to levofloxacin (18 eyes, 9.0%) and gentamicin (12 eyes, 6.0%), and no vancomycin-resistant bacteria were detected. The donor factors did not correlate with the prevalence of bacterial contamination in our criteria. CONCLUSIONS: Pre-banking microbial assessment allows for microbial detection, bacterial susceptibility and resistance testing. This is useful for developing preservation mediums containing effective spectrum antibiotic agents for high quality control of corneal banking.
Ibberson CB, Stacy A, Fleming D, Dees JL, Rumbaugh K, Gilmore MS, Whiteley M. Co-infecting microorganisms dramatically alter pathogen gene essentiality during polymicrobial infection. Nat Microbiol 2017;2:17079.Abstract
Identifying genes required by pathogens during infection is critical for antimicrobial development. Here, we use a Monte Carlo simulation-based method to analyse high-throughput transposon sequencing data to determine the role of infection site and co-infecting microorganisms on the in vivo 'essential' genome of Staphylococcus aureus. We discovered that co-infection of murine surgical wounds with Pseudomonas aeruginosa results in conversion of ∼25% of the in vivo S. aureus mono-culture essential genes to non-essential. Furthermore, 182 S. aureus genes are uniquely essential during co-infection. These 'community dependent essential' (CoDE) genes illustrate the importance of studying pathogen gene essentiality in polymicrobial communities.
Lebreton F, Manson AL, Saavedra JT, Straub TJ, Earl AM, Gilmore MS. Tracing the Enterococci from Paleozoic Origins to the Hospital. Cell 2017;169(5):849-861.e13.Abstract
We examined the evolutionary history of leading multidrug resistant hospital pathogens, the enterococci, to their origin hundreds of millions of years ago. Our goal was to understand why, among the vast diversity of gut flora, enterococci are so well adapted to the modern hospital environment. Molecular clock estimation, together with analysis of their environmental distribution, phenotypic diversity, and concordance with host fossil records, place the origins of the enterococci around the time of animal terrestrialization, 425-500 mya. Speciation appears to parallel the diversification of hosts, including the rapid emergence of new enterococcal species following the End Permian Extinction. Major drivers of speciation include changing carbohydrate availability in the host gut. Life on land would have selected for the precise traits that now allow pathogenic enterococci to survive desiccation, starvation, and disinfection in the modern hospital, foreordaining their emergence as leading hospital pathogens.
Durand ML. Bacterial and Fungal Endophthalmitis. Clin Microbiol Rev 2017;30(3):597-613.Abstract
Endophthalmitis is a severe eye infection that may result in permanent loss of useful vision in the affected eye. Most cases are exogenous and occur as a complication of cataract surgery, an intravitreal injection, or penetrating ocular trauma. Endogenous endophthalmitis results from hematogenous seeding of the eye by bacteria or fungi, but bacteremia or fungemia may be transient and patients may present without symptoms of systemic infection. Nearly all endophthalmitis patients present with decreased vision, and some also have eye pain. Eye examination usually reveals a hypopyon and intraocular inflammation. Diagnosis is clinical, supported by cultures of the vitreous and/or aqueous or by blood cultures in some endogenous cases. Molecular diagnostic techniques have been used in research laboratories for pathogen identification in endophthalmitis and offer the possibility of rapid diagnosis, including in culture-negative cases. Intravitreal injection of antibiotics is the most important component of treatment; some cases also benefit from surgical debridement of the vitreous by a vitrectomy. The visual outcome depends partly on the pathogen: coagulase-negative staphylococcal endophthalmitis has a better prognosis than does streptococcal endophthalmitis, for example. Endophthalmitis is a medical emergency, and prompt diagnosis and treatment are essential for saving vision.
Van Tyne D, Gilmore MS. Raising the Alarmone: Within-Host Evolution of Antibiotic-Tolerant Enterococcus faecium. MBio 2017;8(1)Abstract

Enterococci are ancient commensal bacteria that recently emerged as leading causes of antibiotic-resistant, hospital-acquired infection. Vancomycin-resistant enterococci (VRE) epitomize why drug-resistant enterococcal infections are a problem: VRE readily colonize the antibiotic-perturbed gastrointestinal (GI) tract where they amplify to large numbers, and from there, they infect other body sites, including the bloodstream, urinary tract, and surgical wounds. VRE are resistant to many antimicrobials and host defenses, which facilitates establishment at the site of infection and confounds therapeutic clearance. Having evolved to colonize the GI tract, VRE are comparatively ill adapted to the human bloodstream. A recent study by Honsa and colleagues (E. S. Honsa et al., mBio 8:e02124-16, 2017, https://doi.org/10.1128/mBio.02124-16) found that a strain of vancomycin-resistant Enterococcus faecium evolved antibiotic tolerance within the bloodstream of an immunocompromised host by activating the stringent response through mutation of relA Precisely how VRE colonize and infect and the selective pressures that led to the outgrowth of relA mutants are the subjects of ongoing research.

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