G. Scott Giebink

Clinical efficacy of antimicrobial drugs for acute otitis media: Metaanalysis of 5400 children from thirty-three randomized trials

OBJECTIVE To reconcile conflicting published reports concerning the absolute and comparative clinical efficacy of antimicrobial drugs for acute otitis media in children. STUDY SELECTION Articles were identified by MEDLINE search, Current Contents, and references from review articles, textbook chapters, and retrieved reports. Randomized, controlled trials of therapeutic antimicrobial drugs used in the initial empiric therapy for simple acute otitis media were selected by independent, blinded observers, and scored on 11 measures of study validity. Thirty English and three foreign-language articles met all inclusion criteria. DATA EXTRACTION Data were abstracted for an end point of complete clinical resolution (primary control), exclusive of middle ear effusion, within 7 to 14 days after therapy started. DATA SYNTHESIS The spontaneous rate of primary control--without antibiotics or tympanocentesis--was 81% (95% confidence interval, 69% to 94%). Compared with placebo or no drug, antimicrobial therapy increased primary control by 13.7% (95% confidence interval, 8.2% to 19.2%). No significant differences were found in the comparative efficacy of various antimicrobial agents. Extending antimicrobial coverage to include beta-lactamase-producing organisms did not significantly increase the rates of primary control or resolution of middle ear effusion. Pretreatment tympanocentesis was positively associated with individual group primary control rates, negatively associated with the ability to detect differences in clinical efficacy and unassociated with resolution of MEE. CONCLUSIONS Antimicrobial drugs have a modest but significant impact on the primary control of acute otitis media. Treatment with beta-lactamase-stable agents does not increase resolution of acute symptoms or middle ear effusion; initial therapy should be guided by considerations of safety, tolerability, and affordability, and not by the theoretical advantage of an extended antibacterial spectrum.

Effects of Otitis Media on Extended High-Frequency Hearing in Children:

Extended high-frequency (EHF) hearing was studied in children with and without histories of chronic or recurrent otitis media (OM). The EHF thresholds were found to have good test-retest repeatability. Children with OM histories had poorer EHF hearing than children without OM histories. The EHF hearing in OM children appeared to be related to OM severity. Children with residual tympanometric abnormalities had poorer EHF hearing than OM children with normal middle ear function. The results suggest evidence for middle ear and inner ear components of EHF hearing losses in children with OM.

Epidemiology of otitis media onset by six months of age.

Objective. Although early otitis media (OM) onset predicts later recurrent and chronic OM, little research has been directed at illuminating the role of prenatal exposures in early OM. This prospective study examined prenatal, innate, and early environmental exposures associated with acute otitis media (AOM) onset and recurrent OM (ROM) by age 6 months. Design and Methods. Prospective study of 596 infants from a health maintenance organization followed from birth to 6 months. Mothers completed monthly forms on prenatal exposures (diet, medications, and illnesses) and infant risk factors (eg, smoke exposure and child care) during pregnancy and until infants were 6 months old. Urine samples were collected when infants were 2 months of age and analyzed for cotinine and creatinine. Physicians and nurse practitioners examined infants at each clinic visit and completed standard ear examination forms. Results. Thirty-nine percent had an episode of AOM and 20% had ROM by age 6 months. Using Coxs regression models to control for confounding, respiratory tract infection (relative risk [RR] 7.5), day care (RR 1.7), >1 sibling (RR 1.4), maternal, paternal, and sibling OM history (RR 1.6, 1.5, and 1.7, respectively) were significantly related to early OM onset. ROM was related to respiratory tract infection (RR 9.5), day care (RR 1.9), conjunctivitis (RR 2.0), maternal OM history (RR 1.9), and birth in the fall (RR 2.6). Among prenatal exposures, only high prenatal dietary vitamin C intake was significantly inversely related to early AOM with univariate but not multivariate analysis. Conclusion. Prenatal factors were not linked to early AOM onset with multivariate analysis, but environmental and innate factors play an important role in early AOM onset. Strategies to reduce exposure to environmental variables could reduce rates of early AOM, which could potentially result in declining rates of ROM and chronic OME.

The overwhelming postsplenectomy sepsis problem.

Postsplenectomy vulnerability to infection is not limited to age or disease process. Postsplenectomy infection is an emergency problem that requires immediate and accurate treatment because death is potential within a few hours of onset. Although the pathogenesis of overwhelming postsplenectomy sepsis is not completely understood, experimental evidence suggests that loss of mechanical filtration is more important than immunologic deficiences resulting from splenectomy. Certainly, a combination of both may be present. While no single measure seems to completely protect against overwhelming postsplenectomy sepsis, experimental evidence suggests that by reducing or minimizing the amount of spleen removed by newer surgical techniques, and by the addition of pneumococcal vaccine and prophylactic penicillin, the incidence of overwhelming sepsis can be reduced. Further evaluation of splenic function is necessary to assess the role of autotransplantation in the prevention of postsplenectomy sepsis (Fig. 1).RésuméLa vulnérabilité à l’infection après splénectomie ne dépend ni de l’âge, ni de la maladie originelle. Toute infection survenant après splénectomie est une urgence qui peut tuer en quelques heures: elle exige donc un traitement immédiat et adéquat. La pathogénie est encore mal précisée. Des données expérimentales suggèrent que la perte du mécanisme de filtration splénique est plus importante que le déficit immunologique, ces deux facteurs pouvant cependant coexister. Il est apparemment impossible d’assurer une protection parfaite contre les infections graves après splénectomie. Mais certaines études expérimentales indiquent qu’on peut en réduire la fréquence par les nouvelles techniques chirurgicales qui évitent la splénectomie totale, par la vaccination antipneumococcique et par l’administration préventive de pénicilline. Lorsque les fonctions de la rate seront mieux connues, il sera possible de préciser le rôle prophylactique de l’autotransplantation splénique.

High frequency hearing loss associated with otitis media.

Objective: Long‐term effects of otitis media (OM) on hearing in both conventional and high frequency (HF) regions in children were studied. Design: Children with OM were enrolled in a prospective study of sequelae after tympanostomy tube insertion (intubation) and were examined serially at 6‐mo intervals with audiometry and multifrequency tympanometry, and every 3 mo with tympanometry and otoscopy for at least 3, and up to 5 yr. Hearing thresholds in conventional and HF regions were compared with those of an age‐matched control group of children who had 2 or fewer documented episodes of any type of OM since birth. Frequency of OM during follow‐up, number of intubations, use of ototopical eardrops, age, and sex along with several other factors were analyzed for a relationship to HF hearing loss. Results: Otitis media history was associated with poorer HF hearing, but the presence of subtle residual middle ear dysfunction was not associated with an additional effect on HF hearing. Active middle ear disease significantly affected both conventional and HF thresholds. The number of intubations and frequency of OM during follow‐up were significantly and positively associated with poorer HF thresholds. Several other factors, including middle ear appearance at intubation, presence of tympanosclerosis, age, male gender, and use of ototopical eardrops, were also associated with poorer HF hearing but failed to reach significance after their intercorrelation with number of intubations and frequency of OM was considered. Conclusions: High frequency hearing loss was associated with OM after middle ear disease resolved and after middle ear dysfunction was excluded. Relatively poorer HF hearing thresholds found for older children with OM histories appeared to be attributable to time spent with ear disease. Children at greatest risk for HF hearing loss were those who required multiple intubations. Older children tended to have poorer hearing in both conventional and HF regions, suggesting that the effects of OM on hearing thresholds may be progressive.

Overwhelming Postsplenectomy Infection

The syndrome of overwhelming postsplenectomy infection has become well identified and accepted within the past few years. Included in the surgical armamentarium should be techniques of splenic repair in cases of trauma, awareness of the syndrome of overwhelming postsplenectomy infection, and the need for penicillin prophylaxis and pneumococcal vaccination. Autosplenic transplantation (splenosis) is also discussed.

Otitis Media: The Chinchilla Model

Streptococcus pneumoniae infection and disease have been modeled in several animal species including infant and adult mice, infant and adult rats, infant Rhesus monkeys, and adolescent and adult chinchillas. Most are models of sepsis arising from intravenous or intraperitoneal inoculation of bacteria, and a few were designed to study disease arising from intranasal infection. Chinchillas provide the only animal model of middle ear pneumococcal infection in which the disease can be produced by very small inocula injected into the middle ear (ME) or intranasally, and in which the disease remains localized to the ME in most cases. This model, developed at the University of Minnesota in 1975, has been used to study pneumococcal pathogenesis at a mucosal site, immunogenicity and efficacy of pneumococcal capsular polysaccharide (PS) vaccine antigens, and the kinetics and efficacy of antimicrobial drugs. Pathogenesis experiments in the chinchilla model have revealed variation in ME virulence among different pneumococcal serotypes, enhancement of ME infection during concurrent intranasal influenza A virus infections, and natural resolution of pneumococcal otitis media (OM) without intervention. Research has explored the relative contribution of pneumococcal and host products to ME inflammation. Pneumococcal cell wall components and pneumolysin have been studied in the model. Host inflammatory responses studied in the chinchilla ME include polymorphonuclear leukocyte oxidative products, hydrolytic enzymes, cytokine and eicosanoid metabolites, and ME epithelial cell adhesion and mucous glycoprotein production. Both clinical (tympanic membrane appearance) and histopathology (ME, Eustachian tube, inner ear) endpoints can be quantified. Immunologic and inflammatory studies have been facilitated by the production of affinity-purified antichinchilla immunoglobulin G (IgG), IgM, and secretory IgA polyclonal antibody reagents, and the identification of cross-reactivity between human and chinchilla cytokines, and between guinea pig and chinchilla C3. Alteration of ME mucosa by pneumococcal neuraminidase and alteration of ME epithelial cell (MEEC) surface carbohydrates during intranasal pneumococcal infection have been demonstrated. Pathogenesis studies have been aided by cultured chinchilla MEEC systems, in which the ability of platelet activating factor and interleukin (IL)-1 beta to stimulate epithelial mucous glycoprotein synthesis has recently been demonstrated. Because chronic OM with effusion is characterized by presence of large amounts of mucous glycoprotein in the ME, pneumococcus may have an important role in both acute and chronic ME disease. Both unconjugated PS and PS-protein-conjugated vaccines are immunogenic after intramuscular administration without adjuvant in chinchillas. Passive protection studies with human hyperimmune immunoglobulin demonstrated that anti-PS IgG alone is capable of protecting the chinchilla ME from direct ME challenge with pneumococci. Active PS immunization studies demonstrated protection following direct ME and intranasal pneumococcal challenge with and without concurrent influenza A virus infection. An attenuated influenza A virus vaccine also showed protection for pneumococcal OM. Antimicrobial treatment of acute OM has been based almost exclusively on empirical drug use and clinical trials without a foundation of ME pharmacokinetics. Studies in the chinchilla model have started to bring a rational basis to drug selection and dosing. Microassays have been developed using high-pressure liquid chromatography for many relevant drugs. Studies have explored the in vivo ME response in pneumococcal OM to antimicrobial drugs at supra- and sub-minimum inhibitory concentration (MIC), the effect of concurrent influenza A virus infection on ME drug penetration, and the effect of treatment on sensorineural hearing loss produced by pneumococcal OM.

Amoxicillin middle ear fluid penetration and pharmacokinetics in children with acute otitis media.

BACKGROUND Acute otitis media (AOM) is a common childhood infectious disease. The efficacy of antibiotic dosing regimens is usually assessed by antibiotic plasma pharmacokinetics or middle ear fluid (MEF) concentration at one or two time points. Viral coinfection in AOM reduced antibacterial efficacy of antibiotics. OBJECTIVE To determine amoxicillin MEF penetration and pharmacokinetics in bacterial and combined bacterial and viral AOM. METHODS Thirty-four children with AOM were enrolled, and MEF was collected by tympanocentesis for bacterial culture and viral studies. Nasal wash and venous blood were also obtained for viral culture and serologic studies, respectively. Subjects were treated with amoxicillin 40 mg/kg/day orally, divided in equal doses every 8 h. During the second visit (48 to 72 h later) the subjects, with the regular morning amoxicillin dose withheld, were given an oral amoxicillin dose of 25 mg/kg. Thereafter two blood samples and one MEF sample by tympanocentesis were collected from each child at selected times between 0.5 and 4.0 h after dosing for bacterial and viral studies and amoxicillin concentration determination by high performance liquid chromatography. RESULTS Eleven (37%) children had only bacterial infection, 6 (20%) had viral infection only, 6 (20%) had both bacterial and viral infections and in 7 (23%) neither bacterial nor viral pathogens were recovered. MEF bacterial culture was positive in 23 of 40 ears (57.5%) before treatment with amoxicillin (40 mg/kg/day) and was still positive in 4 of 38 ears (10.5%) after 2 to 3 days of treatment. Amoxicillin plasma concentration reached its peak at 1.0 to 1.5 h after a 25-mg/kg oral dose. The estimated MEF concentration peak occurred 3.0 h after the dose with MEF concentrations ranging from undetectable to 20.6 microg/ml and a mean of approximately 9.5 microg/ml. Geometric mean amoxicillin concentrations were lowest in virus-infected children (2.7 microg/ml), nearly the same in culture-negative samples from children without viral infection (2.9 microg/ml), higher in children with combined bacterial and viral infection (4.1 microg/ml) and highest in children with bacterial-only infection (5.7 microg/ml). CONCLUSIONS MEF amoxicillin penetration tended to be lower in children with viral infection. The current amoxicillin dosing recommendation of 40 mg/kg/day in three divided dose is inadequate to effectively eradicate resistant Streptococcus pneumoniae, particularly during viral coinfection. A dosing regimen of 75 to 90 mg/kg/day is recommended for AOM.

The bacteriology and cytology of chronic otitis media with effusion.

The bacteriology and cytology of middle ear effusion from 729 children with persistent otitis media with effusion were studied. Thirty-five percent of these chronic effusions were culture-positive. Type b and non-type b Haemophilus influenzae, Streptococcus pneumoniae, Neisseria sp. and Staphylococcus epidermidis were the predominant isolates. Serous and mucoid effusion cultures yielded bacteria more often in younger than in older children. In addition bacteria were seen in 17% of the Gram-stained smears of the sterile effusions; Gram-positive cocci predominated in these effusions. Disparate effusion culture results were obtained in 32% of bilateral otitis media cases. Effusions which yielded H. influenzae and S. pneumoniae on culture had more polymorphonuclear leukocytes than did effusions which yielded S. epidermidis or Neisseria or were sterile. Phagocytic cells were equally prevalent in sterile effusions with or without bacteria on Gram stain. Phagocytic cells were seen less often in mucoid effusions from antibiotic-treated patients than in mucoid effusions from untreated patients. The results suggest that certain bacteria in chronic middle ear effusion contribute to the pathogenesis of this condition by eliciting a local inflammatory cell response.

Eustachian Tube Histopathology during Experimental Influenza a Virus Infection in the Chinchilla

The eustachian tubes of 29 influenza a virus–infected chinchillas were examined for histopathologic signs at intervals up to 21 days after inoculation to elucidate the pathologic basis of negative middle ear pressure, which occurs during viral respiratory tract infection in humans. In the animal model, eardrum inflammation and negative middle ear pressure mirrored epithelial damage in the eustachian tube and the accumulation of cellular and mucous debris in the tubal lumen. Epithelial damage was greatest in the proximal two thirds of the tube near the nasopharynx, whereas goblet cell metaplasia and increased secretory activity was greatest in the distal, tympanic one third of the tube. These results provide a morphologic correlate to the development of negative middle ear pressure, and perhaps explain the pathologic basis for purulent otitis media during viral respiratory tract infection.