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Article Reference Non-typeable Haemophilus influenzae and Streptococcus pneumoniae as primary causes of acute otitis media in colombian children: a prospective study.
Acute otitis media (AOM) is one of the most frequently encountered bacterial infections in children aged < 5 years; Streptococcus pneumoniae (S. pneumoniae) and non-typeable Haemophilus influenzae (NTHi) are historically identified as primary AOM causes. Nevertheless, recent data on bacterial pathogens causing AOM in Latin America are limited. This prospective study aimed to identify and characterize bacterial etiology and serotypes of AOM cases including antimicrobial susceptibility in < 5 year old Colombian children.
Article Reference Mechanisms of bacterial resistance to antibiotics in infections of COPD patients.
A key characteristic of airway inflammation in chronic obstructive pulmonary disease (COPD) is the persistent presence of bacteria in the lower airways. The most commonly isolated bacteria in the lower respiratory tract of COPD patients are nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae, with growing evidence of the significance of Pseudomonas aeruginosa infections in severe COPD disease. This review focuses on the antibiotic resistant mechanisms associated with the gram-negative bacteria H. influenzae and M. catarrhalis and comparison with P. aeruginosa infection because of the recent evidence of its significance in patients with severe COPD disease. These mechanisms of resistance to β-lactams in H. influenzae and M. catarrhalis are mostly associated with serine β-lactamases of class A type, whereas P. aeruginosa strains exhibit a much broader repertoire with class A-D type mechanisms. Other mechanisms of antibiotic resistance include membrane permeability, efflux pump systems and mutations in antimicrobial targets. Antimicrobial resistance within biofilm matrices appears to be different to the mechanisms observed when the bacteria are in the planktonic state. P. aeruginosa exhibits a more numerous and diverse range of antimicrobial resistance mechanisms in comparison to M. catarrhalis and H. influenzae. The recognition that P. aeruginosa is associated with exacerbations in patients with more severe COPD and that turnover in infecting strains is detected (unlike in cystic fibrosis patients), then further investigation is required to better understand the contribution of antimicrobial resistance and other virulence mechanisms to poor clinical outcomes to improve therapeutic approaches.
Article Reference Serum intercellular adhesion molecule 1 variations in young children with acute otitis media.
Acute otitis media (AOM) is an inflammatory reaction in the middle ear, most often occurring in young children. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacteria isolated. Intercellular adhesion molecule 1 (ICAM-1) is involved in the innate immune response to infection by microorganisms, in effective antigen presentation, and in subsequent T-cell activation. Here we prospectively studied levels of serum soluble ICAM-1 (sICAM-1) before, at the time of, and after antimicrobial treatment of AOM in a group of 138 children ages 6 to 30 months. Middle ear fluids were collected by tympanocentesis to identify otopathogens. We found that (i) serum levels of sICAM-1 were significantly higher in S. pneumoniae-, nontypeable H. influenzae-, and M. catarrhalis-infected children than in well children (P < 0.001), confirming that a systemic inflammatory response occurs during AOM; (ii) sICAM-1 levels varied from no elevation (110 ng/ml) to elevation to high levels (maximum, 1,470 ng/ml) among children with AOM; (iii) in paired samples, sICAM-1 levels increased 4- to 20-fold when children developed AOM compared to their sICAM-1 levels before infection; and (iv) the level of sICAM-1 returned to the pre-AOM level at the convalescent stage of AOM after successful antimicrobial therapy. We conclude that AOM often causes a systemic inflammatory reaction, as measured by elevation of the serum sICAM-1 level, and that a high variability in sICAM-1 responses occurs with the presence of otopathogens during AOM.
Article Reference Azithromycin inhibits nontypeable Haemophilus influenzae-induced MUC5AC expression and secretion via inhibition of activator protein-1 in human airway epithelial cells.
Nontypeable Haemophilus influenzae (NTHi) is one of the most common pathogens in chronic airway infections and exacerbation. The hallmark of chronic respiratory diseases, including cystic fibrosis, diffuse panbronchiolitis and chronic obstructive pulmonary disease, is mucin overproduction. Prolonged macrolide antibiotic therapy at low doses is known to improve clinical outcome in patients with chronic respiratory diseases via anti-inflammatory effects. In this study, we investigated the effects of macrolide therapy on NTHi-induction of the MUC5AC mucin in human airway epithelial cells. A 15-membered macrolide, azithromycin, but not a 14-membered macrolide, clarithromycin, inhibited NTHi-induction of MUC5AC at both the mRNA and protein levels through selective suppression of activation of the transcription factor activator protein-1. Our findings suggest that each macrolide affects MUC5AC production in different ways and that azithromycin is more suitable for the treatment of NTHi-induced respiratory infection.
Article Reference Appropriate treatment of acute otitis media in the era of antibiotic resistance.
The outcome of treatment for acute otitis media (AOM) differs between various antibiotic drugs. Outcome depends upon the drugs' pharmacokinetics, but in the case of infectious diseases also on the susceptibility of the organism and the interaction between the drug and the organisms at the specific site of infection (pharmacodynamics). In the era of antibiotic resistance, it is thus important to understand the pharmacokinetics/pharmacodynamics of the various available drugs in the context of AOM and its main two pathogens, Streptococcus pneumoniae and non-typeable Haemophilus influenzae. In terms of clinical outcome, it is also important to realize that AOM is a self-limiting disease in most cases, so that response to treatment is always compared with the expected background response when not treated. A favourable clinical outcome (cure/improvement) at the end of the treatment period is expected for those in whom the pathogens are eradicated within 3-5 days, thus clinical failure rates are several fold lower in children with early eradication (within 3-5 days) compared with those in whom no early eradication takes place. Because of the higher spontaneous bacterial elimination this might not always be appreciated. In this review, the relationship between antibiotic resistance, the various antibiotic drugs and their pharmacokinetic/pharmacodynamic patterns, the bacteriological outcome and clinical outcomes are addressed. This review is meant to assist the clinician in both a better understanding of the current recommendations for the treatment of AOM and the steps to be taken to follow AOM patients.
Article Reference Urinary tract infection caused by nontypable Haemophilus influenzae in the elderly.
Article Reference Eleven-year study of causes of neonatal bacterial meningitis in Ahvaz, Iran.
Bacterial meningitis is a devastating infection with a high mortality rate, especially in neonates. The aim of this study was to determine the causative agents that cause bacterial meningitis in Khuzestan province in the south-western region of Iran.
Article Reference Current management of pediatric acute otitis media.
Acute otitis media (AOM) is the most common childhood bacterial infection for which antibiotics are prescribed worldwide. The most common pathogens causing AOM in children are Streptococcus pneumoniae, nontypeable Haemophilus influenzae, Moraxella catarrhalis and Group A streptococcus. Antibiotic resistance is increasing among the bacterial pathogens causing AOM, with percentages of penicillin- and macrolide-resistant S. pneumoniae strains estimated to be between 30 and 70%, and of beta-lactamase-producing H. influenzae ranging between 20 and 40%. The introduction of the seven-valent pneumococcal conjugated vaccine had a major role in decreasing the number of vaccine-related S. pneumoniae AOM episodes, recurrent AOM cases and cases requiring the insertion of ventilation tubes. In parallel, it caused a rapid shift in the microbiology of AOM, characterized by an increase in the number of non-vaccine S. pneumoniae serotypes and H. influenzae isolates. The management of AOM in childhood has evolved considerably during recent years as a result of the new insights provided by the publication of the American Academy of Pediatrics and American Academy of Family Physicians guidelines for the treatment of AOM. The new treatment guidelines establish a clear hierarchy among various antibacterials used in the treatment of AOM and also the use of an age-stratified approach to AOM by recommending an observation strategy ('watchful waiting') without the use of antibacterials for some groups of AOM patients. Adherence to such a policy in patients with uncertain/questionable AOM diagnosis and/or mild-to-moderate symptoms, in addition to its implementation in patients over 2 years of age, could substantially reduce the use of antibacterials for the treatment of AOM and play a major role in the strategy of decreasing antibacterial resistance.
Article Reference Haemophilus ducreyi SapA contributes to cathelicidin resistance and virulence in humans.
Haemophilus ducreyi is an extracellular pathogen of human epithelial surfaces that resists human antimicrobial peptides (APs). The organism's genome contains homologs of genes sensitive to antimicrobial peptides (sap operon) in nontypeable Haemophilus influenzae. In this study, we characterized the sap-containing loci of H. ducreyi 35000HP and demonstrated that sapA is expressed in broth cultures and H. ducreyi-infected tissue; sapA is also conserved among both class I and class II H. ducreyi strains. We constructed a nonpolar sapA mutant of H. ducreyi 35000HP, designated 35000HPsapA, and compared the percent survival of wild-type 35000HP and 35000HPsapA exposed to several human APs, including alpha-defensins, beta-defensins, and the cathelicidin LL-37. Unlike an H. influenzae sapA mutant, strain 35000HPsapA was not more susceptible to defensins than strain 35000HP was. However, we observed a significant decrease in the survival of strain 35000HPsapA after exposure to LL-37, which was complemented by introducing sapA in trans. Thus, the Sap transporter plays a role in resistance of H. ducreyi to LL-37. We next compared mutant strain 35000HPsapA with strain 35000HP for their ability to cause disease in human volunteers. Although both strains caused papules to form at similar rates, the pustule formation rate at sites inoculated with 35000HPsapA was significantly lower than that of sites inoculated with 35000HP (33.3% versus 66.7%; P = 0.007). Together, these data establish that SapA acts as a virulence factor and as one mechanism for H. ducreyi to resist killing by antimicrobial peptides. To our knowledge, this is the first demonstration that an antimicrobial peptide resistance mechanism contributes to bacterial virulence in humans.
Article Reference Characterization of nontypeable Haemophilus influenzae collected from respiratory infections and invasive disease cases in Manitoba, Canada.
With the introduction of the Haemophilus influenzae serotype b (Hib) vaccine, invasive Hib disease has decreased substantially, but nontypeable H. influenzae (NT Hi) disease appears to be increasing. In order to understand the origin of NT Hi strains and their relationship with serotypeable strains, we analysed 125 NT Hi isolates collected from individual patients with either invasive disease (70 isolates) or respiratory tract infections (55 isolates). Serotype-specific and capsular transport genes were absent by PCR analysis, confirming their nonencapsulated status, which also suggested the NT Hi isolates were not encapsulated strains that shed their capsules. Multilocus sequence typing confirmed the NT Hi isolates did not have the same genetic background as serotypeable strains, including Hib. Despite the genetic heterogeneity found, two major genetic clusters were identified, both containing invasive and respiratory isolates. Fourteen invasive isolates and nine respiratory isolates produced beta-lactamase and were ampicillin resistant. More invasive (26.8%) than respiratory isolates (10.9%) showed decreased susceptibility towards ampicillin by a mechanism unrelated to beta-lactamase production. Besides a change in the capsule status of invasive Hi strains, the burden of invasive Hi disease, which used to be mainly a childhood disease, has now shifted to involve both adults and infants.
Article Reference Epiglottitis due to nontypeable Haemophilus influenzae in a vaccinated child.
Once a prevalent disease, acute epiglottitis in children has become a rare entity. The introduction of the Haemophilus influenzae type b vaccine has had a dramatic impact on the number of invasive infections caused by this organism. However, physicians must be aware that epiglottitis may result from vaccine failures or from infection with other pathogenic organisms. Vaccinated children with epiglottitis present in a similar fashion to those who are not vaccinated. We present a rare case of acute epiglottitis in a fully vaccinated child due to nontypeable H. influenzae and discuss the clinical presentation and management.
Article Reference Chronic obstructive pulmonary disease: role of bacteria and updated guide to antibacterial selection in the older patient.
Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality worldwide. COPD is especially prevalent in the elderly, affecting 25% of those aged>or=75 years. The course of the disease in the elderly is often complicated by co-morbid conditions, and its management is complicated by drug-drug interactions. Exacerbations of COPD increase rates of hospitalization and mortality and decrease quality of life. Exacerbations are marked by an increase from baseline in dyspnoea, sputum volume and sputum purulence. Approximately 50% of acute exacerbations of symptoms in COPD are caused by non-typeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa. Stratification of exacerbations based on severity of symptoms and signs, and severity of underlying COPD, is useful in selecting patients likely to benefit from antibacterial therapy. Patients who are hospitalized with exacerbations, those who have all three symptoms (increased dyspnoea, sputum volume and sputum purulence), and those with severe underlying COPD and exacerbations benefit most from antibacterials. Antibacterial susceptibility patterns among the bacterial pathogens are evolving, and knowledge of local susceptibility patterns is useful in antibacterial selection. Penicillin, amoxicillin, cotrimoxazole (trimethoprim/sulfamethoxazole) and doxycycline should not be used as an initial antibacterial because of resistance patterns. We recommend second-/third-generation cephalosporins, amoxicillin/clavulanic acid, azithromycin and respiratory fluoroquinolones as initial choices. In patients at risk of colonization by, and infection as a result of, P. aeruginosa, ciprofloxacin, levofloxacin or an advanced penicillin/penicillinase combination effective against this species should be used. Drug-drug interactions should be considered in antibacterial choice. The goals of antibacterial therapy for exacerbations of COPD are the prevention of complications such as respiratory failure and death, and the reduction of treatment failures. The role of pathogenic bacteria in progression of stable COPD and the use of prophylactic antibacterials in stable COPD are under investigation. Currently available evidence does not support routine clinical use of prophylactic antibacterials in stable COPD. In conclusion, pathogenic bacteria cause a significant proportion of acute exacerbations of COPD. Use of antibacterials, based on current susceptibility patterns, is beneficial in patients with severe COPD experiencing exacerbations and in patients with severe exacerbations.
Article Reference Otitis media: viruses, bacteria, biofilms and vaccines.
Otitis media typically presents as either acute otitis media (AOM), with symptoms including fever, otalgia, otorrhoea or irritability and short duration; or as otitis media with effusion (OME), which is often asymptomatic and characterised by accumulation of fluid in the middle ear. Diagnostic certainty of otitis media is challenging, given the young age of patients and variability of symptoms. Otitis media predominantly occurs as coincident to viral upper respiratory tract infections and/or bacterial infections. Common viruses that cause upper respiratory tract infection are frequently associated with AOM and new-onset OME. These include respiratory syncytial virus, rhinovirus, adenovirus, parainfluenza and coronavirus. Predominant bacteria that cause otitis media are Streptococcus pneumoniae, Moraxella catarrhalis, and non-typeable Haemophilus influenzae. Antibiotic therapy does not significantly benefit most patients with AOM, but long-term prophylactic antibiotic therapy can reduce the risk of otitis media recurrence among children at high risk. In Australia, 84% of AOM is treated with antibiotic therapy, which contributes to development of antibiotic resistance. Vaccine development is a key future direction for reducing the world burden of otitis media, but requires polymicrobial formulation and ongoing monitoring and modification to ensure sustained reduction in disease burden.
Article Reference Nontypeable Haemophilus influenzae isolated from intractable acute otitis media internalized into cultured human epithelial cells.
The aim of this study is to examine the internalization of nontypeable Haemophilus influenzae (NTHi) into human epithelial cells.
Article Reference In vivo efficacy of sitafloxacin in a new murine model of non-typeable Haemophilus influenzae pneumonia by sterile intratracheal tube.
A novel murine model of non-typeable Haemophilus influenzae (NTHi) pneumonia was established. A plastic tube was inserted into the trachea 7 days before bacterial inoculation. Numbers of NTHi recovered from the lungs and trachea were determined for 7 days. Histologically, bronchioles and adjacent alveoli in the intubation group were filled with numerous inflammatory cells. The efficacy of sitafloxacin was compared with ciprofloxacin using the new murine pneumonia model. The data suggest that sitafloxacin displays equivalent efficacy to ciprofloxacin against H. influenzae pneumonia. This new murine NTHi pneumonia model appears useful not only for in vivo evaluation of antibiotics but also for analysis of the pathogenesis of H. influenzae pneumonia.
Article Reference Susceptibilities of Haemophilus influenzae, Streptococcus pneumoniae, including serotype 19A, and Moraxella catarrhalis paediatric isolates from 2005 to 2007 to commonly used antibiotics.
The aim of this study was to evaluate susceptibility to common paediatric antibiotics for Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis isolated from 2005 through 2007.
Article Reference Formation of biofilm by Haemophilus influenzae isolated from pediatric intractable otitis media.
The aims of this study are to evaluate biofilm formation by nontypeable Haemophilus influenzae (NTHi) isolated from children with acute otitis media (AOM) and its relation with clinical outcome of the disease.
Article Reference Myeloid differentiation primary response gene 88 is required for the resolution of otitis media.
Signaling defects in the Toll-like receptor (TLR) pathway, such as interleukin-1 receptor-associated kinase 4 deficiency, highlight the prominence of TLR signaling in the defense against bacterial disease. Because myeloid differentiation primary response gene 88 (MyD88) can transduce signals from almost all TLRs, we studied its role in otitis media (OM), the most common upper respiratory tract bacterial infectious disease in young children.
Article Reference Low rate of nasopharyngeal carriage and high rate of ampicillin resistance for Haemophilus influenzae among healthy children younger than 5 years old in northern Taiwan.
Surveillance data of colonization by Haemophilus influenzae in Taiwan are lacking. This study aimed to define the nasopharyngeal carriage rate of H. influenzae among children younger than 5 years in northern Taiwan, and to determine the antibiotic susceptibility, serotype and the clonal relationship of these isolates.
Article Reference Failure to achieve early bacterial eradication increases clinical failure rate in acute otitis media in young children.
The objective of this study was to determine the association between early bacteriologic failure and clinical failure in acute otitis media (AOM).