Alternative Therapies for Otitis Media

Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 08, 2009

Introduction:

          Since the 1950s, antibiotic  resistance has been recognized as a problem (1-3). Ironically, some  of the scientists who first identified antibiotic processes had  warned decades previously that overuse would lead to resistant  bacteria (4). More recently, news reports and medical articles have  described "flesh-eating bacteria" and amputations related to  methicillin-resistant Staphylococcus aureus (6; MRSA). Furthermore,  antibiotic resistant microbes including MRSA have been identified  in children with persistent otitis (eg, 7-8, see also 9-10).

          The increasing prevalence of  resistant microbes has prompted various medical organizations to  offer guidelines wherein antibiotics are to be used far less in  pediatric otitis (eg, 11-14). The need to reduce the use of  antibiotics has led to consideration and preliminary evaluation of  alternative therapies which might be helpful in treatment of otitis  and respiratory infections which can exacerbate otitis (eg, 15-19).  Indeed, some therapeutics within complimentary and alternative  medicine (CAM) have been found to be efficacious (cites below).


Some quotes from peer-reviewed journals

"Acute otitis media (AOM) is the most common cause of physicians'  office visits for children ages 1-4 years in the United States...  Some of these children develop hearing deficits resulting in poor  school performance and often require surgical procedures to improve  middle ear drainage. Moreover, children with recurrent AOM require  frequent use of antibiotics, making AOM the most common reasons for  antibiotic prescription in the United States... As a result, AOM  treatment has also contributed to the rapid emergence of multi-drug  resistant bacteria. Direct and indirect costs of AOM are estimated  to exceed 4 billion dollars per year in the United States..."  (15). 

"Bacteria that antibiotics have controlled in the past are  increasingly developing resistance to these drugs. Today, virtually  all important bacterial infections in the United States and  throughout the world are becoming resistant...  The overuse of  antimicrobials is beginning to be discouraged as scientific  evidence is emerging to support the use of other therapies. In  pediatric practice an emphasis on accurate diagnoses, control of  environmental risk factors, and utilization of complementary and  alternative medicine (CAM) therapies could reduce antibiotic  prescribing. Antibiotic resistance poses a growing threat to  health. CAM therapies may provide a safer, more effective treatment  for many acute infections of childhood." (16)

"Patients who were given [naturopathic] ear drops alone had a better response than patients who were given ear drops together with  amoxicillin. (17)

"Viral infection of the upper respiratory tract results in  congestion of the nasal and nasopharyngeal mucosa. Congestion in  and around the nasopharyngeal orifice of the Eustachian tube leads  to dysfunction of the tube, which is considered the most important  factor in the development of AOM..." (18)

"A combination of echinacea, propolis, and ascorbic acid decreased  the number of URTI [upper respiratory tract infection] episodes,  the duration of symptoms, and the number of days of illness (p <  0.001)." (19)

 

Comment:

The quotes represent a rationale supported by peer-reviewed medical  literature: Otitis is common and can be severe. Antibiotic  resistance (AR) has become a major problem. Many children have  antibiotic-resistant bacteria in MEF and/or in nasopharynx. In  response to AR, guidelines about using antibiotics for otitis have  changed. Among advances in otitis media, there is increasing  appreciation for the role of respiratory infections. CAM has been  proposed as a way to prevent or alleviate ROM, AOM, and respiratory  infections; and, although a range of results is reported, many  alternative therapies have been found helpful.

As we consider CAM therapuetics in relation to otitis media and  otitis-associated respiratory infections, we shall also consider  factors associated with otitis, eg, gastro intestinal pathology,  hypersensitivity to specific foods, suboptimal nutrient status, day  care for infants, tobacco smoke, and air pollution.

A major purpose of this document is to present citations related to  various CAM therapies that may be helpful for some individuals.  However, a caveat is in order. Although the following information  is based upon published medical literature, otitis media can have  severe ramifications. These include but are not limited to impaired  hearing and meningitis. There is much variation between individuals  in regard to symptoms, recurrence, and outcomes. A qualified health  practitioner is a valuable partner when a parent has a child with  acute or recurrent otitis media.

The following topics are considered: nutrient levels, supplements,  herbs with microbial or anti-inflammatory properties, and  environmental factors such as tobacco smoke, air pollution, and  excessive oxidative stress. Another way to address recurrent or  acute otitis and related respiratory infections is to consider  pathogens associated with otitis and with respiratory infections,  inflammation that exacerbates otitis, and circumstances which  elevate oxidative stress. Each domain can be addressed via CAM.
 

CAM therapies helpful in some cases of otitis

Glutathione is helpful in many cases of otitis (20).

Garlic is bactericidal and may be helpful (21), although garlic may  induce respiratory symptoms in some individuals (22).

Echinacea may produce a rash and, in some individuals, may reduce  the rate or severity of otitis-associated recurrent upper  respiratory infections (URTIs) in some children (23-24).

A combination of echinacea, bee propolis, and vitamin C has been  found helpful in minimizing effects of otitis-associated  respiratory infections (25; see also 26). 

Cow's Milk Allergy is associated with recurrent otitis media  (26b).

Naturopathic Herbal Extract Ear Drops (NHED) were more effective in  treating otitis media ear pain than were antibiotics (17).

Vitamin C studies have described mixed findings, including  subgroups of younger children who had "shorter and less severe  episodes" of otitis-associated URTIs (27-28, discussed in 29).  Vitamin C and other antioxidant nutrients were found low in a group  of children with otitis and tonsillitis (cites below).

 
Nutrients related to otitis and immunity

Immunity, nutrients, and nutritional status have functional,  important interactions (eg, 30-31).

"high prenatal dietary vitamin C intake was significantly inversely  related to early AOM" (31, see also 32)

"Oxidants and antioxidants played a significant role in the  pathogenesis of otitis media with effusion in children. These  children are under significant oxidative stress." (33)

"The organism maintains defense systems including nonenzymatic  antioxidants such as Vitamins A, E and C and reduced glutathione  (GSH) against reactive oxygen species (ROS). In the present study,  lipid peroxidation status and nonenzymatic antioxidant capacity  were investigated in children with AOM and AT [acute  tonsillitis]... All of the antioxidant vitamins such as  beta-carotene, retinol, Vitamin E, and Vitamin C levels were  observed to be significantly decreased in the both patient  groups... GSH levels were also decreased in the patient groups. MDA  levels were found to be higher in children with AOM and AT than in  the healthy control subjects." (34)

 
Factors related to otitis and to respiratory infections

Tobacco smoke, air pollution, and household mold increase the  likelihood of otitis in children (35-37). Day care increases the  rate at which an infant or toddler is exposed to pathogens  associated with otitis and with respiratory infections (38-39).

 
Oxidative stress in otitis

"Oxidative stress is caused by an imbalance between the production  of reactive oxygen and a biological system's ability to readily  detoxify the reactive intermediates or easily repair the resulting  damage." (40)  Elevated oxidative stress and lower levels of  antioxidant nutrients are found in otitis and tonsillitis (27,  33-34). Elevated oxidative stress is associated with autism and  with ADHD (41-44; 45-47). Antioxidant nutrients may reduce elevated  oxidative stress in some and perhaps many individuals (eg, 42).  However, no crystal clear rules apply.

Peer-reviewed literature about using supplements to alleviate  oxidative stress shows mixed results. There is no overwhelming  conclusion that supplements can reduce elevated oxidative stress in  all situations, even as there are studies which show that nutrients  having antioxidant functions are low in various human pathologies.  Indeed, in some subgroups (schizophrenia, autism), positive effects  from using vitamin supplements to reduce elevated levels of  oxidative stress has been reported (42 and cites therein).   Nutrients found helpful include vitamin C, carnosine, vitamin B6,  magnesium, zinc, selenium, and glutathione (42).

Precaution: excessive intake of biologically necessary nutrients  can induce adverse effects. Some health-care providers use lab  tests as a basis for recommending a specific nutrient-protocol for  a given child.

 
Other nutrients, other herbs

Otitis media can be bacterial, viral, or a combination of viral and  bacterial (15). PCR has identified fungi in many case of otitis  (49). Many herbs have antibacterial or antiviral properties. Not  all have been tested in regard to pediatric otitis media.  Therefore, the following comments and citations should be  considered suggestions for research - in the context that overuse  of antibiotics and the prevalence of antibiotic-resistant strains  has prompted searches for CAM therapeutics which are both  efficacious and safe.

Bacteria associated with otitis media (18, 50, 67):

      Haemophilus influenzae non-type b

      Moraxella catarrhalis

      Peptostreptococcus species

      Pseudomonas aeruginosa

      Streptococcus pneumoniae

      Streptococcus pyogenes

      Staphylococcus aureus

 
Otitis-related bacteria with antibiotic resistance (eg, 48, 51,  67)

      Haemophilus influenzae

      Moraxella catarrhalis

      Pseudomonas aeruginosa

      Staphylococcus aureus

      Streptococcus pneumonia

      Streptococcus pyogenes

 
Viruses associated with otitis media (eg, 18,51; not in order of  prevalence)

      Cytomegalovirus (CMV)

      Enterovirus

      Herpes simplex virus (HSV)

      Influenza

      Parainfluenza viruses

      Respiratory syncytial virus (RSV)

      Rhinovirus

 
Combinations: Many cases of recurrent or acute otitis media (ROM, AOM) have combinations (i) of bacterial and viruses, (ii) of several  bacteria, or (iii) of several viruses (eg, 15, 18).

 
Additional antimicrobial herbs that merit research: The  following list is preliminary and is intended to suggest directions  for research regarding CAM treatments for otitis media and for  related respiratory infections. Each herb listed here has either  antimicrobial and/or anti-inflammatory properties or may boost the  immune system. The list presented here is not intended to be  complete. When parents have a child with ROM or AOM, consulting a  qualified health-care practitioner is recommended.

 
     Astragalus membranaceus & other species (eg,  52-54)

     Cinnamomi cortex & other species (cinnamon;  58-60)

     Glycyrrhiza glabra (licorice; 61-64)

     Olea europaea (olive leaf; 65-66)

     Origanum compactum, Origanum vulgare (oregano;  68-70)

     Uncaria tomentosa, Uncaria guianensis (cat's claw;  55-57)

Conclusion:

         This e-document calls attention to  complementary and alternative medicine findings that have  documented or implied relevance to otitis media (especially ROM and  AOM) and to otitis-related respiratory infections. Some peer  reviewed studies have concluded that various CAM therapies are  helpful in treating otitis media or otitis-associated respiratory  infections. The mechanisms by which these CAM-related therapies are  efficacious may not yet have been firmly established. Possible  mechanisms include anti-pathogen, anti-inflammatory, and  immune-boosting effects. Antioxidant effects are also relevant.  Indeed, some nutrients have anti-oxidant significance and, if  suboptimal within a specific child, can boost immunity.  Furthermore, the more that otitis-associated environmental  exposures can be avoided, the better the child's likelihood of not  progressing to recurrent or acute otitis.  Perhaps before many  years have passed, clinically oriented researchers will have  explored some of the anti-microbial herbs presented in this  preliminary document.

 
References:

 

1. "The overuse of antibiotics like penicillin and erythromycin  which used to be one-time miracle cures were associated with  emerging resistance since the 1950s."

  http://en.wikipedia.org/wiki/Antibiotic#Antibiotic_resistance

 

2. The growing burden of antimicrobial resistance.

Hawkey PM.  J Antimicrob Chemother. 2008 Sep;62 Suppl  1:i1-9.

  http://jac.oxfordjournals.org/cgi/content/full/62/suppl_1/i1

 

3. Community factors in the development of antibiotic  resistance.

Larson E.  Annu Rev Public Health. 2007;28:435-47.

  http://arjournals.annualreviews.org/doi/pdf/10.1146/annurev.publhealth.28.021406.144020

 

4. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys  Their Curative Powers.

Stuart B. Levy; Da Capo Press, 2002.

 

5. Methicillin resistant Staphylococcus aureus (MRSA)

  http://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureus

 

6. MRSA in lower limb amputation and the role of antibiotic  prophylaxis.

Richards T et al.  J Cardiovasc Surg (Torino). 2005  Feb;46(1):37-41.

 

AIM: Methicillin Resistant Staphylococcus Aureus (MRSA)  colonisation is reported in 3-20% of vascular patients. Many  develop infective complications. MRSA is associated with poor  prognosis. Aim of the study is to assess MRSA in lower limb  amputation and efficacy of antibiotic prophylaxis. METHODS:  Prospective study of lower limb amputation. MRSA screen and wound  swabs were taken at operation. Antibiotic prophylaxis included  teicoplanin (400 mg) 1 dose at operation. RESULTS: Twenty-five  patients underwent 33 primary amputations. At operation 15 legs  (45%) were colonised with MRSA and 18 legs (58%) had active wound  infection; MRSA (4) and other (14). Following surgery 3 patients  died. Twenty-two legs (76%) had primary healing. Infection  developed in 7 stumps (24%), MRSA (5) and Pseudomonas (2). Stump  infection increased time to wound healing (p<0.0001). MRSA stump  infection increased revision amputation (p=0.009) and duration of  hospital stay (p<0.0074). MRSA wound infection at operation  increased the risk of MRSA stump infection (p=0.007). Non-MRSA  wound infection at operation was not associated with a worse  outcome. No patient colonised with MRSA at operation developed  postoperative MRSA stump infection. CONCLUSIONS: MRSA is more  prevalent that previously reported. MRSA infection has a poor  prognosis. Prophylaxis may be effective for patients colonised with  MRSA.

 

7. Methicillin-resistant Staphylococcus aureus: pediatric  otitis.

Santos F et al.  Arch Otolaryngol Head Neck Surg. 2000  Nov;126(11):1383-5.

  http://archotol.ama-assn.org/cgi/content/full/126/11/1383

 

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a  potentially lethal organism in pediatric patients. MRSA is an  uncommon otologic pathogen that requires special diagnostic and  therapeutic intervention. METHODS: Three pediatric patients with  community-acquired MRSA otologic infections were identified during  1999. SETTING: Tertiary care ear institution. RESULTS: All patients  required intravenous antibiotic therapy to achieve resolution of  the infections. CONCLUSIONS: MRSA in children can be community  acquired and can cause otitis externa, otitis media with otorrhea,  or acute mastoiditis; intravenous therapy that includes vancomycin  is necessary for resolution.

 

8. Methicillin-resistant Staphylococcus aureus otorrhea after  tympanostomy tube placement.

Coticchia JM, Dohar JE.  Arch Otolaryngol Head Neck Surg. 2005  Oct;131(10):868-73.

  http://archotol.ama-assn.org/cgi/content/full/131/10/868

 

OBJECTIVE: To compare a retrospective cohort of nonhospitalized  children with methicillin-resistant Staphylococcus aureus (MRSA)  otorrhea with those with methicillin-sensitive S aureus (MSSA)  otorrhea to determine the risk factors predisposing to MRSA  otorrhea and the treatments used. DESIGN: Retrospective  case-controlled series. SETTING: Tertiary pediatric care facility.  PATIENTS: Seventeen children with MRSA otorrhea after bilateral  myringotomy with tympanostomy tube insertion (BM&T) and 19 age-  and sex-matched control subjects who demonstrated MSSA otorrhea.  The average age at culture in MRSA patients was 52 months; in MSSA  patients, 54 months. There were 8 boys and 3 girls in the MRSA  group and 8 boys and 4 girls in the MSSA group. INTERVENTIONS:  Oral, topical, and intravenous antimicrobial agents. MAIN OUTCOME  MEASURES: Antibiotic exposure and history of otitis media and  routine antibiotic administration (topical, oral, or intravenous).  RESULTS: The following findings were statistically significant (P  < or = .06, Mann-Whitney test): (1) longer duration of  antibiotic treatment after BM&T for patients with MRSA vs those  with MSSA; (2) increased number of episodes of acute otitis media  before BM&T in patients with MRSA vs those with MSSA; and (3)  increased number of courses of antibiotics after BM&T in  patients with MRSA vs those with MSSA. CONCLUSIONS:  Methicillin-resistant S aureus otorrhea is commonly seen as a  community-acquired infection in otherwise healthy pediatric  outpatients. Risk factors for development of MRSA otorrhea include  the number of episodes of acute otitis media before BM&T and  number of treatment courses and duration of antibiotic therapy  after BM&T.

 

9. Microbial interactions during upper respiratory tract  infections.

Pettigrew MM et al. Emerg Infect Dis. 2008 Oct;14(10):1584-91.  [free online]

  http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2609881&blobtype=pdf

 

Streptococcus pneumoniae, Haemophilus influenzae, Moraxella  catarrhalis, and Staphylococcus aureus often colonize the  nasopharynx. Children are susceptible to bacterial infections  during or soon after upper respiratory tract infection (URI). We  describe colonization with these 4 bacteria species alone or in  combination during URI. Data were from a prospective cohort of  healthy children 6 to 36 months of age followed up for 1 year.  Analyses of 968 swabs from 212 children indicated that S.  pneumoniae colonization is negatively associated with colonization  by H. influenzae. Competitive interactions shifted when H.  influenzae and M. catarrhalis colonized together. In this  situation, the likelihood of colonization with all 3 species is  higher. Negative associations were identified between S. pneumoniae  and S. aureus and between H. influenzae and S. aureus.  Polymicrobial interactions differed by number and species of  bacteria present. Antimicrobial therapy and vaccination strategies  targeting specific bacterial species may alter the flora in  unforeseen ways.

 

10. Rates of antimicrobial resistance among common bacterial  pathogens causing respiratory, blood, urine, and skin and soft  tissue infections in pediatric patients.

Jones ME et al.  Eur J Clin Microbiol Infect Dis. 2004  Jun;23(6):445-55.

  http://www.springerlink.com/content/4keva25dt73m92lc/

 

Antimicrobial resistance patterns among the principal bacterial  pathogens from infections of the respiratory tract, blood, skin and  soft tissue, and urinary tract of pediatric patients from the USA,  Canada, Germany, France, and Italy were studied using the The  Surveillance Network (TSN) database. Among Streptococcus pneumoniae  isolates from respiratory tract infections, the prevalence of  high-level penicillin resistance (MIC>/=2 microg/ml) ranged from  1.1 (Italy) to 36.2% (USA); erythromycin resistance was higher,  ranging from 13.4 (Germany) to 63.8% (France). The prevalence of  beta-lactamase-positive Haemophilus influenzae among isolates from  lower respiratory tract infections ranged from <10 (Italy and  Germany) to 38.4% (USA). Among isolates from blood and skin and  soft tissue infections, the prevalence of methicillin-resistant  Staphylococcus aureus (MRSA) ranged from 7.2% (Canada and Germany)  to 27.3% (Italy). The prevalence of Escherichia coli and Klebsiella  pneumoniae with putative extended-spectrum beta-lactamases among  isolates from blood, urinary tract, and skin and soft tissue  infections ranged from 0 (Germany and France) to 29.6% (Italy).  With the exception of pseudomonal infections or infections with  MRSA, amoxicillin-clavulanate retained moderate activity, whilst  ceftriaxone and cefepime were the most effective broad-spectrum  injectable agents. Meropenem was the most effective agent against  Pseudomonas aeruginosa with <5% resistance. Low levels of  resistance, along with acceptable safety profiles and the  availability of convenient oral formulations, continue to support  the use of ceftriaxone, cefepime, amoxicillin-clavulanate, and  meropenem as viable options for the treatment of infections in  pediatric patients.

 

11. New guidelines on acute otitis media: an overview of their key  principles for practice.

Marcy SM.  Cleve Clin J Med. 2004 Jun;71 Suppl 4:S3-9. [free  online]

  http://www.ccjm.org/content/71/Suppl_4/S3.long

 

12. Clinical practice guideline: Otitis media with effusion.

Rosenfeld RM et al.

Otolaryngol Head Neck Surg. 2004 May;130(5 Suppl):S95-118.

 

The clinical practice guideline on otitis media with effusion (OME)  provides evidence-based recommendations on diagnosing and managing  OME in children. This is an update of the 1994 clinical practice  guideline "Otitis Media With Effusion in Young Children," which was  developed by the Agency for Healthcare Policy and Research (now the  Agency for Healthcare Research and Quality). In contrast to the  earlier guideline, which was limited to children aged 1 to 3 years  with no craniofacial or neurologic abnormalities or sensory  deficits, the updated guideline applies to children aged 2 months  through 12 years with or without developmental disabilities or  underlying conditions that predispose to OME and its sequelae. The  American Academy of Pediatrics, American Academy of Family  Physicians, and American Academy of Otolaryngology-Head and Neck  Surgery selected a subcommittee composed of experts in the fields  of primary care, otolaryngology, infectious diseases, epidemiology,  hearing, speech and language, and advanced practice nursing to  revise the OME guideline. The subcommittee made a strong  recommendation that clinicians use pneumatic otoscopy as the  primary diagnostic method and distinguish OME from acute otitis  media (AOM). The subcommittee made recommendations that clinicians  should (1) document the laterality, duration of effusion, and  presence and severity of associated symptoms at each assessment of  the child with OME; (2) distinguish the child with OME who is at  risk for speech, language, or learning problems from other children  with OME and more promptly evaluate hearing, speech, language, and  need for intervention in children at risk; and (3) manage the child  with OME who is not at risk with watchful waiting for 3 months from  the date of effusion onset (if known), or from the date of  diagnosis (if onset is unknown). The subcommittee also made  recommendations that (4) hearing testing be conducted when OME  persists for 3 months or longer, or at any time that language  delay, learning problems, or a significant hearing loss is  suspected in a child with OME; (5) children with persistent OME who  are not at risk should be reexamined at 3- to 6-month intervals  until the effusion is no longer present, significant hearing loss  is identified, or structural abnormalities of the eardrum or middle  ear are suspected; and (6) when a child becomes a surgical  candidate, tympanostomy tube insertion is the preferred initial  procedure. Adenoidectomy should not be performed unless a distinct  indication exists (nasal obstruction, chronic adenoiditis); repeat  surgery consists of adenoidectomy plus myringotomy, with or without  tube insertion. Tonsillectomy alone or myringotomy alone should not  be used to treat OME. The subcommittee made negative  recommendations that (1) population-based screening programs for  OME not be performed in healthy, asymptomatic children and (2)  antihistamines and decongestants are ineffective for OME and should  not be used for treatment; antimicrobials and corticosteroids do  not have long-term efficacy and should not be used for routine  management. The subcommittee gave as options that (1) tympanometry  can be used to confirm the diagnosis of OME and (2) when children  with OME are referred by the primary clinician for evaluation by an  otolaryngologist, audiologist, or speech-language pathologist, the  referring clinician should document the effusion duration and  specific reason for referral (evaluation, surgery), and provide  additional relevant information such as history of AOM and  developmental status of the child. The subcommittee made no  recommendations for (1) complementary and alternative medicine as a  treatment for OME based on a lack of scientific evidence  documenting efficacy and (2) allergy management as a treatment for  OME based on insufficient evidence of therapeutic efficacy or a  causal relationship between allergy and OME. Last, the panel  compiled a list of research needs based on limitations of the  evidence reviewed. The purpose of this guideline is to inform  clinicians of evidence-based methods to identify methods to  identify, monitor, and manage OME in children aged 2 months through  12 years. The guideline may not apply to children older than 12  years because OME is uncommon and the natural history is likely to  differ from younger children who experience rapid developmental  change. The target population includes children with or without  developmental disabilities or underlying conditions that predispose  to OME and its sequelae. The guideline is intended for use by  providers of health care to children, including primary care and  specialist physicians, nurses and nurse practitioners, physician  assistants, audiologists, speech-language pathologists, and child  development specialists. The guideline is applicable to any setting  in which children with OME would be identified, monitored, or  managed. This guideline is not intended as a sole source of  guidance in evaluating children with OME. Rather, it is designed to  assist primary care and other clinicians by providing an  evidence-based framework for decision-making strategies. It is not  intended to replace clinical judgment or establish a protocol for  all children with this condition, and may not provide the only  appropriate approach to diagnosing and managing this problem.

 

13. Nonsevere acute otitis media: a clinical trial comparing  outcomes of watchful waiting versus immediate antibiotic  treatment.

McCormick DP, Chonmaitree T et al.  Pediatrics. 2005  Jun;115(6):1455-65. [Free online]

  http://pediatrics.aappublications.org/cgi/content/full/115/6/1455

 

OBJECTIVE: The widespread use of antibiotics for treatment of acute  otitis media (AOM) has resulted in the emergence of  multidrug-resistant pathogens that are difficult to treat. However,  it has been shown that most children with nonsevere AOM recover  without ABX. The objective of this study was to evaluate the  safety, efficacy, acceptability, and costs of a non-ABX  intervention for children with nonsevere AOM. METHODOLOGY: Children  6 months to 12 years old with AOM were screened by using a novel  AOM-severity screening index. Parents of children with nonsevere  AOM received an educational intervention, and their children were  randomized to receive either immediate antibiotics (ABX;  amoxicillin plus symptom medication) or watchful waiting (WW;  symptom medication only). The investigators, but not the parents,  were blinded to enrollment status. Primary outcomes included parent  satisfaction with AOM care, resolution of symptoms, AOM  failure/recurrence, and nasopharyngeal carriage of Streptococcus  pneumoniae strains resistant to ABX. Secondary outcomes included  medication-related adverse events, serious adverse events,  unanticipated AOM-related office and emergency department visits  and telephone calls, the child's absence from day care or school  resulting from AOM, the parent's absence from school or work  because of their child's AOM, and costs of treatment. Subjects were  defined as failing (days 0-12) or recurring (days 13-30) if they  experienced a higher AOM-severity score on reexamination. RESULTS:  A total of 223 subjects were recruited: 73% were nonwhite, 57% were  <2 years old, 47% attended day care, 82% had experienced prior  AOM, and 83% had not been fully immunized with heptavalent  pneumococcal vaccine. One hundred twelve were randomized to ABX,  and 111 were randomized to WW. Ninety-four percent of the subjects  were followed to the 30-day end point. Parent satisfaction with AOM  care was not different between the 2 treatment groups at either day  12 or 30. Compared with WW, symptom scores on days 1 to 10 resolved  faster in subjects treated with immediate ABX. At day 12, among the  immediate-ABX group, 69% of tympanic membranes and 25% of  tympanograms were normal, compared with 51% of normal tympanic  membranes and 10% of normal tympanograms in the WW group. Parents  of children in the ABX group gave their children fewer doses of  pain medication than did parents of children in the WW group.  Subjects in the ABX group experienced 16% fewer failures than  subjects in the WW group. Of the children in the WW group, 66%  completed the study without needing ABX. Immediate ABX resulted in  eradication of S pneumoniae carriage in the majority of children,  but S pneumoniae strains cultured from children in the ABX group at  day 12 were more likely to be multidrug-resistant than strains from  children in the WW group. More ABX-related adverse events were  noted in the ABX group, compared with the WW group. No serious  AOM-related adverse events were observed in either group. Office  and emergency department visits, phone calls, and days of  work/school missed were not different between groups. Prescriptions  for ABX were reduced by 73% in the WW group compared with the ABX  group. Costs of ABX averaged $47.41 per subject in the ABX group  and $11.43 in the WW group. CONCLUSIONS: Sixty-six percent of  subjects in the WW group completed the study without ABX. Parent  satisfaction was the same between groups regardless of treatment.  Compared with WW, immediate ABX treatment was associated with  decreased numbers of treatment failures and improved symptom  control but increased ABX-related adverse events and a higher  percent carriage of multidrug-resistant S pneumoniae strains in the  nasopharynx at the day-12 visit. Key factors in implementing a WW  strategy were (a) a method to classify AOM severity; (b) parent  education; (c) management of AOM symptoms; (d) access to follow-up  care; and (e) use of an effective ABX regimen, when needed. When  these caveats are observed, WW may be an acceptable alternative to  immediate ABX for some children with nonsevere AOM.

 

14. Age inconsistency in the American Academy of Pediatrics  guidelines for acute otitis media.

Meropol SB, Glick HA, Asch DA.  Pediatrics. 2008  Apr;121(4):657-68.  [free online]

  http://pediatrics.aappublications.org/cgi/content/full/121/4/657

 

15. Role of respiratory syncytial virus in acute otitis media:  implications for vaccine development.

Patel JA et al.  Vaccine. 2007 Feb 19;25(9):1683-9. [free  online]

  http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1828634&blobtype=pdf

 

We summarize herein the results of various virologic studies of  acute otitis media (AOM) conducted at our site over a 10-year  period. Among 566 children with AOM, respiratory syncytial virus  (RSV) was the most common virus identified in either middle ear  fluid or nasal wash; it was found in 16% of all children and 38% of  virus-positive children. Seventy-one percent of the children with  RSV were 1 year of age or older, which was significantly older than  all other viruses combined (P=0.045). RSV infection was associated  with the common bacterial pathogens causing AOM. Past efforts to  develop vaccines for RSV have emphasized prevention of lower  respiratory tract infection in infants, which is a more serious  problem but less common than AOM. Our results suggest that RSV  vaccines that work only against infection in older children may  have value in preventing AOM, the most common pediatric  disease.

 

 

16. Can CAM therapies help reduce antibiotic resistance?

MacKay D Altern Med Rev. 2003 Feb;8(1):28-42.

  http://www.thorne.com/media/cam_therapies_8-1.pdf

 

17. Naturopathic treatment for ear pain in children.

Sarrell EM et al.  Pediatrics. 2003 May;111(5 Pt  1):e574-9.  [free online

  http://pediatrics.aappublications.org/cgi/content/full/111/5/e574

 

18. Importance of respiratory viruses in acute otitis media.

Heikkinen T, Chonmaitree T. Clin Microbiol Rev. 2003 16(2):230-41.  [free online, important review]

  http://cmr.asm.org/cgi/reprint/16/2/230

 

Acute otitis media is usually considered a simple bacterial  infection that is treated with antibiotics. However, ample evidence  derived from studies ranging from animal experiments to extensive  clinical trials supports a crucial role for respiratory viruses in  the etiology and pathogenesis of acute otitis media. Viral  infection of the upper respiratory mucosa initiates the whole  cascade of events that finally leads to the development of acute  otitis media as a complication. The pathogenesis of acute otitis  media involves a complex interplay between viruses, bacteria, and  the host's inflammatory response. In a substantial number of  children, viruses can be found in the middle-ear fluid either alone  or together with bacteria, and recent studies indicate that at  least some viruses actively invade the middle ear. Viruses appear  to enhance the inflammatory process in the middle ear, and they may  significantly impair the resolution of otitis media. Prevention of  the predisposing viral infection by vaccination against the major  viruses would probably be the most effective way to prevent acute  otitis media. Alternatively, early treatment of the viral infection  with specific antiviral agents would also be effective in reducing  the occurrence of acute otitis media.

 

19. Complementary and alternative medicine for  upper-respiratory-tract infection in children

Carr RR, Nahata MC.  Am J Health Syst Pharm. 2006 Jan  1;63(1):33-9.

 

20. Management of chronic otitis media with effusion: the role of  glutathione.

Testa B et al.  Laryngoscope. 2001 Aug;111(8):1486-9.

 

BACKGROUND: The inflammatory cells documented in chronic otitis  media with effusion (OME) spontaneously release oxidants which can  induce middle ear (ME) epithelial cell damage. Glutathione (GSH), a  major extracellular antioxidant in humans, plays a central role in  antioxidant defense. PURPOSE: To evaluate the effects of GSH  treatment on chronic otitis media with effusion (OME). SUBJECTS AND  INTERVENTION: Sixty children with chronic OME were enrolled, 30 of  whom were randomly assigned to the treatment group and 30 to the  placebo group. Patients in the treatment group received 600 mg  glutathione in 4 mL saline per day subdivided into five 2-minute  administrations given by nasal aerosol every 3 or 4 waking hours  for 2 weeks. Patients in the control group received 4 mL saline per  day following the same procedure as for GSH treatment. RESULTS:  Three months after therapy improvement had occurred in 66.6% of  patients in the GSH-treated group and in 8% of the control subjects  (P <.01). CONCLUSION: On the basis of these results, GSH  treatment could be considered for the nonsurgical management of  chronic OME.

 

21. Management of acute otitis media in an era of increasing  antibiotic resistance.

Klein JO.  Int J Pediatr Otorhinolaryngol. 1999 Oct 5;49 Suppl  1:S15-7.

 

Development of resistance to available antimicrobial agents has  been identified in every decade since the introduction of the  sulfonamides in the 1930s. Current concerns for management of acute  otitis media (AOM) are multi-drug resistant Streptococcus  pneumoniae and beta-lactamase producing Haemophilus influenzae and  Moraxella catarrhalis. In the USA, amoxicillin remains the drug for  choice for AOM. Increasing the current dose to 80 mg/kg/day in two  doses provides increased concentrations of drug in serum and middle  ear fluid and captures additional resistant strains of S.  pneumoniae. For children who fail initial therapy with amoxicillin  an expert panel convened by the Centers for Disease Control and  Prevention suggested amoxicillin-clavulanate, cefuroxime axetil or  intramuscular ceftriaxone. To protect the therapeutic advantage of  antimicrobial agents used for AOM, it is important to promote  judicious use of antimicrobial agents and avoid uses if it is  likely that viral infections are the likely cause of the disease,  to implement programs for parent education and to increase the  accuracy of diagnosis of AOM. Conjugate polysaccharide pneumococcal  vaccines are currently in clinical trial; early results indicate  protective levels of antibody can be achieved with a three dosage  schedule beginning at 2 months of age. Finally, alternative  medicine remedies may be of value for some infectious diseases  including AOM; garlic extract is bactericidal for the major  bacterial pathogens of AOM but is heat- and acid-labile and loose  activity when cooked or taken by mouth.

 

22. Cross-reactions between respiratory and food allergens.

de Blay F, Pauli G, Bessot JC.  Allergy Proc. 1991  Sep-Oct;12(5):313-7.

 

Cross-reactions between inhaled and food allergens are usually  attributed to pollen hypersensitivity associated with fruit and  vegetable allergy. However, other allergens are involved in these  types of cross-reactions. In a few cases, there is a complete  similarity between the inhaled and food allergens (garlic,  crustacea proteins). More frequently, partial similarity has been  demonstrated: whole inhaled allergens are included in ingested  substances. Moreover, immunological techniques can demonstrate  common antigenic epitopes in organic substances without any  apparent relationship. This has been demonstrated by  RAST-inhibition and/or immunoblot techniques, using sera from  patients cross-sensitized to (1) pollens and fruits or vegetables  or (2) avian sera and eggs. Respiratory sensitization always seems  to precede food allergy symptoms.

 

23.  Efficacy and safety of echinacea in treating upper  respiratory tract infections in children: a randomized controlled  trial.

Taylor JA et al.  JAMA. 2003 Dec 3;290(21):2824-30. [free  online]

  http://jama.ama-assn.org/cgi/content/full/290/21/2824

 

CONTEXT: Echinacea is a widely used herbal remedy for treatment of  upper respiratory tract infections (URIs). However, there are few  data on the efficacy and safety of echinacea in treating URIs in  children. OBJECTIVES: To determine if Echinacea purpurea is  effective in reducing the duration and/or severity of URI symptoms  in children and to assess its safety in this population. DESIGN,  SETTING, AND PARTICIPANTS: Randomized, double-blind,  placebo-controlled trial of healthy children 2 to 11 years old  recruited from a regional practice-based network and an alternative  medical center in 4-month periods from 2000 through 2002.  INTERVENTIONS: Study patients were randomized to receive either  echinacea or placebo for up to 3 URIs over a 4-month period. Study  medication was begun at the onset of symptoms and continued  throughout the URI, for a maximum of 10 days. MAIN OUTCOME  MEASURES: Primary outcomes were duration and severity of symptoms  and adverse events recorded by parents; secondary outcomes included  peak severity of symptoms, number of days of peak severity, number  of days of fever, and a global assessment of severity of symptoms  by parents of study children. RESULTS: Data were analyzed on 707  URIs that occurred in 407 children, including 337 URIs treated with  echinacea and 370 with placebo. There were 79 children who  completed their study period without having a URI. The median  duration of URIs was 9 days (95% confidence interval, 8-10 days);  there was no difference in duration between URIs treated with  echinacea or placebo (P =.89). There was also no difference in the  overall estimate of severity of URI symptoms between the 2  treatment groups (median, 33 in both groups; P =.69). In addition,  there were no statistically significant differences between the 2  groups for peak severity of symptoms (P =.68), number of days of  peak symptoms (1.60 in the echinacea group and 1.64 in the placebo  group; P =.97), number of days of fever (0.81 in the echinacea  group vs 0.64 in the placebo group; P =.09), or parental global  assessment of severity of the URI (P =.67). Overall, there was no  difference in the rate of adverse events reported in the 2  treatment groups; however, rash occurred during 7.1% of the URIs  treated with echinacea and 2.7% of those treated with placebo (P  =.008). CONCLUSIONS: Echinacea purpurea, as dosed in this study,  was not effective in treating URI symptoms in patients 2 to 11  years old, and its use was associated with an increased risk of  rash.

 

24.  Echinacea purpurea for prevention of upper respiratory  tract infections in children.

Weber W et al. J Altern Complement Med. 2005 Dec;11(6):1021-6.

  http://www.liebertonline.com/doi/abs/10.1089/acm.2005.11.1021

25. Effectiveness of an herbal preparation containing echinacea, propolis, and

vitamin C in preventing respiratory tract infections in children: a randomized,

double-blind, placebo-controlled, multicenter study.

Cohen HA et al. Arch Pediatr Adolesc Med. 2004 Mar;158(3):217-21. [free online]

http://archpedi.ama-assn.org/cgi/content/full/158/3/217

OBJECTIVE: To evaluate the effectiveness and safety of a preparation containing

echinacea, propolis, and vitamin C in the prevention of respiratory tract infections

in children during a 12-week winter period. DESIGN: Randomized, double-blind,

placebo-controlled study. SUBJECTS: Four hundred thirty children, aged 1 to 5 years,

were randomized to an herbal extract preparation (n = 215) or a placebo elixir (n =

215). INTERVENTION: Administration of an herbal preparation (Chizukit) containing 50

mg/mL of echinacea, 50 mg/mL of propolis, and 10 mg/mL of vitamin C, or placebo (5.0

mL and 7.5 mL twice daily for ages 1 to 3 years and 4 to 5 years, respectively) for

12 weeks. RESULTS: Significant mean ± SD reductions of illnesses were seen in the

Chizukit group in the number of illness episodes, 138 vs 308 (55% reduction); number

of episodes per child, 0.9 ± 1.1 vs 1.8 ± 1.3 (50% reduction, P<.001); and

number of days with fever per child, 2.1 ± 2.9 vs 5.4 ± 4.4) (62% reduction,

P<.001). The total number of illness days and duration of individual episodes were

also significantly lower in the Chizukit group. Adverse drug reactions were rare,

mild, and transient. CONCLUSION: A preventive effect of a product containing

echinacea, propolis, and vitamin C on the incidence of respiratory tract infections

was observed.

26. Comparison of bee products based on assays of antioxidant capacities.

Nakajima Y et al. BMC Complement Altern Med. 2009 Feb 26;9:4. [free online]

http://www.biomedcentral.com/1472-6882/9/4

BACKGROUND: Bee products (including propolis, royal jelly, and bee pollen) are

popular, traditional health foods. We compared antioxidant effects among water and

ethanol extracts of Brazilian green propolis (WEP or EEP), its main constituents,

water-soluble royal jelly (RJ), and an ethanol extract of bee pollen. METHODS: The

hydrogen peroxide (H2O2)-, superoxide anion (O2.-)-, and hydroxyl radical (HO.)-

scavenging capacities of bee products were measured using antioxidant capacity

assays that employed the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-

chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA)

or aminophenyl fluorescein (APF). RESULTS: The rank order of antioxidant potencies

was as follows: WEP > EEP > pollen, but neither RJ nor 10-hydroxy-2-decenoic acid

(10-HDA) had any effects. Concerning the main constituents of WEP, the rank order of

antioxidant effects was: caffeic acid >artepillin C > drupanin, but neither

baccharin nor coumaric acid had any effects. The scavenging effects of caffeic acid

were as powerful as those of trolox, but stronger than those of N-acetyl cysteine

(NAC) or vitamin C. CONCLUSION: On the basis of the present assays, propolis is the

most powerful antioxidant of all the bee product examined, and its effect may be

partly due to the various caffeic acids it contains. Pollen, too, exhibited strong

antioxidant effects.

26b. Cow's milk allergy is associated with recurrent otitis media during childhood.

Juntti H et al. Acta Otolaryngol. 1999;119(8):867-73.

To determine whether cow's milk allergy (CMA) in infancy is associated with

recurrent otitis media (ROM) or other chronic ear infections, we conducted a cohort

study by enrolling 56 milk-allergic and 204 control schoolchildren. We also studied

the association between ear problems and different atopic manifestations. A higher

proportion of children with CMA had had ROM. defined as at least 15 acute otitis

media episodes by the age of 10 years (27%, vs 12%, p = 0.009), and had undergone

adenoidectomy and or tympanostomy compared with the controls (48%, vs 28%, p =

0.005). However, this was only true of the children who had developed respiratory

atopy. Asthma and/or allergic rhinitis, but not atopic dermatitis, posed a

significant risk for ROM, while all the three atopic manifestations enhanced the

risk for secretory otitis media. Positive skin prick tests with food, but not with

inhaled allergens, tended to be associated with ear problems. In conclusion, we

found that children with CMA in infancy, even when properly treated, had experienced

significantly more ROM, the risk associating with concomitant development of

respiratory atopy.

27. Oxidant and antioxidant levels in children with acute otitis media and tonsillitis: a comparative study.

Cemek M et al. Int J Pediatr Otorhinolaryngol. 2005 Jun;69(6):823-7.

OBJECTIVE: Recurrent episodes of acute otitis media (AOM) and acute tonsillitis (AT)

are a common problem in infectious disorders during childhood and are major cause of

morbidity in children. The organism maintains defense systems including nonenzymatic

antioxidants such as Vitamins A, E and C and reduced glutathione (GSH) against

reactive oxygen species (ROS). In the present study, lipid peroxidation status and

nonenzymatic antioxidant capacity were investigated in children with AOM and AT. Our

aim was to compare the lipid peroxidation and responses of the body's antioxidant

status in the closely associated infections such as AOM and acute tonsillitis.

METHODS: The study included 23 (14 males, 9 females) children with AOM, 27 (14

males, 13 females) with AT and 29 (16 males, 13 females) healthy control subjects.

The ages of the study and control subjects were between 2 and 7 years. Serum beta-

carotene, retinol, Vitamin E, Vitamin C, and whole blood malondialdehyde (MDA) (as

an indicator of lipid peroxidation) and GSH levels were studied in all subjects.

RESULTS: There was a statistically significant difference between the groups for all

parameters (P<0.05). All of the antioxidant vitamins such as beta-carotene, retinol,

Vitamin E, and Vitamin C levels were observed to be significantly decreased in the

both patient groups. Nevertheless, GSH levels were also decreased in the patient

groups. MDA levels were found to be higher in children with AOM and AT than in the

healthy control subjects. When compared the AOM and AT groups, there was

statistically significant difference between the groups for whole blood MDA

(P<0.05).

28. Malondialdehyde

http://en.wikipedia.org/wiki/Malondialdehyde

29. Complementary and alternative medicine for upper-respiratory-tract infection in

children.

Carr RR, Nahata MC. Am J Health Syst Pharm. 2006 Jan 1;63(1):33-9.

http://www.ajhp.org/cgi/content/full/63/1/33

30. Nutrition and the immune system from birth to old age.

Chandra RK. Eur J Clin Nutr. 2002 Aug;56 Suppl 3:S73-6. [free online]

http://www.nature.com/ejcn/journal/v56/n3s/abs/1601492a.html

For millennia, food has been at the center ff social events, in times of joy and in

times of sorrow. Protein-energy malnutrition is associated with a significant

impairment of cell-mediated immunity, phagocyte function, complement system,

secretory immunoglobulin A antibody concentrations, and cytokine production.

Deficiency of single nutrients also results in altered immune response: this is

observed even when the deficiency state is relatively mild. Of the micronutrients,

zinc, selenium, iron, copper, vitamins A, C, E and B(6), and folic acid have

important influences on immune responses. Overnutrition and obesity also reduce

immunity. Low-birth-weight infants have a prolonged impairment of cell-mediated

immunity that can be partly restored by providing extra amounts of dietary zinc. In

the elderly, impaired immunity can be enhanced by modest amounts of a combination of

micronutrients. These findings have considerable practical and public health

significance.

31. The history of nutrition: malnutrition, infection and immunity.

Keusch GT. J Nutr. 2003 Jan;133(1):336S-340S. [free online]

http://jn.nutrition.org/cgi/content/full/133/1/336S

The relationship between nutritional status and the immune system has been a topic

of study for much of the 20th century. Dramatic increases in our understanding of

the organization of the immune system and the factors that regulate immune function

have demonstrated a remarkable and close concordance between host nutritional status

and immunity. This report traces the increasing sophistication of our understanding

of these relationships and their impact on susceptibility to infection through six

stages to the present time. The cyclical relationship between poor nutrition,

increased susceptibility to infectious diseases, leading to immunological

dysfunction and metabolic responses that further alter nutritional status is

described and, wherever possible, related to physiological mechanisms. In addition,

the particular role of Nevin Scrimshaw in guiding the progress over the past 50 y is

discussed.

32. Epidemiology of otitis media onset by six months of age.

Daly KA et al. Pediatrics. 1999 Jun;103(6 Pt 1):1158-66.

http://pediatrics.aappublications.org/cgi/content/full/103/6/1158

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 Cox's 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.

33. The role of free oxygen radicals on the development of otitis media with

effusion.

Yariktas M, Doner F, Dogru H, Yasan H, Delibas N.

Int J Pediatr Otorhinolaryngol. 2004 Jul;68(7):889-94.

OBJECTIVE: The purpose of this study was to determine if free oxygen radicals (FORs)

and antioxidant enzyme activities have some role in pathogenesis of otitis media

with effusion (OME) in children with adenoid hyperplasia. METHODS: Seventy-four

patients were enrolled in three groups of this study. The study group (Group I)

included 26 patients who had adenoidectomy with ventilation tube placement due to

chronic OME. The control adenoid group (Group II) consisted of 28 age-matched

patients who had adenoidectomy without ventilation tube insertion. Twenty children

were included in the healthy control group (Group III). Erythrocyte malondialdehyde

(MDA) levels, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase

(GSH-Px) enzyme activities were investigated in the venous blood sample. RESULTS:

Erythrocyte MDA level and GSH-Px enzyme activity in the blood samples of study group

(Group I) were significantly higher than those of Group II and Group III (P < 0.05).

SOD enzyme activity in the blood samples of Group I was significantly lower than

Group II (P < 0.05), and were significantly higher than Group III (P < 0.05). CAT

enzyme activity of Group I was significantly lower than that of Group III (P <

0.05). However, there was no statistically significant difference between Group I

and Group II regarding CAT antioxidant enzyme activity (P < 0.05). CONCLUSIONS: The

inflammation of the middle ear increases the level of FORs in erythrocyte. FOR level

is normally maintained at a steady state by antioxidant enzymes. When the

antioxidant defense system is weakened, the increased FORs may contribute to OME

formation. We supposed that, antioxidant vitamins C and E, and scavenger enzymes

such as CAT, SOD and GSH-Px may be added in the management of OME.

34. The role of oxidants and antioxidants in otitis media with effusion in children.

Yilmaz T et al. Otolaryngol Head Neck Surg. 2004 Dec;131(6):797-803.

OBJECTIVE: Determine the possible role of oxidants and antioxidants in the

pathogenesis of otitis media with effusion in children. STUDY DESIGN AND SETTING:

Randomized controlled trial, tertiary referral center. The study group was made up

of children with otitis media with effusion who were to undergo bilateral

ventilation tube insertion and adenoidectomy. The control group was comprised of

otherwise healthy children. The blood levels of antioxidants (retinol, beta-

carotene, alpha-tocopherol, laycopene, ascorbic acid, superoxide dismutase,

glutathione peroxidase, GSH) and oxidation products (malondialdehyde) were

determined before and 1 month after the operation in the study group and once only

in the control group. These substances were also measured in the adenoid tissue and

middle ear fluids. RESULTS: In the study group, the blood levels of antioxidants and

oxidants before and after the operation were significantly different when compared

with the control group (P < 0.05). In the study group, the blood antioxidant levels

increased and oxidant levels decreased significantly after the operation (P < 0.05).

The levels after the operation never reached those of the control group. CONCLUSIONS

AND SIGNIFICANCE: Oxidants and antioxidants played a significant role in the

pathogenesis of otitis media with effusion in children. These children are under

significant oxidative stress. Insertion of a ventilation tube and adenoidectomy

significantly decreased the oxidative stress in these patients, but could not

normalize it completely. Additional studies are necessary in the clinical use of

antioxidants in otitis media with effusion.

35. Exposure to environmental tobacco smoke as a risk factor for recurrent acute

otitis media in children under the age of five years.

Stenstrom R et al. Int J Pediatr Otorhinolaryngol. 1993 Aug;27(2):127-36.

Exposure to environmental tobacco smoke (ETS) has remained a controversial risk

factor for otitis media in children. This study evaluates the association between

exposure to ETS and recurrent acute otitis media (RAOM) in 85 cases and 85 age and

gender matched controls under the age of 5 years. Cases and controls were obtained

from outpatient otolaryngology and ophthalmology clinics, respectively, at the

Children's Hospital of Eastern Ontario. Cases were defined as having four or more

physician documented AOM episodes in the preceding 12 months and controls were

otitis free in the prior 12 months. Exposure status was assessed via parental

questionnaire. Controlling for other risk factors (via conditional logistic

regression), such as daycare attendance, socioeconomic status, prematurity and

family history of otitis media, a significant association between ETS and RAOM was

evident (odds ratio = 2.68, 95% CI = 1.27-5.65). When categorized, a significant

exposure response relationship between increasing level of exposure to ETS and

increased risk of RAOM was evident. The population etiologic fraction indicated that

up to 34% of RAOM cases may be accounted for by ETS exposure. We conclude that

exposure to ETS is an important and modifiable risk factor for RAOM in children

under the age of 5 years.

36. Traffic-related air pollution and otitis media.

Brauer M et al. Environ Health Perspect. 2006 Sep;114(9):1414-8. [free online]

http://www.ehponline.org/members/2006/9089/9089.html

BACKGROUND: Otitis media is one of the most common infections in young children.

Although exposure to environmental tobacco smoke is a known risk factor associated

with otitis media, little information is available regarding the potential

association with air pollution. OBJECTIVE: We set out to study the relationship

between exposure to traffic-related air pollution and otitis media in two birth

cohorts. METHODS: Individual estimates of outdoor concentrations of traffic-related

air pollutants-nitrogen dioxide, fine particles [particulate matter with aerodynamic

diameters </= 2.5 microm (PM2.5)], and elemental carbon-were calculated for home

addresses of approximately 3,700 and 650 infants from birth cohort studies in the

Netherlands and Germany, respectively. Air pollution exposure was analyzed in

relation to physician diagnosis of otitis media in the first 2 years of life.

RESULTS: Odds ratios (adjusted for known major risk factors) for otitis media

indicated positive associations with traffic-related air pollutants. An increase in

3 microg/m3 PM2.5, 0.5 microg/m3 elemental carbon, and 10 microg/m3 NO2 was

associated with odds ratios of 1.13 (95% confidence interval, 1.00-1.27) , 1.10

(1.00-1.22) , and 1.14 (1.03-1.27) in the Netherlands and 1.24 (0.84-1.83) , 1.10

(0.86-1.41) , and 1.14 (0.87-1.49) in Germany, respectively. CONCLUSIONS: These

findings indicate an association between exposure to traffic-related air pollutants

and the incidence of otitis media. Given the ubiquitous nature of air pollution

exposure and the importance of otitis media to children's health, these findings

have significant public health implications.

37. Association of early-onset otitis media in infants and exposure to household

mould.

Pettigrew MM et al. Paediatr Perinat Epidemiol. 2004 Nov;18(6):441-7.

Otitis media is one of the most common infections of early childhood. Children who

first experience acute otitis media at an early age (before 6 months) are at

increased risk for recurrent otitis media. This prospective study investigated

exposure to measured levels of airborne household mould and the risk of early otitis

media in the first 6 months of life among a cohort of infants at high risk for

asthma. Between September 1996 and December 1998, women were invited to participate

if they had at least one other child with physician-diagnosed asthma. Mothers were

given a standardised questionnaire within 4 months of their infant's birth. Airborne

mould samples were also taken at this time, and culturable fungi were categorised

into four levels according to the report of the Commission of European Communities:

0 (undetectable), 1-499 colony forming units (CFU)/m(3) (low), 500-999 CFU/m(3)

(medium), > or =1000 CFU/m(3) (high). Infant respiratory symptoms were collected

during quarterly telephone interviews at 6, 9 and 12 months of age. Of the 806

children in the study, 27.8% experienced otitis media before six months of age.

Household levels of Penicillium and Cladosporium were modestly associated with the

number of otitis media episodes (P = 0.056 and 0.081 respectively). After

controlling for potential confounders, Penicillium and Cladosporium were not

associated with early otitis media. High levels of 'other' mould (defined as total

spore count minus counts for Penicillium, Cladosporium, and yeast) were associated

with early otitis media (OR 3.49; 95% CI [1.38, 8.79]). We also found associations

between day-care outside of the home and birth during the summer or fall season with

early otitis media. This study is suggestive of a relationship between otitis media

and mould that warrants further study.

38. Acute otitis media in children: association with day care centers--antibacterial

resistance, treatment, and prevention.

Greenberg D et al. Paediatr Drugs. 2008;10(2):75-83.

Children attending day care centers (DCCs) frequently carry antibacterial-resistant

organisms in their nasopharynx, leading to acute otitis media (AOM) that may be

refractory to antibacterial treatment. The development and spread of resistant

organisms are facilitated in DCCs as a result of the following: (i) large numbers of

children; (ii) frequent close person-to-person contact; and (iii) a wide use of

antimicrobial medications. Intensive antimicrobial usage provides the selection

pressure that favors the emergence of resistant organisms, while DCCs provide an

ideal environment for transmission of these organisms...

39. Incidence of acute otitis media and sinusitis complicating upper respiratory

tract infection: the effect of age.

Revai K et al. Pediatrics. 2007 Jun;119(6):e1408-12. [free online]

http://pediatrics.aappublications.org/cgi/reprint/119/6/e1408

Infants and young children are prone to developing upper respiratory tract

infections, which often result in bacterial complications such as acute otitis media

and sinusitis. We evaluated 623 upper respiratory tract infection episodes in 112

children (6-35 months of age) to determine the proportion of upper respiratory tract

infection episodes that result in acute otitis media or sinusitis. Of all upper

respiratory tract infections, 30% were complicated by acute otitis media and 8% were

complicated by sinusitis. The rate of acute otitis media after upper respiratory

tract infection declined with increasing age, whereas the rate of sinusitis after

upper respiratory tract infection peaked in the second year of life. Risk for acute

otitis media may be reduced substantially by avoiding frequent exposure to

respiratory viruses (eg, avoidance of day care attendance) in the first year of

life.

40. Oxidative stress

http://en.wikipedia.org/wiki/Oxidative_stress

41. Metabolic biomarkers of increased oxidative stress and impaired methylation

capacity in children with autism.

James SJ et al. Am J Clin Nutr. 2004 Dec;80(6):1611-7. [free online]

http://www.ajcn.org/cgi/content/full/80/6/1611

BACKGROUND: Autism is a complex neurodevelopmental disorder that usually presents in

early childhood and that is thought to be influenced by genetic and environmental

factors. Although abnormal metabolism of methionine and homocysteine has been

associated with other neurologic diseases, these pathways have not been evaluated in

persons with autism. OBJECTIVE: The purpose of this study was to evaluate plasma

concentrations of metabolites in the methionine transmethylation and

transsulfuration pathways in children diagnosed with autism. DESIGN: Plasma

concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine

(SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced

glutathione were measured in 20 children with autism and in 33 control children. On

the basis of the abnormal metabolic profile, a targeted nutritional intervention

trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of

the autistic children. RESULTS: Relative to the control children, the children with

autism had significantly lower baseline plasma concentrations of methionine, SAM,

homocysteine, cystathionine, cysteine, and total glutathione and significantly

higher concentrations of SAH, adenosine, and oxidized glutathione. This metabolic

profile is consistent with impaired capacity for methylation (significantly lower

ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio

of reduced glutathione to oxidized glutathione) in children with autism. The

intervention trial was effective in normalizing the metabolic imbalance in the

autistic children. CONCLUSIONS: An increased vulnerability to oxidative stress and a

decreased capacity for methylation may contribute to the development and clinical

manifestation of autism.

42. Oxidative stress in autism.

McGinnis WR. Altern Ther Health Med. 2004 Nov-Dec;10(6):22-36.

STATEMENT OF PURPOSE: Indirect markers are consistent with greater oxidative stress

in autism. They include greater free-radical production, impaired energetics and

cholinergics, and higher excitotoxic markers. Brain and gut, both abnormal in

autism, are particularly sensitive to oxidative injury. Higher red-cell lipid

peroxides and urinary isoprostanes in autism signify greater oxidative damage to

biomolecules. A preliminary study found accelerated lipofuscin deposition--

consistent with oxidative injury to autistic brain in cortical areas serving

language and communication. Double-blind, placebo-controlled trials of potent

antioxidants--vitamin C or carnosine--significantly improved autistic behavior.

Benefits from these and other nutritional interventions may be due to reduction of

oxidative stress. Understanding the role of oxidative stress may help illuminate the

pathophysiology of autism, its environmental and genetic influences, new treatments,

and prevention. OBJECTIVES: Upon completion of this article, participants should be

able to: 1. Be aware of laboratory and clinical evidence of greater oxidative stress

in autism. 2. Understand how gut, brain, nutritional, and toxic status in autism are

consistent with greater oxidative stress. 3. Describe how anti-oxidant nutrients are

used in the contemporary treatment of autism.

43. Altered vascular phenotype in autism: correlation with oxidative stress.

Yao Y et al. Arch Neurol. 2006 Aug;63(8):1161-4. [free online]

http://archneur.ama-assn.org/cgi/content/full/63/8/1161

BACKGROUND: Autism is a neurologic disorder characterized by impaired communication

and social interaction. Results of previous studies showed biochemical evidence for

abnormal platelet reactivity and altered blood flow in children with autism.

OBJECTIVE: To evaluate the vascular phenotype in children with autism. DESIGN AND

MAIN OUTCOME MEASURES: Urinary levels of isoprostane F(2alpha)-VI, a marker of lipid

peroxidation; 2,3-dinor-thromboxane B(2), which reflects platelet activation; and 6-

keto-prostaglandin F(1alpha), a marker of endothelium activation, were measured by

means of gas chromatography-mass spectrometry in subjects with autism and healthy

control subjects. SETTING AND SUBJECTS: Children with a clinical diagnosis of autism

attending the Pfeiffer Treatment Center. RESULTS: Compared with controls, children

with autism had significantly higher urinary levels of isoprostane F(2alpha)-VI,

2,3-dinor-thromboxane B(2), and 6-keto-prostaglandin F(1alpha). Lipid peroxidation

levels directly correlated with both vascular biomarker ratios. CONCLUSION: Besides

enhanced oxidative stress, platelet and vascular endothelium activation also could

contribute to the development and clinical manifestations of autism.

44. Metabolic endophenotype and related genotypes are associated with oxidative

stress in children with autism.

James SJ et al. Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.

[free online]

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2610366&blobtype=pdf

Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in

early childhood that is characterized by impairment in reciprocal communication and

speech, repetitive behaviors, and social withdrawal. Although both genetic and

environmental factors are thought to be involved, none have been reproducibly

identified. The metabolic phenotype of an individual reflects the influence of

endogenous and exogenous factors on genotype. As such, it provides a window through

which the interactive impact of genes and environment may be viewed and relevant

susceptibility factors identified. Although abnormal methionine metabolism has been

associated with other neurologic disorders, these pathways and related polymorphisms

have not been evaluated in autistic children. Plasma levels of metabolites in

methionine transmethylation and transsulfuration pathways were measured in 80

autistic and 73 control children. In addition, common polymorphic variants known to

modulate these metabolic pathways were evaluated in 360 autistic children and 205

controls. The metabolic results indicated that plasma methionine and the ratio of S-

adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of

methylation capacity, were significantly decreased in the autistic children relative

to age-matched controls. In addition, plasma levels of cysteine, glutathione, and

the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity

and redox homeostasis, were significantly decreased. Differences in allele frequency

and/or significant gene-gene interactions were found for relevant genes encoding the

reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-

methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C >

T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an

increased vulnerability to oxidative stress (endogenous or environmental) may

contribute to the development and clinical manifestations of autism. (c) 2006 Wiley-

Liss, Inc.

45. Lipid profile, fatty acid composition and pro- and anti-oxidant status in

pediatric patients with attention-deficit/hyperactivity disorder.

Spahis S et al. Prostaglandins Leukot Essent Fatty Acids. 2008 Jul-Aug;79(1-2):47-

53.

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent behavioral

disorder in children and the pathophysiology remains obscure. In addition to the

pharmacotherapy, which is the primary treatment of ADHD, nutritional intervention

may have a significant impact on ADHD symptoms. We studied lipid and lipoprotein

profiles, fatty acid (FA) composition, and oxidant-antioxidant status in 37

pediatric ADHD patients and 35 healthy control subjects. Our results show that

plasma triacylglycerols and phospholipids were lower, whereas free cholesterol, HDL,

and apolipoprotein A-I were higher in ADHD patients compared with controls. The

proportion of plasma EPA and DHA was higher, but that of oleic and alpha-linolenic

(ALA) acids was lower. As expected from these findings, the proportions of both

total saturates and polyunsaturates fatty acids (PUFA) were higher and lower,

respectively, in ADHD patients than in controls, which led to a significant decrease

in the PUFAs/saturates ratio. On the other hand, the ratios of eicosatrienoic acid

to arachidonic acid and of palmitoleic acid to linoleic acid, established indexes of

essential fatty acid (EFA) status remained unchanged revealing that EFA did not

affect ADHD patients. Similarly, the activity of delta-6 desaturase, estimated by

the ratio of 18:2(n-6)/20:4(n-6), was found unaffected, whereas ALA/EPA was

diminished. Lessened lipid peroxidation was noted in ADHD subjects as documented by

the diminished values of plasma malondialdehyde accompanied by increased

concentrations of gamma-tocopherol. In conclusions, significant changes occur in the

lipid and lipoprotein profiles, as well as in the oxidant-antioxidant status of ADHD

patients, however, the FA distribution does not reflect n-3 FA deficiency.

46. Malondialdehyde levels in adult attention-deficit hyperactivity disorder.

Bulut M et al. J Psychiatry Neurosci. 2007 Nov;32(6):435-8.[free online]

http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-32/issue-

6/pdf/pg435.pdf

OBJECTIVE: To evaluate the biochemical basis of adult attention-deficit

hyperactivity disorder (A-ADHD), we compared lipid peroxidation status in the plasma

of A-ADHD patients, and that of control subjects without A-ADHD by quantifying the

levels of malondialdehyde (MDA), an end product of fatty acid oxidation. We aimed to

examine the association between MDA and A-ADHD. METHOD: The study comprised 20 A-

ADHD patients from Gaziantep University Sahinbey Research Hospital Psychiatry

Clinic, diagnosed by 2 psychiatrists (H.A.S. and S.S.) according to the Turkish

version of the adult ADD/ADHD DSM-IV-Based Diagnostic Screening and Rating Scale,

and 21 healthy volunteers. Malondialdehyde levels were measured in plasma samples of

both study groups. RESULTS: The mean (standard deviation [SD]) MDA levels in

patients (2.44 [0.84] nmol/mL) were significantly higher than those of control

subjects (0.36 [0.20] nmol/mL) (t=11.013, df=39, p<0.01). MDA levels were correlated

with overall number of criteria met (n=20, p=0.01, Ro=0.56) and total

hyperactivity/impulsivity score (n=20, p=0.02, Ro=0.51). CONCLUSION: The fact that

MDA levels were increased in A-ADHD could be an indication of increased oxidative

stress in this disease. We suggest that such changes may have a pathological role in

A-ADHD. This is the first study evaluating the MDA levels in A-ADHD, and our

findings may provide a scientific guide for the further clinical enzymologic and

biochemical studies on this disorder.

47. Oxidative imbalance in adult attention deficit/hyperactivity disorder.

Selek S et al. Biol Psychol. 2008 Oct;79(2):256-9. Epub 2008 Jul 3.

OBJECTIVE: There are few studies evaluating the biochemical basis of adult attention

deficit/hyperactivity disorder (A-ADHD). In the present study, we evaluated whether

nitric oxide (NO), an oxidant, level and superoxide dismutase (SOD), an antioxidant,

activity are associated with A-ADHD or not. METHODS: Twenty A-ADHD patients from

Gaziantep University Sahinbey Research Hospital, Psychiatry Clinic, diagnosed

according to The Turkish version of Adult ADD/ADHD DSM IV-Based Diagnostic Screening

and Rating Scale by two psychiatrists (H.A.S. and S.S.), and twenty-one healthy

volunteer controls were included. Blood samples were collected; NO levels and SOD

activities were measured. RESULTS: The mean NO levels in patients were significantly

higher than those of controls and SOD activity of patients was significantly lower

than controls. CONCLUSIONS: Remarkable high levels of oxidant NO, and low SOD

activities suggest an oxidative imbalance in A-ADHD. This is the first study

evaluating the oxidative metabolism in A-ADHD.

48. Pseudomonas aeruginosa: resistance and therapy.

Cunha BA. Semin Respir Infect. 2002 Sep;17(3):231-9.

Pseudomonas aeruginosa resistance to antimicrobials is an important therapeutic

consideration. Antibiotic resistance to P. aeruginosa may be chromosomally or

plasmid mediated. Resistance to P. aeruginosa may also be affected by changes in the

cellular membrane or intracellular environment. P. aeruginosa is primarily a

nosocomial organism that most commonly colonizes respiratory secretions and urine.

The selection of an antipseudomonal antibiotic depends on its inherent in vitro

activity and its resistance potential. Anti-P. aeruginosa antibiotics with a high-

resistance potential include gentamicin, tobramycin, ciprofloxacin, ceftazidime, and

imipenem. Anti-P. aeruginosa antibiotics with a low-resistance potential include

amikacin, piperacillin, cefoperazone, cefepime, meropenem, and polymyxin B.

49. Detection of fungal DNA in effusion associated with acute and serous otitis

media.

Kim EJ et al. Laryngoscope. 2002 Nov;112(11):2037-41.

OBJECTIVES/HYPOTHESIS: Routine bacterial and viral cultures of middle ear fluid are

often negative, suggesting that other infectious agents may be involved. Because of

the similarities between the paranasal sinuses and middle ear space and the recent

recognition of fungi as important pathogens in inflammation of the paranasal

sinuses, we investigated the potential role of fungi in acute otitis media and

serous otitis media using culture and polymerase chain reaction techniques. STUDY

DESIGN: Prospective study. METHODS: Middle ear effusions of 29 patients who

underwent myringotomy and pressure equalization tube placement for persistent serous

otitis media or recurrent acute otitis media were collected. Fungal culture of the

effusion samples was performed on potato flake agar. DNA from the effusion was

isolated using standard techniques. Polymerase chain reaction, using radiolabeled

universal fungus primer for internal transcribed spacer of 5.8s ribosomal DNA, was

performed to detect the presence of any fungal DNA in the samples. RESULTS: Culture

of middle ear effusions showed no evidence of fungal growth. Polymerase chain

reaction analysis was able to detect the constituent ribosomal DNA of a single

fungal genome. Fungal DNA was present in 34% of middle ear effusion samples.

CONCLUSIONS: Fungal DNA is present in recurrent acute otitis media and serous otitis

media suggesting that it may play an etiological role in serous otitis media and

acute otitis media. However, additional studies are necessary to delineate the role

of fungi in the pathogenesis of otitis media.

50. Microbiologic characteristics of persistent otitis media.

Brook I, Gober AE. Arch Otolaryngol Head Neck Surg. 1998 Dec;124(12):1350-2. [free

online]

http://archotol.ama-assn.org/cgi/content/full/124/12/1350

OBJECTIVE: To identify the pathogens isolated from children with acute otitis media

who did not respond to antimicrobial drug therapy. METHODS: Retrospective analysis

of cultures obtained by tympanocentesis from 46 children. RESULTS: Organisms were

recovered from 34 children (74%), and 43 isolates were recovered from these

individuals. The organisms were Streptococcus pneumoniae (16 isolates), Haemophilus

influenzae non-type b (12 isolates), Moraxella catarrhalis (5 isolates),

Streptococcus pyogenes (5 isolates), Staphylococcus aureus (3 isolates), and

Peptostreptococcus species (2 isolates). Resistance to the antimicrobial agent used

was found in 27 (63%) of 43 isolates found in 22 patients (48%). Of patients who did

not respond to amoxicillin therapy, H influenzae predominated. Streptococcus

pneumoniae was recovered from 5 (56%) of 9 of those who did not respond to

trimethoprim and sulfamethoxazole therapy, 4 (44%) of 9 patients after azithromycin

therapy, 3 (25%) of 12 patients after amoxicillin therapy, and 2 (40%) of 5 patients

after cefixime therapy. Streptococcus pyogenes was recovered from 2 (40%) of 5

patients after trimethoprim and sulfamethoxazole therapy and from 2 (40%) of 5

patients after cefixime therapy. CONCLUSIONS: The data illustrate the relation

between resistance to antimicrobial drug therapy and failure of patients with otitis

media to improve. They also highlight the importance of diagnostic tympanocentesis

in establishing the presence of resistant microorganisms.

51. Community factors in the development of antibiotic resistance.

Larson E. Annu Rev Public Health. 2007;28:435-47.

The global impact of antibiotic resistance is potentially devastating, threatening

to set back progress against certain infectious diseases to the pre-antibiotic era.

Although most antibiotic-resistant bacteria originally emerged in hospitals, drug-

resistant strains are becoming more common in the community. Factors that facilitate

the development of resistance within the community can be categorized as behavioral

or environmental/policy. Behavioral factors include inappropriate use of antibiotics

and ineffective infection control and hygiene practices. Environmental/policy

factors include the continued use of antibiotics in agriculture and the lack of new

drug development. A multifaceted approach that includes behavioral strategies in the

community and the political will to make difficult regulatory decisions will help to

minimize the problem of antimicrobial resistance globally.

52. Experimental study of the effect of Astragalus membranaceus against herpes

simplex virus type 1

Sun Y, Yang J. [Article in Chinese]

Di Yi Jun Yi Da Xue Xue Bao. 2004 Jan;24(1):57-8.

OBJECTIVE: To study the inhibitory effects of Astragalus membranaceus on herpes

simplex virus type 1(HSV-1). METHODS: In the 2BS cells infected with HSV-1, the

antiviral effect of Astragalus membranaceus decoction was investigated by observing

the inhibition of HSV-1-induced cytopathic effect in response to treatment with the

decoction. RESULTS: The half inhibition concentration (IC50) and minimal inhibition

concentration (MIC) of Astragalus membranaceus were 0.98 and 1.95 g/ml respectively,

with the therapeutic index (TI) of 128. CONCLUSION: Astragalus membranaceus has

obvious HSV-1-inhibiting efficacy and low cytotoxicity.

53. Macrophage activation by polysaccharide isolated from Astragalus membranaceus.

Lee KY, Jeon YJ. Int Immunopharmacol. 2005 Jul;5(7-8):1225-33.

We show that APS, a polysaccharide isolated from the roots of Astragalus

membranaceus, significantly induces nitric oxide (NO) production and inducible NO

synthase (iNOS) transcription through the activation of nuclear factor-kappaB/Rel

(NF-kappaB/Rel). In vivo administration of APS induced NO production by peritoneal

macrophages of B6C3F1 mice. APS also dose-dependently induced the production of NO

in isolated mouse peritoneal macrophages and RAW 264.7, a mouse macrophage-like cell

line. Moreover, iNOS protein and mRNA transcription were strongly induced by APS in

RAW 264.7 cells. To further investigate the mechanism responsible for the induction

of iNOS gene expression, we investigated the effect of APS on the activation of

transcription factors including NF-kappaB/Rel and Oct, whose binding sites were

located in the promoter of iNOS gene. Treatment of RAW 264.7 cells with APS produced

strong induction of NF-kappaB/Rel-dependent reporter gene expression, whereas Oct-

dependent gene expression was not affected by APS. Nuclear translocation and DNA

binding activity of NF-kappaB/Rel was significantly induced by APS. The treatment

with NF-kappaB SN50, an inhibitor of NF-kappaB/Rel nuclear translocation,

effectively inhibited the activation of NF-kappaB/Rel binding complexes and NO

production. In conclusion, we demonstrate that APS stimulates macrophages to express

iNOS gene through the activation of NF-kappaB/Rel.

54. Effects of triterpene saponins from Astragalus species on in vitro cytokine

release.

Yesilada E et al. J Ethnopharmacol. 2005 Jan 4;96(1-2):71-7.

Roots of Astragalus species are used to treat leukemia and for wound healing in

Turkish folk medicine. In order to evaluate this information, the effect of 13

cycloartane- and 1 oleanan-type triterpene saponins isolated from Turkish species

(Astragalus brachypterus, Astragalus cephalotes, Astragalus microcephalus, and

Astragalus trojanus), as well as methanol extracts from the roots of three

Astragalus species (Astragalus cephalotes, Astragalus oleifolius and Astragalus

trojanus) were studied. Cytokine concentrations of interleukins IL-1beta, IL-8 and

TNF-alpha after bacterial lipopolysaccharide (LPS) and IL-2, IL-4 and INF-gamma

after phorbolacetate (PHA) stimulation were determined using commercial enzyme-

linked immunosorbent assay (ELISA) kits. All triterpene saponins tested in the

present study showed a prominent IL-2 inducing activity between 35.9% and 139.6%.

Among the extracts the highest score was obtained for Astragalus oleifolius

(141.2%). Glycosides of 20,24-epoxy and 20,25-epoxy cycloartanes showed higher IL-2

inducing activity than those of acyclic-cycloartane derivatives as well as aglycone

of 20,24-epoxy cycloartanes, cycloastrogenol. Especially the activity of

Astragaloside VII, a tridesmosidic glycoside of cycloastrogenol, was the most

remarkable. The oleanan-type triterpene saponin also showed a prominent IL-2

inducing activity. IL-2 is a cytokine produced by activated T cells, which has shown

powerful immunostimulatory and antineoplastic properties. Accordingly, the IL-2

inducing activity of the triterpene saponins might be the mechanism involved in

order to explain the immunomodulatory and anticancer effects of Astragalus species.

55. Antimicrobial activity of Uncaria tomentosa against oral human pathogens.

Ccahuana-Vasquez RA et al. Braz Oral Res. 2007 Jan-Mar;21(1):46-50. [free online]

http://tinyurl.com/dz2h9e

Uncaria tomentosa is considered a medicinal plant used over centuries by the

peruvian population as an alternative treatment for several diseases. Many

microorganisms usually inhabit the human oral cavity and under certain conditions

can become etiologic agents of diseases. The aim of the present study was to

evaluate the antimicrobial activity of different concentrations of Uncaria tomentosa

on different strains of microorganisms isolated from the human oral cavity.

Micropulverized Uncaria tomentosa was tested in vitro to determine the minimum

inhibitory concentration (MIC) on selected microbial strains. The tested strains

were oral clinical isolates of Streptococcus mutans, Staphylococcus spp., Candida

albicans, Enterobacteriaceae and Pseudomonas aeruginosa. The tested concentrations

of Uncaria tomentosa ranged from 0.25-5% in Müeller-Hinton agar. Three percent

Uncaria tomentosa inhibited 8% of Enterobacteriaceae isolates, 52% of S. mutans and

96% of Staphylococcus spp. The tested concentrations did not present inhibitory

effect on P. aeruginosa and C. albicans. It could be concluded that micropulverized

Uncaria tomentosa presented antimicrobial activity on Enterobacteriaceae, S. mutans

and Staphylococcus spp. isolates.

56. Ethnobotany, phytochemistry and pharmacology of Uncaria (Rubiaceae).

Heitzman ME et al. Phytochemistry. 2005 Jan;66(1):5-29

The Uncaria genus is an important source of medicinal natural products, particularly

alkaloids and triterpenes. The collected information is an attempt to cover the more

recent developments in the ethnobotany, pharmacology and phytochemistry of this

genus. During the past 20 years, alkaloids, terpenes, quinovic acid glycosides,

flavonoids and coumarins have been isolated from Uncaria. Fifty-three novel

structures are reported in this review. The species in which the largest number of

compounds has been identified is the Peruvian Uncaria tomentosa or 'cat's claw.'

Pharmacological studies are described according to cytotoxicity, anti-inflammatory,

antiviral, immunostimulation, antioxidant, CNS-related response, vascular,

hypotensive, mutagenicity and antibacterial properties. The potential for

development of leads from Uncaria continues to grow, particularly in the area of

immunomodulatory, anti-inflammatory and vascular-related conditions. The information

summarized here is intended to serve as a reference tool to practitioners in the

fields of ethnopharmacology and natural products chemistry.

57. Anti-inflammatory activity of two different extracts of Uncaria tomentosa

(Rubiaceae).

Aguilar JL et al. J Ethnopharmacol. 2002 Jul;81(2):271-6.

We assessed in vivo the anti-inflammatory activity of two Cat's claw bark extracts,

by comparing a spray-dried hydroalcoholic extract against an aqueous freeze-dried

extract, to determine which extract was more effective. We used the carrageenan-

induced paw edema model in mice. In addition, to assess the molecular mechanism of

action, we determined the inhibition of NF-kappa B through the Electrophoretic

Mobility Shift Assay (EMSA) and the effects on cycloxygenase-1 and -2. Results

showed that the anti-inflammatory activity was significantly higher using the

hydroalcoholic compared with the aqueous extract (P<0.05). The extracts also showed

little inhibitory activity on cyclooxygenase-1 and -2. It cannot be excluded that

the slight inhibitory activity on DNA binding of NF-kappa B is due to cytotoxic

effects.

58. Inhibitory effect of cinnamaldehyde, derived from Cinnamomi cortex, on the

growth of influenza A/PR/8 virus in vitro and in vivo.

Hayashi K et al. Antiviral Res. 2007 Apr;74(1):1-8.

We have investigated the inhibitory effect of trans-cinnamaldehyde (CA), one of the

principal constituents of essential oil derived from Cinnamomi cortex, on the growth

of influenza A/PR/8 virus in vitro and in vivo. When 1-h drug treatment was

initiated at various times post-infection (p.i.) in Madin-Darby canine kidney cells

using a fixed dose of CA (40 microM), the maximum inhibitory effect (29.7% virus

yield of control) was obtained when drug treatment was started at 3h p.i. Under the

same treatment schedule, CA inhibited the virus growth in a dose-dependent manner

(20-200 microM), and, at 200 microM, the virus yield was reduced to an undetectable

level. RT-PCR and SDS-PAGE analyses showed that CA inhibited viral protein synthesis

at the post-transcriptional level. In mice infected with the lung-adapted PR-8

virus, inhalation (50mg/cage/day) and nasal inoculation (250 microg/mouse/day) of CA

significantly increased survival rates on the 8 days to 100% and 70%, respectively,

in contrast to a survival rate of 20% in the untreated control group. Importantly,

inhalation of CA caused virus yield reduction by 1 log in bronchoalveolar lavage

fluid on day 6 after infection, compared with that of the untreated control group.

These findings might provide further support to the empirical indication of

Cinnamomi cortex-containing Kampo medicines for acute respiratory infectious

diseases.

59. Antimicrobial activities of cinnamon oil and cinnamaldehyde from the Chinese

medicinal herb Cinnamomum cassia Blume.

Ooi LS et al. Am J Chin Med. 2006;34(3):511-22.

Both Cinnamomum verum J.S. Presl. and Cinnamomum cassia Blume are collectively

called Cortex Cinnamonmi for their medicinal cinnamon bark. Cinnamomum verum is more

popular elsewhere in the world, whereas C. cassia is a well known traditional

Chinese medicine. An analysis of hydro-distilled Chinese cinnamon oil and pure

cinnamaldehyde by gas chromatography/mass spectrometry revealed that cinnamaldehyde

is the major component comprising 85% in the essential oil and the purity of

cinnamaldehyde in use is high (>98%). Both oil and pure cinnamaldehyde of C. cassia

were equally effective in inhibiting the growth of various isolates of bacteria

including Gram-positive (1 isolate, Staphylococcus aureus), and Gram-negative (7

isolates, E. coli, Enterobacter aerogenes, Proteus vulgaris, Pseudomonas aeruginosa,

Vibrio cholerae, Vibrio parahaemolyticus and Samonella typhymurium), and fungi

including yeasts (four species of Candida, C. albicans, C. tropicalis, C. glabrata,

and C. krusei), filamentous molds (4 isolates, three Aspergillus spp. and one

Fusarium sp.) and dermatophytes (three isolates, Microsporum gypseum, Trichophyton

rubrum and T. mentagraphytes). Their minimum inhibition concentrations (MIC) as

determined by agar dilution method varied only slightly. The MICs of both oil and

cinnamaldehyde for bacteria ranged from 75 microg/ml to 600 microg/ml, for yeasts

from 100 microg/ml to 450 microg/ml, for filamentous fungi from 75 microg/ml to 150

microg/ml, and for dermatophytes from 18.8 microg/ml to 37.5 microg/ml. The

antimicrobial effectiveness of C. cassia oil and its major constituent is comparable

and almost equivalent, which suggests that the broad-spectrum antibiotic activities

of C. cassia oil are due to cinnamaldehyde. The relationship between structure and

function of the main components of cinnamon oil is also discussed.

60. Antibacterial activity of leaf essential oils and their constituents from

Cinnamomum osmophloeum.

Chang ST, Chen PF, Chang SC. J Ethnopharmacol. 2001 Sep;77(1):123-7.

The antibacterial activities of the essential oils from leaves of two Cinnamomum

osmophloeum clones (A and B) and their chemical constituents were investigated in

this study. The nine strains of bacteria, including Escherichia coli, Pseudomonas

aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Staphylococcus

epidermidis, methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella

pneumoniae, Salmonella sp., and Vibrio parahemolyticus, were used in the

antibacterial tests. Results from the antibacterial tests demonstrated that the

indigenous cinnamon B leaf essential oils had an excellent inhibitory effect. The

MICs (minimum inhibitory concentrations) of the B leaf oil were 500 microg/ml

against both K. pneumoniae and Salmonella sp. and 250 microg/ml against the other

seven strains of bacteria. Cinnamaldehyde possessed the strongest antibacterial

activity compared to the other constituents of the essential oils. The MICs of

cinnamaldehyde against the E. coli, P. aeruginosa, E. faecalis, S. aureus, S.

epidermidis, MRSA, K. pneumoniae, Salmonella sp., and V. parahemolyticus were 500,

1000, 250, 250, 250, 250, 1000, 500, and 250 microg/ml, respectively. These results

suggest that C. osmophloeum leaf essential oil and cinnamaldehyde are beneficial to

human health, having the potential to be used for medical purposes and to be

utilized as anti-bacterial additives in making paper products.

61. Antimicrobial effect and resistant regulation of Glycyrrhiza uralensis on

methicillin-resistant Staphylococcus aureus.

Lee JW et al. Nat Prod Res. 2009;23(2):101-11.

In the present study, we investigated antimicrobial activity of Glycyrrhiza

uralensis against various strains of methicillin-resistant Staphylococcus aureus

(MRSA) (KCCM 11812, 40510, 40512). Glycyrrhiza uralensis was extracted by 80% MeOH

and fractionated by organic solutions. The extract and fractions showed

antimicrobial activity against standard S. aureus as well as MRSA. In the minimum

inhibitory concentration test, G. uralensis showed 0.25 mg mL(-1) in hexane fraction

and 0.10-0.12 mg mL(-1) in chloroform fraction. Especially, chloroform fraction

showed 2.5 times higher antimicrobial activity than penicillin. Furthermore,

chloroform fraction correlated with MRSA gene expression (MecA, MecI, MecRI, FemA).

These results suggest that G. uralensis may have potent antimicrobial activity and

thus, this medicinal herb can be a suitable phytotherapeutic agent for treating MRSA

infections.

62. Antifungal activity of Glycyrrhiza glabra extracts and its active constituent

glabridin.

Fatima A et al. Phytother Res. 2009 Jan 23. [Epub ahead of print]

Glabridin, an active constituent of Glycyrrhiza glabra roots, was found to be active

against both yeast and filamentous fungi. Glabridin also showed resistance modifying

activity against drug resistant mutants of Candida albicans at a minimum inhibitory

concentration of 31.25-250 microg/mL. Although the compound was reported earlier to

be active against Candida albicans, but this is the first report of its activity

against drug resistant mutants.

63. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive

compounds.

Asl MN, Hosseinzadeh H. Phytother Res. 2008 Jun;22(6):709-24.

The roots and rhizomes of licorice (Glycyrrhiza) species have long been used

worldwide as a herbal medicine and natural sweetener. Licorice root is a traditional

medicine used mainly for the treatment of peptic ulcer, hepatitis C, and pulmonary

and skin diseases, although clinical and experimental studies suggest that it has

several other useful pharmacological properties such as antiinflammatory, antiviral,

antimicrobial, antioxidative, anticancer activities, immunomodulatory,

hepatoprotective and cardioprotective effects. A large number of components have

been isolated from licorice, including triterpene saponins, flavonoids,

isoflavonoids and chalcones, with glycyrrhizic acid normally being considered to be

the main biologically active component. This review summarizes the phytochemical,

pharmacological and pharmacokinetics data, together with the clinical and adverse

effects of licorice and its bioactive components.

64. Antiviral effects of Glycyrrhiza species.

Fiore C et al. Phytother Res. 2008 Feb;22(2):141-8.

Historical sources for the use of Glycyrrhiza species include ancient manuscripts

from China, India and Greece. They all mention its use for symptoms of viral

respiratory tract infections and hepatitis. Randomized controlled trials confirmed

that the Glycyrrhiza glabra derived compound glycyrrhizin and its derivatives

reduced hepatocellular damage in chronic hepatitis B and C. In hepatitis C virus-

induced cirrhosis the risk of hepatocellular carcinoma was reduced. Animal studies

demonstrated a reduction of mortality and viral activity in herpes simplex virus

encephalitis and influenza A virus pneumonia. In vitro studies revealed antiviral

activity against HIV-1, SARS related coronavirus, respiratory syncytial virus,

arboviruses, vaccinia virus and vesicular stomatitis virus. Mechanisms for antiviral

activity of Glycyrrhiza spp. include reduced transport to the membrane and

sialylation of hepatitis B virus surface antigen, reduction of membrane fluidity

leading to inhibition of fusion of the viral membrane of HIV-1 with the cell,

induction of interferon gamma in T-cells, inhibition of phosphorylating enzymes in

vesicular stomatitis virus infection and reduction of viral latency. Future research

needs to explore the potency of compounds derived from licorice in prevention and

treatment of influenza A virus pneumonia and as an adjuvant treatment in patients

infected with HIV resistant to antiretroviral drugs.

65. Antimicrobial activity of commercial Olea europaea (olive) leaf extract.

Sudjana AN et al. Int J Antimicrob Agents. 2009 May;33(5):461-3.

The aim of this research was to investigate the activity of a commercial extract

derived from the leaves of Olea europaea (olive) against a wide range of

microorganisms (n=122). Using agar dilution and broth microdilution techniques,

olive leaf extract was found to be most active against Campylobacter jejuni,

Helicobacter pylori and Staphylococcus aureus [including meticillin-resistant S.

aureus (MRSA)], with minimum inhibitory concentrations (MICs) as low as 0.31-0.78%

(v/v). In contrast, the extract showed little activity against all other test

organisms (n=79), with MICs for most ranging from 6.25% to 50% (v/v). In conclusion,

olive leaf extract was not broad-spectrum in action, showing appreciable activity

only against H. pylori, C. jejuni, S. aureus and MRSA. Given this specific activity,

olive leaf extract may have a role in regulating the composition of the gastric

flora by selectively reducing levels of H. pylori and C. jejuni.

66. In vitro antimicrobial activity of olive leaves.

Markin D et al. Mycoses. 2003 Apr;46(3-4):132-6.

We investigated the antimicrobial effect of olive leaves against bacteria and fungi.

The microorganisms tested were inoculated in various concentrations of olive leaf

water extract. Olive leaf 0.6% (w/v) water extract killed almost all bacteria

tested, within 3 h. Dermatophytes were inhibited by 1.25% (w/v) plant extract

following a 3-day exposure whereas Candida albicans was killed following a 24 h

incubation in the presence of 15% (w/v) plant extract. Olive leaf extract fractions,

obtained by dialysis, that showed antimicrobial activity consisted of particles

smaller than 1000 molecular rate cutoffs. Scanning electron microscopic observations

of C. albicans, exposed to 40% (w/v) olive leaf extract, showed invaginated and

amorphous cells. Escherichia coli cells, subjected to a similar treatment but

exposed to only 0.6% (w/v) olive leaf extract showed complete destruction. These

findings suggest an antimicrobial potential for olive leaves.

67. Emergence of ciprofloxacin-resistant pseudomonas in pediatric otitis media.

Jang CH, Park SY. Int J Pediatr Otorhinolaryngol. 2003 Apr;67(4):313-6.

OBJECTIVE: The widespread use of fluoroquinolone otic drops has resulted in the

emergence and subsequent increase of fluoroquinolone resistance, at rates greater

than anticipated. To evaluate the patients with recurrent otorrhea that were

unresponsive to topical ciprofloxacin. METHODS: Seventeen pediatric patients who

were treated with refractory otorrhea between 2000 and 2001 were reviewed

retrospectively. RESULTS: All patients had ciprofloxacin-resistant pseudomonas on

culture and sensitivity test. Ciprofloxacin-resistant pseudomonas from these

patients were multidrug resistant. Imipenem was the most sensitive antibiotic agent,

followed by amikacin. Most patients were treated with intramuscular amikacin and two

patients were treated with intravenous imipenem. CONCLUSION: In our series,

resistance to cirpfloxacin in patients with otitis media is increasing recently.

Culture and antibiotic sensitivity test may help guide management. Continuous

surveillance is necessary to monitor antibiotic resistance and to guide

antibacterial therapy.

68. Investigation of functional and morphological changes in Pseudomonas aeruginosa

and Staphylococcus aureus cells induced by Origanum compactum essential oil.

Bouhdid S et al. J Appl Microbiol. 2009 Feb 16. [Epub ahead of print]

Abstract Aims: Evaluation of the cellular effects of Origanum compactum essential

oil on Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213.

Methods and Results: The damage induced by O. compactum essential oil on these two

strains has been studied using different techniques: plate count, potassium leakage,

flow cytometry (FC) and transmission electron microscopy (TEM). The results showed

that oil treatment led to reduction of cells viability and dissipated potassium ion

gradients. Flow cytometric analysis showed that oil treatment promoted the

accumulation of bis-oxonol and the membrane-impermeable nucleic acid stain propidium

iodide (PI), indicating the loss of membrane potential and permeability. The ability

to reduce 5-cyano-2,3-ditolyl tetrazolium chloride was inhibited. Unlike in Ps.

aeruginosa, membrane potential and membrane permeability in Staph. aureus cells were

affected by oil concentration and contact time. Finally, TEM showed various

structural effects. Mesosome-like structures were seen in oil-treated Staph. aureus

cells whereas in Ps. aeruginosa, coagulated cytoplasmic material and liberation of

membrane vesicles were observed, and intracellular material was seen in the

surrounding environment. Both FC and TEM revealed that the effects in Ps. aeruginosa

were greater than in Staph. aureus. Conclusions: Oregano essential oil induces

membrane damage showed by the leakage of potassium and uptake of PI and bis-oxonol.

Ultrastructural alterations and the loss of cell viability were observed.

Significance and Impact of the Study: Understanding the mode of antibacterial effect

of the oil studied is of a great interest in it further application as natural

preservative in food or pharmaceutical industries.

69. Effects of oregano, carvacrol and thymol on Staphylococcus aureus and

Staphylococcus epidermidis biofilms.

Nostro A et al. J Med Microbiol. 2007 Apr;56(Pt 4):519-23.

http://jmm.sgmjournals.org/cgi/content/full/56/4/519

The aim of this study was to evaluate the effect of oregano essential oil, carvacrol

and thymol on biofilm-grown Staphylococcus aureus and Staphylococcus epidermidis

strains, as well as the effects of the oils on biofilm formation. For most of the S.

aureus (n=6) and S. epidermidis (n=6) strains tested, the biofilm inhibitory

concentration (0.125-0.500 %, v/v, for oregano, and 0.031-0.125 %, v/v, for

carvacrol and thymol) and biofilm eradication concentration (0.25-1.0 %, v/v, for

oregano and 0.125-0.500 %, v/v, for carvacrol and thymol) values were twofold or

fourfold greater than the concentration required to inhibit planktonic growth.

Subinhibitory concentrations of the oils attenuated biofilm formation of S. aureus

and S. epidermidis strains on polystyrene microtitre plates.

70. Inhibition of Helicobacter pylori and associated urease by oregano and cranberry

phytochemical synergies.

Lin YT et al. Appl Environ Microbiol. 2005 Dec;71(12):8558-64. [free online]

http://aem.asm.org/cgi/content/full/71/12/8558?view=long&pmid=16332847

Ulcer-associated dyspepsia is caused by infection with Helicobacter pylori. H.

pylori is linked to a majority of peptic ulcers. Antibiotic treatment does not

always inhibit or kill H. pylori with potential for antibiotic resistance. The

objective of this study was to determine the potential for using phenolic

phytochemical extracts to inhibit H. pylori in a laboratory medium. Our approach

involved the development of a specific phenolic profile with optimization of

different ratios of extract mixtures from oregano and cranberry. Subsequently,

antimicrobial activity and antimicrobial-linked urease inhibition ability were

evaluated. The results indicated that the antimicrobial activity was greater in

extract mixtures than in individual extracts of each species. The results also

indicate that the synergistic contribution of oregano and cranberry phenolics may be

more important for inhibition than any species-specific phenolic concentration.

Further, based on plate assay, the likely mode of action may be through urease

inhibition and disruption of energy production by inhibition of proline

dehydrogenase at the plasma membrane.

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