Relapse of acute purulent otitis media: antibiotic sensitivities of nasopharyngeal pathogens

The present investigation was conducted to find out if a relapse of acute purulent otitis media is associated with a decreased sensitivity of nasopharyngeal pathogens to commonly used antimicrobial agents. All but one of 63 children with relapse included in this study yielded one or more of the classical middle ear pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, S. pyogenes) in their nasopharynx (NPH) secretions. S. pneumoniae was the predominating isolate from NPH (71% of the patients) as well as from middle ear effusion (53%). At a control visit 4 weeks after the start of antibiotic therapy, 91% were NPH carriers of potential pathogens and S. pneumoniae was still the most common isolate (53%). Beta-lactamase was produced by 55% of B. catarrhalis isolates from the NPH specimens on the first visit, but only by 33% of B. catarrhalis isolates on the control visit. Two NPH isolates of H. influenzae produced beta-lactamase. One isolate of S. pneumoniae (serotype 18) was intermediately sensitive to phenoxymethylpenicillin. Generally low MICs were found for erythromycin and cefaclor. H. influenzae isolates were generally sensitive to ampicillin in vitro, but only 1 isolate was fully sensitive to erythromycin. B. catarrhalis isolates were uniformly sensitive to doxycycline and trimethoprim/sulphamethoxazole. No tolerance to penicillin was demonstrated in S. pneumoniae and H. influenzae. The present data indicate that the relapse of acute otitis media is not associated with development of tolerance or resistance to therapeutic antimicrobials commonly used.     

Antimicrobial treatment of otitis media.

The major pathogens causing acute otitis media (AOM) are Streptococcus pneumoniae and Haemophilus influenzae, with Moraxella catarrhalis, Streptococcus pyogenes, and Staphylococcus aureus less frequently isolated. The same organisms and Staphylococcus epidermidis are found in chronic otitis media with effusion. In chronic suppurative otitis media, Pseudomonas aeruginosa and S aureus are most frequently found. Antimicrobial agents found to be most effective in treating AOM are amoxicillin, trimethoprimsulfamethoxazole, erythromycin-sulfisoxazole, amoxicillin-clavulanate, and cefaclor. Cefuroxime axetil and cefixime are alternatives for which there are less data. Currently, about 20% of AOM cases are caused by beta-lactamase-producing strains (usually H influenzae or M catarrhalis) that are resistant to amoxicillin, thus favoring the use of the other agents listed. Concentrations of antibiotics in middle ear infections range from 10% to 76% of peak serum levels for the listed agents and are higher in AOM than in chronic otitis media with effusion, emphasizing the importance of adequate dosing for successful treatment.     

Experimental otitis media in chinchillas following nasal colonization with type 7F Streptococcus pneumoniae: prevention after vaccination with pneumococcal capsular polysaccharide.

Chinchillas were colonized intranasally with type 7F Streptococcus pneumoniae, and pneumococcal otitis media developed in greater than 50% of the animals during the first week after negative middle ear pressure (-25 mm Hg) was briefly applied. Twenty-three chinchillas were vaccinated subcutaneously with the capsular polysaccharde of type 7F S. pneumoniae to determine whether vaccination could prevent the development of experimental otitis media. Following vaccination, 14 animals seroconverted with at least a twofold rise in serum antibody concentration; nine animals that were vaccinated did not seroconvert. All of 23 vaccinated animals and 42 of 42 unvaccinated control animals became colonized after intranasal inoculation with pneumococci. Only one (7%) of the vaccinated seroconverting animals developed pneumococcal otitis media, whereas 26 (62%) of the control animals developed middle ear infection with type 7F pneumococci. Four (44%) of nine vaccinated nonseroconverting animals developed pneumococcal otitis media. Protection was associated with high levels of serum antibody prior to intranasal inoculation. Higher antibody levels were found in sterile middle ear effusions than in S. pneumoniae-infected effusions. Vaccination with type 7F pneumococcal capsular polysaccharide significantly reduced the incidence of pneumococcal otitis media following intranasal inoculation of type 7F S. pneumoniae in chinchillas.     

Modification of otitis media following vaccination with the capsular polysaccharide of Streptococcus pneumoniae in chinchillas.

An animal model was used to determine whether vaccination with the capsular polysaccharide of Streptococcus pneumoniae could alter the development of experimental otitis media induced by the same type of S. pneumoniae as the vaccine. Following vaccination with the capsular polysaccharide of S. pneumoniae type 7, 36(63%) of 57 chinchillas seroconverted with at least a 100% increase in concentration of antibody in serum which remained elevated for at least six weeks. The middle ears of 23 chinchillas that were vaccinated and seroconverted, 13 that were vaccinated and did not seroconvert, and 47 that were not vaccinated were inoculated with S. pneumoniae type 7. Vaccinated animals that seroconverted developed otitis media as readily as nonseroconverting and unvaccinated animals but had fewer pneumococci in their middle ears, a lower incidence of bacteremia, and lower mortality rates during the first week after inoculation of bacteria. Animals that did not seroconvert showed no evidence of modification of their middle ear infections. These results indicate that type 7 pneumococcal capsular polysaccharide vaccine is antigenic for the chinchilla and modifies experimental otitis media due to type 7 S. pneumoniae.     

Immunoglobulin- and complement-coated bacteria in middle ear effusions during the early course of acute otitis media.

We used an immunofluorescence assay to investigate the content of secretory IgA- (SIgA), IgG-, IgM- and C3b-coated bacteria in middle ear effusions obtained within 12-72 h after the onset of acute symptoms of purulent otitis in 28 patients (37 ears). Simultaneously we analyzed the bacteria, both qualitatively and quantitatively, using standard culturing methods and fluorescein conjugated (FITC) antibodies to Haemophilus influenzae and Streptococcus pneumoniae. The ages of the patients were in the range of 5 months to 17 years; 18 were males and 10 females. 73% of the samples harboured no antibody- or C3b-coated bacteria, and particularly those of young patients (< 20 months). 92% of the samples were culture-positive, while 8% showed dormant bacteria. The predominant species were S. pneumoniae and H. influenzae. In 8% of the samples there was heavy and in 11% slight peripheral SIgA-coating of the 5% showed heavy and 19% slight peripheral IgG-coating. Only 3 samples were intensely opsonized, i.e. the bacteria were coated with IgG and C3b simultaneously. In most cases of acute purulent otitis media, the middle ear cavity of young individuals is not able to coat pathogens with SIgA, IgG, IgM and C3b during the early course of infection.     

Immune response to surface protein A of Streptococcus pneumoniae and to high-molecular-weight outer membrane protein A of Moraxella catarrhalis in children with acute otitis media

The immune response was evaluated in 11 children with Streptococcus pneumoniae and in 9 children with Moraxella catarrhalis otitis media. The age of the children had a range of 4-32 months. The mean IgG, IgM, and IgA antibody responses to surface protein A (PspA) of S. pneumoniae in sera from children at the acute and convalescent stages were 4864 versus 5831 ng/mL, P<.05, 1075 versus 3752 ng/mL, P<.05, and 67 versus 93 ng/mL, nonsignificant (NS), respectively. The mean IgG, IgM, and IgA antibody responses to the high-molecular-weight outer membrane protein (UspA) of M. catarrhalis in sera from children at acute and convalescent stages were 710 versus 935 mg/mL, NS; 1895 versus 2646 ng/mL, NS; and 121 versus 204 ng/mL, P<.05, respectively. These data show that PspA and UspA are immunogenic in children after otitis media.     

Identification of respiratory virus antigens in middle ear fluids of children with acute otitis media

Antigens of respiratory viruses were tested by immunoassay of the middle ear fluids and nasopharyngeal secretions of 137 children with acute otitis media. The following were found: (1) an epidemic of infection with respiratory syncytial virus (RSV) caused a significant increase in the occurrence of acute otitis media. (2) Fifteen percent of the children had RSV antigens in middle ear fluid, and in 7% RSV was the sole pathogen found. Adenovirus antigens were found in the middle ear fluid of 3% of the children. (3) Bacteriologic findings in otitis media related and unrelated to viral (RSV) infection were similar. These findings indicate that some episodes of otitis media are associated with viral infection and that the disease may be solely due to viral infection. Thus, at least during an epidemic of respiratory virus infections, treatment failures--e.g., fever and earache unresponsive to antimicrobial therapy--may be due to a viral etiology of acute otitis media.     

Branhamella catarrhalis septicemia in an immunocompetent adult

A 68-year-old man with otitis media developed signs of disseminated intravasal coagulation (DIC) and shock. Beta-lactamase positive Branhamella catarrhalis grew in all blood cultures and in secretion from the middle ear. The patient was immunocompetent and previously healthy. Severe B. catarrhalis septicemia has so far mainly been described in immunocompromised patients, mostly children, but this report shows that it may occasionally occur in immunocompetent adults.     

The contribution of pneumococcal cell wall to the pathogenesis of experimental otitis media

We studied the contribution of pneumococcal cell wall to the pathogenesis of otitis media in chinchillas after middle ear inoculation of killed, encapsulated type 7F Streptococcus pneumoniae; killed, unencapsulated R6 S. pneumoniae; and isolated R6 pneumococcal cell wall. Ears inoculated with encapsulated and unencapsulated pneumococci had significantly higher concentrations of polymorphonuclear and mononuclear leukocytes and lysozyme in middle ear fluid and developed more epithelial metaplasia and granulation tissue than did saline-inoculated ears. The mean concentration of lysozyme in middle ear fluid was higher in ears inoculated with killed, unencapsulated than encapsulated pneumococci. The middle ear mucoperiosteum of ears inoculated with pneumococcal cell wall showed significantly more polymorphonuclear leukocytes, epithelial metaplasia, subepithelial congestion, and granulation tissue than did control ears. Because nonviable, unencapsulated pneumococci and pneumococcal cell wall caused middle ear inflammation in the chinchilla model of otitis media, it is possible that cell envelope and cell wall components released during bacterial lysis may contribute to chronic otitis media with effusion in humans.     

Acute otitis media caused by Branhamella catarrhalis: biology and therapy

Since 1980, we have observed an epidemic of otitis media caused by Branhamella catarrhalis. This event was characterized by studying the nasopharyngeal colonization of infants and children with B. catarrhalis and the clinical presentation and therapeutic outcome of acute otitis media caused by this organism. Pharyngeal colonization with B. catarrhalis was commoner in winter than summer. B. catarrhalis was present in middle-ear fluid (MEF) of 17% of children with otitis media, and was commoner in fall and winter (20%) than in spring and summer (11%, P less than .05). Seventy-five percent of isolates produced beta-lactamase (Ravasio type). In five of 20 patients, treatment with beta-lactamase-susceptible agents failed to sterilize B. catarrhalis-infected MEF. All of these five patients were infected with beta-lactamase-producing strains. The increasing prominence of antibiotic-resistant B. catarrhalis in acute otitis media may lead to a reevaluation of initial antibiotic therapy for acute otitis media, particularly in winter or in areas where colonization with such strains is prevalent.     

A case of otitis media with effusion by Mycoplasma pneumoniae

A 10-year-old male demonstrating otitis media with effusion by Mycoplasma pneumoniae is reported. The patient was brought to my hospital because of hearing disturbance. Beta-lactam antibiotics were not effective and we performed a tympanotomy. Microbacterial materials were obtained from the middle ear effusion and nasopharynx. Mycoplasma pneumoniae was detected by the PCR method from both materials and antibody to Mycoplasma pneumoniae was also detected. It is very rare for otitis media with effusion due to Mycoplasma pneumoniae to occur without pneumonia. It is reported that some cases of otitis media with effusion have demonstrated good results by long-term low-dose macrolide therapy. We believe some of these cases were caused by Mycoplaema pneumoniae.     

Secretory otitis media: microbiology of the middle ear and the nasopharynx

Specimens for bacterial culture were obtained from 117 children with secretory otitis media (SOM). From the nasopharynx Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis and group A streptococci were isolated in 79% of the patients. Of 168 ear exudates, 30 yielded growth (18%) from 26 of the patients (22%). Pneumococcal capsular polysaccharides could not be detected in exudates assayed by counterimmunoelectrophoresis. The recovery rate of bacteria from the ear exudates was significantly higher in patients with positive than with negative nasopharyngeal culture (p less than 0.05). The nasopharyngeal pathogens invading the middle ear in SOM seem to survive there for a period of time and are then replaced by other strains according to the fluctuation of the nasopharyngeal flora where approximately 40% of the strains were eliminated and replaced by other strains over a period of 12 to 13 days.     

Lysozyme activity and immunoglobulins in middle ear effusion fluid in acute purulent otitis media and in otitis media with effusion.

147 samples of punctured middle ear effusion fluid from cases of otitis media with effusion and 150 samples from patients with acute purulent otitis media were tested for lysozyme activity. In otitis media with effusion the concentration was 182.0 U/ml, in acute otitis 433.8 U/ml. The lysozyme concentration in otitis media with effusion depended upon the nature of the effusion. Serous fluid showed an activity of 124.8 U/ml and mucoid 311.6 U/ml, respectively. In culture-positive cases of acute otitis media the lysozyme level was 423.4 U/ml. Culture-negative cases showed about the same concentration, 438.3 U/ml. The possible role of lysozyme in defence systems of the middle ear is discussed.     

Reduced serum IgG responses to pneumococcal antigens in otitis-prone children may be due to poor memory B-cell generation

A low level of serum antibody to antigens expressed by Streptococcus pneumoniae has been proposed to explain the susceptibility of children to recurrent episodes of acute otitis media (hereafter, "otitis-prone children"). By use of enzyme-linked immunospot assays, the percentages of memory B cells to pneumococcal protein antigens PhtD, LytB, PcpA, PhtE, and Ply were compared between otitis-prone and non-otitis-prone children at the time of acute otitis media or nasopharyngeal colonization with S. pneumoniae. We found significantly lower percentages of memory B cells to 3 pneumococcal protein antigens (PhtD, PhtE, and Ply) and reduced antigen-specific immunoglobulin G concentrations in otitis-prone children, compared with non-otitis-prone children.     

Diagnosis and management of acute otitis media in the urgent care setting

The prevalence of otitis media is increasing, which affects health care resource utilization across all segments, including the urgent care setting. One of the greatest challenges in the management of acute otitis media (AOM) is the effective treatment of cases caused by pathogens that are resistant to commonly used antibiotics. Whereas the production of beta-lactamases among strains of Haemophilus influenzae and Moraxella catarrhalis is an important consideration for antimicrobial therapy, the high prevalence of resistance to penicillin and other classes of antibiotics among strains of Streptococcus pneumoniae represents a greater clinical concern. The Centers for Disease Control and Prevention (CDC) recently convened the Drug Resistant S. pneumoniae Therapeutic Working Group to develop evidence-based recommendations for the treatment of AOM in an era of prevalent resistance. The recommendations from this group included amoxicillin as the preferred first-line drug because of the demonstrated activity against penicillin-intermediate and -resistant strains of S. pneumoniae, using higher dosages of up to 90 mg/kg per day in certain settings. For patients in whom initial treatment is unsuccessful after 3 days, the recommended agents included high-dose amoxicillin-clavulanate (for activity against beta-lactamase-producing pathogens), clindamycin, cefuroxime axetil, or 1 to 3 doses of intramuscular ceftriaxone. The principles set forth in these guidelines can assist the therapeutic decisionmaking process for practitioners in the urgent care setting.     

Experimental otitis media due to Streptococcus pneumoniae: immunopathogenic response in the chinchilla.

Acute otitis media was produced in 110 chinchillas by inoculation of type 23 Streptococcus pneumoniae directly into the middle ear cavity by tympanotomy. During the first three days after inoculation, inflammatory cells were seen in the mucoperiosteum of the middle ear. After four to seven days, there was purulent exudation in the middle ear cavity, and 40% of the animals had pneumococcal meningitis and/or bacteremia. The middle ears were sterile in five of 28 animals sacrificed during the second week and in six of seven animals sacrificed at six weeks, although subepithelial changes persisted in the mucoperiosteum. Levels of antibody to S. pneumoniae in serum were measured by radioimmunoassay; mean values were 6.1 ng of pneumococcal antibody nitrogen/ml in 28 uninfected control animals and 16.5 ng of antibody nitrogen/ml in 29 animals sacrificed two weeks after inoculation (P less than 0.025). Opsonic activity of serum against S. pneumoniae was evaluated in infected and uninfected chinchillas. The opsonic titer was significantly higher in infected animals sacrificed at six weeks than in uninfected controls. Although pneumococcal polysaccharide antigen was found by counterimmunoelectrophoresis in 25 of 30 middle ear effusions, it could not be detected in the serum from infected animals. Methods for infection and sacrifice of chinchillas yielded reproducible results. This model should permit evaluation of the pathologic response to other serotypes of S. pneumoniae and possibly to prophylactic and therapeutic regimes.     

Innate Immunity and the Role of Defensins in Otitis Media

Otitis media is the most common pediatric disease in developed countries and a significant cause of morbidity and hearing loss in developing countries. The innate immune system is essential to protecting the middle ear from infection. Defensins, broad-spectrum cationic antimicrobial peptides, have been implicated in prevention of and the early response to acute otitis media; however, the mechanisms by which defensins and other antimicrobial molecules mediate this protection have not been completely elucidated. In both animal otitis media models and human middle ear epithelial cell culture models, β-defensins are highly induced and effectively kill the common pathogens associated with otitis media. We review the importance of innate immunity in protecting the middle ear and recent advances in understanding the roles of defensins and other antimicrobial molecules in the prevention and treatment of otitis media. The extremely high prevalence of otitis media, in spite of sophisticated innate and adaptive immune systems, is a vexing problem for clinicians and scientists. We therefore also review mechanisms by which bacteria evade innate immune defenses.     

Double-blind comparison of cefixime and cefaclor in the treatment of acute otitis media in children

In a double-blind study cefixime, an oral cephalosporin of the third generation, was compared to cefaclor in the treatment of acute otitis media in 397 children aged 6 months to 12 years. Clinical evaluation was carried out at the beginning, at day 10-12 and day 28-35 after the start of the treatment. Specimens for bacterial culture and sensitivity testings were taken from the nasopharynx at the initial visit. Patients were randomized either to cefixime in a dose of 8 mg/kg/day or cefaclor in a dose 40 mg/kg/day in the proportion of 2 cefixime patients to 1 cefaclor patient. Two daily doses were administered for 7 days. At day 10-12, 93.5% in the cefixime group and 90.5% in the cefaclor group (p = 0.08) were clinically cured or improved. At day 28-35 the rate of cured or improved patients had decreased, mostly due to reinfections, to 90.1% in the cefixime group and to 86.6% in the cefaclor group (p = 0.12), respectively. 375 patients (69.9%) had positive bacterial culture in the nasopharynx of at least one strain of Haemophilus influenzae, Streptococcus pneumoniae, Branhamella (Moraxella) catarrhalis or combinations of these 3.73.6% of the B. catarrhalis strains were beta-lactamase producing and 11.4% of the H. influenzae strains, respectively. All isolated bacteria were sensitive to cefixime. Adverse events were reported in 17.9% in the cefixime and 10.6% in the cefaclor group. Most reactions were of moderate or mild nature and mostly affected skin or the gastrointestinal region. No serious adverse experiences occurred. In view of the good clinical results obtained cefixime seems to be at least as effective as cefaclor in the treatment of acute otitis media in children.     

Demonstration of Chlamydia pneumoniae in the adenoid from children with and without secretory otitis media using immunohistochemistry and PCR

Chlamydia pneumoniae has been found in patients with middle ear inflammation. The adenoid, which has a central role in the development of secretory otitis media (SOM), may act as a reservoir for bacteria causing ear infection. Adenoid tissue was examined for the presence of C. pneumoniae. Twenty children undergoing adenoidectomy because of hyperplastic adenoids, 10 with SOM and 10 without SOM, were examined with nasopharyngeal swabs for routine bacteriological culture, serology for C. pneumoniae and throat swabs for C. pneumoniae PCR. The removed tissues were analyzed for C. pneumoniae using immunohistochemical (IHC) analysis and PCR. In the group of children with SOM samples were also taken from the middle ear fluid for routine bacteriological culture and PCR for C. pneumoniae. C. pneumoniae was found in the adenoid by PCR in 3 cases from each group and from all 20 children by IHC. Four children in each group had increased levels of specific antibodies to C. pneumoniae. Two children with SOM had high antibody titers and a positive PCR from a throat swab. Two children were PCR-positive for C. pneumoniae in fluid from the middle ear. The significance of these findings is not yet clear.     

Phenoxymethylpenicillin and therapeutic failure in acute otitis media

The aim of the present investigation was to determine to what extent beta-lactamase producing Haemophilus influenzae (H.i.) and Branhamella catarrhalis (B.c.) were isolated in cases of failure of treatment of acute otitis media (AOM) with phenoxymethylpenicillin. Among children with suspected therapeutic failure referred to an ENT specialist altogether 11, 15% of those referred, fulfilled the criteria of AOM. Three of them were on erythromycin, 1 on ampicillin and 7 on phenoxymethylpenicillin. In 5 of the children treated with phenoxymethylpenicillin H.i. was isolated from middle ear exudate and/or the nasopharynx. All H.i. isolates were non-capsulated and beta-lactamase negative. One beta-lactamase producing B.c. was isolated from the nasopharynx in a patient with pure culture of H.i. in the ear exudate. The present investigation did not support the suggestion that beta-lactamase producing H.i. or B.c. are major causative agents in therapeutic failures of AOM treated with phenoxymethylpenicillin and did not produce any evidence supporting a change from the recommended ampicillin esters/amoxycillin in therapeutic failures.