scholarly journals Biofilm Biology and Vaccine Strategies for Otitis Media Due to Nontypeable Haemophilus influenzae

2018 ◽  
Vol 14 (02) ◽  
pp. 069-078 ◽  
Author(s):  
Laura Novotny ◽  
Kenneth Brockman ◽  
Elaine Mokrzan ◽  
Joseph Jurcisek ◽  
Lauren Bakaletz
Keyword(s):  
Haemophilus Influenzae ◽  
Otitis Media ◽  
Middle Ear ◽  
Causative Agent ◽  
Upper Respiratory Tract ◽  
Nontypeable Haemophilus Influenzae ◽  
Physical Defenses ◽  
Upper Respiratory ◽  
Recurrent Nature ◽  
Gain Access

AbstractOtitis media (OM) is one of the most common diseases of childhood, and nontypeable Haemophilus influenzae (NTHI) is the predominant causative agent of chronic and recurrent OM, as well as OM for which treatment has failed. Moreover, NTHI is now as important a causative agent of acute OM as the pneumococcus. NTHI colonizes the human nasopharynx asymptomatically. However, upon perturbation of the innate and physical defenses of the airway by upper respiratory tract viral infection, NTHI can replicate, ascend the Eustachian tube, gain access to the normally sterile middle ear space, and cause disease. Bacterial biofilms within the middle ear, including those formed by NTHI, contribute to the chronic and recurrent nature of this disease. These multicomponent structures are highly resistant to clearance by host defenses and elimination by traditional antimicrobial therapies. Herein, we review several strategies utilized by NTHI to persist within the human host and interventions currently under investigation to prevent and/or resolve NTHI-induced diseases of the middle ear and uppermost airway.

scholarly journals Toll-Like Receptors: Expression and Roles in Otitis Media

2021 ◽  
Vol 22 (15) ◽  
pp. 7868
Author(s):  
Su Young Jung ◽  
Dokyoung Kim ◽  
Dong Choon Park ◽  
Sung Soo Kim ◽  
Tong In Oh ◽  
...  
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Otitis Media ◽  
Middle Ear ◽  
Upper Respiratory Tract Infection ◽  
Upper Respiratory Tract ◽  
Toll Like Receptors ◽  
Upper Respiratory

Otitis media is mainly caused by upper respiratory tract infection and eustachian tube dysfunction. If external upper respiratory tract infection is not detected early in the middle ear, or an appropriate immune response does not occur, otitis media can become a chronic state or complications may occur. Therefore, given the important role of Toll-like receptors (TLRs) in the early response to external antigens, we surveyed the role of TLRs in otitis media. To summarize the role of TLR in otitis media, we reviewed articles on the expression of TLRs in acute otitis media (AOM), otitis media with effusion (OME), chronic otitis media (COM) with cholesteatoma, and COM without cholesteatoma. Many studies showed that TLRs 1–10 are expressed in AOM, OME, COM with cholesteatoma, and COM without cholesteatoma. TLR expression in the normal middle ear mucosa is absent or weak, but is increased in inflammatory fluid of AOM, effusion of OME, and granulation tissue and cholesteatoma of COM. In addition, TLRs show increased or decreased expression depending on the presence or absence of bacteria, recurrence of disease, tissue type, and repeated surgery. In conclusion, expression of TLRs is associated with otitis media. Inappropriate TLR expression, or delayed or absent induction, are associated with the occurrence, recurrence, chronicization, and complications of otitis media. Therefore, TLRs are very important in otitis media and closely related to its etiology.

scholarly journals Prevalence and Distribution of the hmwand hia Genes and the HMW and Hia Adhesins among Genetically Diverse Strains of Nontypeable Haemophilus influenzae

1998 ◽  
Vol 66 (1) ◽  
pp. 364-368 ◽  
Author(s):  
Joseph W. St. Geme ◽  
Vini V. Kumar ◽  
David Cutter ◽  
Stephen J. Barenkamp
Keyword(s):  
Haemophilus Influenzae ◽  
Genetic Relatedness ◽  
Upper Respiratory Tract ◽  
Nontypeable Haemophilus Influenzae ◽  
Insertion Element ◽  
Common Cause ◽  
Capsule Locus ◽  
Upper Respiratory ◽  
Related Proteins ◽  
Small Clusters

ABSTRACT Nontypeable Haemophilus influenzae is a common cause of human disease and initiates infection by colonizing the upper respiratory tract. In previous work we identified high-molecular-weight adhesins referred to as HMW1 and HMW2, expressed by nontypeable strain 12, and determined that most strains of nontypeable H. influenzae express one or two antigenically related proteins. More recently, we determined that some strains lack HMW1- and HMW2-like proteins and instead express an adhesin called Hia. In the present study, we determined the prevalence and distribution of thehmw and hia genes in a collection of 59 nontypeable strains previously characterized in terms of genetic relatedness. Based on Southern analysis, 47 strains contained sequences homologous to the hmw1 and hmw2 genes and nine strains contained homologs to hia. No strain harbored bothhmw and hia, and three strains harbored neither. Although the hmw and hia genes failed to define distinct genetic divisions, the hmw-deficient strains formed small clusters or lineages within the larger population structure. Additional analysis established that the IS1016insertion element was uniformly absent from strains containinghmw sequences but was present in two-thirds of thehmw-deficient strains. As IS1016 is associated with the capsule locus (cap) in most encapsulated strains of H. influenzae, we speculate thathmw-deficient nontypeable strains evolved more recently from an encapsulated ancestor.

scholarly journals A Mutation in the sap Operon Attenuates Survival of Nontypeable Haemophilus influenzae in a Chinchilla Model of Otitis Media

2005 ◽  
Vol 73 (1) ◽  
pp. 599-608 ◽  
Author(s):  
Kevin M. Mason ◽  
Robert S. Munson ◽  
Lauren O. Bakaletz
Keyword(s):  
Haemophilus Influenzae ◽  
Antimicrobial Peptides ◽  
Otitis Media ◽  
Middle Ear ◽  
Parent Strain ◽  
Upper Airway ◽  
Nontypeable Haemophilus Influenzae ◽  
Nthi Strain ◽  
Passage Number ◽  
Low Passage

ABSTRACT Bacteria have evolved strategies to resist killing by antimicrobial peptides (APs), important effectors of innate immunity. The sap (sensitivity to antimicrobial peptides) operon confers resistance to AP-mediated killing of Salmonella. We have recently shown that sapA gene expression is upregulated in the middle ear in a chinchilla model of nontypeable Haemophilus influenzae (NTHI)-induced otitis media. Based on these findings, we constructed an NTHI strain containing a Lux reporter plasmid driven by the sapA promoter and demonstrated early yet transient expression of the sap operon within sites of the chinchilla upper airway upon infection. We hypothesized that the sap operon products mediate NTHI resistance to APs. In order to test this hypothesis, we constructed a nonpolar mutation in the sapA gene of NTHI strain 86-028NP, a low-passage-number clinical isolate. The sapA mutant was approximately eightfold more sensitive than the parent strain to killing by recombinant chinchilla β-defensin 1. We then assessed the ability of this mutant to both colonize and cause otitis media in chinchillas. The sapA mutant was significantly attenuated compared to the parent strain in its ability to survive in both the nasopharynx and the middle ear of the chinchilla. In addition, the mutant was impaired in its ability to compete with the parent strain in a dual-strain challenge model of infection. Our results indicate that the products of the sap operon are important for resisting the activity of APs and may regulate, in part, the balance between normal carriage and disease caused by NTHI.

scholarly journals Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae

2016 ◽  
Vol 60 (9) ◽  
pp. 5533-5538 ◽  
Author(s):  
M. Figueira ◽  
P. Fernandes ◽  
S. I. Pelton
Keyword(s):  
Streptococcus Pneumoniae ◽  
Haemophilus Influenzae ◽  
Otitis Media ◽  
Middle Ear ◽  
Fourth Generation ◽  
Minimal Bactericidal Concentration ◽  
Nontypeable Haemophilus Influenzae ◽  
Time Curve ◽  
Content Type ◽  
Middle Ear Fluid

ABSTRACTSolithromycin (CEM-101) is a “fourth-generation” macrolide, as it has three binding site and is acid stable. The three binding sites confer activity against bacteria resistant to the older macrolides and ketolides, including multidrug-resistantStreptococcus pneumoniaeand nontypeableHaemophilus influenzae(NTHi). The objective of this study was to evaluate solithromycin pharmacokinetics (PK), middle ear fluid (MEF) concentrations, and microbiologic efficacy in a chinchilla model of experimental otitis media (EOM) due to strains ofS. pneumoniaeor NTHi. Plasma PK (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0–24]) and middle ear fluid (MEF) concentrations were determined. Isolates with specified antimicrobial susceptibility patterns were inoculated directly into the middle ear (ME). Plasma and MEF were collected for PK and MEF cultures performed to determine efficacy. Solithromycin administered at 150 mg/kg of body weight/day resulted inCmaxand AUC0–24values of 2.2 μg/ml and 27.4 μg · h/ml in plasma and 1.7 μg/ml and 28.2 μg · h/ml in extracellular MEF on day 1. By day 3,Cmaxand AUC0–24values had increased to 4.5 μg/ml and 54 μg · h/ml in plasma and 4.8 μg/ml and 98.6 μg · h/ml in extracellular MEF. For NTHi EOM, three isolates with MIC/minimal bactericidal concentration (MBC) ratios of 0.5/1 μg/ml (isolate BCH1), 2/2 μg/ml (isolate BMC1247C), and 4/4 μg/ml (isolate BMC1213C) were selected. The MEF of >85% of animals infected with BCH1 and BMC1247C was sterilized. For NTHi BMC1213, >85% of MEF cultures remained positive. ForS. pneumoniaeEOM, 3 isolates with MIC/MBC ratios of 0.06/0.125 μg/ml (S. pneumoniae331), 0.125/1 μg/ml (S. pneumoniaeCP-645 [MLSBphenotype]), and 0.5/2 μg/ml (CP-712 [mefAsubclassmefAresistance]) were selected. Solithromycin sterilized MEF in 100% of animals infected withS. pneumoniae331 andS. pneumoniaeCP-645. ME infection persisted in 60% of animals infected with CP-712. In a model of EOM, solithromycin sterilized MEF in >85% of animals challenged with NTHi with an MIC of ≤2 μg/ml and 100% of ME infected withS. pneumoniaewith an MIC of ≤0.125 μg/ml.

Otologic and Systemic Manifestations of Experimental Influenza a Virus Infection in the Ferret

1995 ◽  
Vol 112 (4) ◽  
pp. 572-578 ◽  
Author(s):  
Craig A. Buchman ◽  
J. Douglas Swarts ◽  
James T. Seroky ◽  
Nicholas Panagiotou ◽  
Frederick Hayden ◽  
...  
Keyword(s):  
Otitis Media ◽  
Influenza A Virus ◽  
Eustachian Tube ◽  
Middle Ear ◽  
Influenza A ◽  
Upper Respiratory Tract Infections ◽  
Upper Respiratory Tract ◽  
Upper Respiratory ◽  
Influenza A Virus Infection ◽  
Tract Infections

In an effort to further validate an animal model and to better define the mechanisms relating viral upper respiratory tract infections and acute otitis media, we infected 10 ferrets intranasally with influenza A virus. Infection was monitored by cultures and antibody titers, illness was monitored by signs and temperatures, and otologic complications were monitored by otoscopy, tympanometry, and eustachian tube function testing. All animals became infected. Forced-response test results showed progressive increases in the passive function variables after inoculation. Inflation-deflation test results documented progressive impairment of active tubal function, which was accompanied by the development of middle ear underpressures. No otitis media was seen. The results suggest that influenza A virus infection results in progressive, subtotal occlusion of the eustachian tube lumen, which compromises the ventilatory function of the tube, thereby promoting the development of middle ear underpressures. These findings support the hypothesized pathophysiologic relationship between viral upper respiratory tract infections, eustachian tube dysfunction, middle ear underpressures, and acute otitis media. Given these pathophysiologic changes and previously documented physiologic similarities to the eustachian tube-middle ear system of human beings, we conclude that the ferret represents an appropriate animal model for studying the pathogenic processes related to viral upper respiratory tract infections, eustachian tube dysfunction, and otitis media and for testing of potential prophylactic and therapeutic regimens.

scholarly journals Experimental Acute Otitis Media Due to Nontypeable Haemophilus influenzae: Comparison of High and Low Azithromycin Doses with Placebo

2002 ◽  
Vol 46 (7) ◽  
pp. 2194-2199 ◽  
Author(s):  
Franz E. Babl ◽  
Stephen I. Pelton ◽  
Zhong Li
Keyword(s):  
Haemophilus Influenzae ◽  
Otitis Media ◽  
Middle Ear ◽  
Clinical Success ◽  
Acute Otitis Media ◽  
Published Data ◽  
Nontypeable Haemophilus Influenzae ◽  
Ear Infection ◽  
Dependent Effect ◽  
Middle Ear Infection

ABSTRACT Treatment of acute otitis media (AOM) with azithromycin results in apparent clinical success, but tympanocentesis performed 4 to 6 days after initiation of therapy in children with nontypeable Haemophilus influenzae (NTHI) recovered from initial middle ear cultures demonstrates persistence of infection in more than 50% of episodes. We sought to determine the effect of azithromycin at different doses on the density of middle ear infection due to NTHI to provide additional understanding of this dichotomy between clinical and microbiologic outcome measures in AOM. In a chinchilla model of experimental otitis media (EOM), animals treated with placebo were compared to animals receiving a single daily dose 30 or 120 mg of azithromycin per kg of body weight per day for 5 days. Microbiologic outcome was assessed by obtaining quantitative cultures from the middle ear during a 5-day course and for 1 week following therapy. Azithromycin concentrations were measured to ascertain whether a concentration-dependent effect was present. Azithromycin at 30 and 120 mg/kg/day demonstrated a dose-dependent effect on the quantitative assessment of middle ear infection due to NTHI. A 30-mg/kg dose of azithromycin daily resulted in levels in serum and areas under the serum concentration-time curve at 24 h comparable to published data obtained with children given azithromycin at 5 to 10 mg/kg in multiday regimens. Increased doses of azithromycin (120 mg/kg) achieved 2.5- to 4-fold-higher levels in serum and 3- to 6-fold-higher total levels and levels in extracellular middle ear fluid as well as more rapid reduction in bacterial density and a greater proportion of middle ears with complete sterilization than either placebo or the 30-mg/kg/day regimen.

scholarly journals The HMW1 and HMW2 Adhesins Enhance the Ability of Nontypeable Haemophilus influenzae To Colonize the Upper Respiratory Tract of Rhesus Macaques

2016 ◽  
Vol 84 (10) ◽  
pp. 2771-2778 ◽  
Author(s):  
Katherine A. Rempe ◽  
Eric A. Porsch ◽  
Jolaine M. Wilson ◽  
Joseph W. St. Geme
Keyword(s):  
Respiratory Tract ◽  
Haemophilus Influenzae ◽  
Parent Strain ◽  
Double Mutant ◽  
Rhesus Macaques ◽  
Upper Respiratory Tract ◽  
Nontypeable Haemophilus Influenzae ◽  
Upper Respiratory

NontypeableHaemophilus influenzae(NTHi) initiates infection by colonizing the upper respiratory tract and is a common cause of localized respiratory tract disease. Previous work has established that the NTHi HMW1 and HMW2 proteins are potent adhesins that mediate efficientin vitroadherence to cultured human respiratory epithelial cells. In this study, we used a rhesus macaque model to assess the contributions of HMW1 and HMW2 toin vivocolonization. In experiments involving inoculation of individual isogenic derivatives of NTHi strain 12, the parent strain expressing both HMW1 and HMW2 and the mutant strains expressing either HMW1 or HMW2 were able to colonize more frequently than the double mutant strain lacking HMW1 and HMW2. In competition experiments, the parent strain efficiently outcompeted the double mutant lacking HMW1 and HMW2. Colonization with strains expressing HMW2 resulted in development of antibody against HMW2 in a number of the animals, demonstrating that colonization can stimulate an antibody response. In conclusion, we have established that the HMW1 and HMW2 adhesins play a major role in facilitating colonization of the upper respiratory tract of rhesus macaques, in some cases associated with stimulation of an immune response.

scholarly journals Upper Respiratory Tract Microbiome and Otitis Media Intertalk: Lessons from the Literature

2020 ◽  
Vol 9 (9) ◽  
pp. 2845
Author(s):  
Francesco Folino ◽  
Luca Ruggiero ◽  
Pasquale Capaccio ◽  
Ilaria Coro ◽  
Stefano Aliberti ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Otitis Media ◽  
Middle Ear ◽  
Bacterial Communities ◽  
Acute Otitis Media ◽  
Upper Respiratory Tract ◽  
Suppurative Otitis Media ◽  
Major Interest ◽  
Culture Independent ◽  
Upper Respiratory

Otitis media (OM) is one of the most common diseases occurring during childhood. Microbiological investigations concerning this topic have been primarily focused on the four classical otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes) mainly because most of the studies have been conducted with culture-dependent methods. In recent years, the introduction of culture-independent techniques has allowed high-throughput investigation of entire bacterial communities, leading to a better comprehension of the role of resident flora in health and disease. The upper respiratory tract (URT) is a region of major interest in otitis media pathogenesis, as it could serve as a source of pathogens for the middle ear (ME). Studies conducted with culture-independent methods in the URT and ME have provided novel insights on the pathogenesis of middle ear diseases through the identification of both possible new causative agents and of potential protective bacteria, showing that imbalances in bacterial communities could influence the natural history of otitis media in children. The aim of this review is to examine available evidence in microbiome research and otitis media in the pediatric age, with a focus on its different phenotypes: acute otitis media, otitis media with effusion and chronic suppurative otitis media.

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