INFECTIOUS DISEASE UPDATE
From the 49th Annual Pediatrics Symposium, presented October 12-13, 2007, by Kaiser Permanente
Michael E. Pichichero, MD, Professor of Microbiology and Immunology, Pediatrics, and Medicine, University of
Rochester School of Medicine and Dentistry, Rochester, NY
| IMPROVING OUTCOMES IN ACUTE OTITIS MEDIA (AOM)
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| American Academy of Pediatrics (AAP) Red Book guidelines for managing AOM, 2006: criteria for
initial treatment—older the child, the more likely AOM is to improve spontaneously (consider observation); recommended
antibacterial agents—high-dose amoxicillin; high-dose amoxicillin–potassium clavulanate (Augmentin);
cefdinir (Omnicef); cefpodoxime (Vantin); cefuroxime (eg, Ceftin); ceftriaxone (Rocephin); treatment
recommendations—high-dose amoxicillin still treatment of choice for initial empiric therapy, but some data question
that selection (eg, speaker does not use); standard duration 10 days (for children [>2 yr of age], 5 days)
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| Changes in pathogens causing AOM, 1995-2003 (Casey and Pichichero, 2004): among pathogens causing
AOM, percentage of Streptococcus pneumoniae decreased and percentage of Haemophilus influenzae increased, due
to use of high-dose amoxicillin and pneumococcal 7-valent conjugate vaccine (PCV; Prevnar); most common strain
may be β-lactamase–producing H influenzae
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| Emergence of multiresistant S pneumoniae causing AOM in children (Pichichero and Casey, 2007):
since 2003, increasing frequency of non-PCV serotypes as otopathogens, especially serotypes 19A, 6A, 3, and 15
(80% of non-PCV serotypes penicillin-resistant); in 9 children, 19A strain resistant to all Food and Drug Administration
(FDA)-approved antibiotics for treatment of pediatric ear infections; strain susceptible only to levofloxacin
(Levaquin); based on animal models, quinolones not approved for use in children (theoretic concern, arthropathy;
problem not seen in humans); 5 children with 19A serotype treated with levofloxacin, and all cured; speaker’s
advice—if treatment fails after use of high-dose amoxicillin or Augmentin and 3 injections of ceftriaxone, obtain
tympanocentesis; if 19A serotype identified by culture, give Levaquin; recent AAP guideline allows use of quinolones
when benefits outweigh risks
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| Deciding whether to treat AOM: 80% of cases of AOM due to S pneumoniae and 50% of cases due to H influenzae
do not resolve as quickly without antimicrobial use
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| Comparative in vitro activity of antibiotics: against susceptible S pneumoniae—best medication ceftriaxone
(3 injections); next-best group, high-dose amoxicillin and Augmentin; against β-lactamase–producing H
influenzae—cefixime (Suprax) best medication, but activity against S pneumoniae poor
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| Pharmacokinetic (PK) and pharmacodynamic (PD) profiles of antibiotics and clinical efficacy in
AOM: PK and PD reasonable predictors of bacteriologic outcomes; parameters used to assess potential antibiotic
performance when bacteriologic efficacy data not available; PK and PD analyses do not account for—patient-to-
patient variations in PK; differences in frequency distribution of minimum inhibitory concentration (MIC) seen in
clinical practice
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| Variability in absorption of amoxicillin (Barr, 1996): 15% of amoxicillin absorbed in some subjects (98% in
others)
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 | Intestinal saturable “pump” mechanism affects PK and PD of amoxicillin (Pichichero and Reed, paper submitted
2007): amoxicillin absorption driven by pump in small intestine under genetic control; patient with poor pump
may absorb only 15% of amoxicillin (treatment does not achieve adequate levels in blood or middle-ear fluid)
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| Percentage of children who are poor absorbers: meta-analysis by Pichichero and Reed (study not yet published);
Harrison et al, 1998—middle ear fluid collected from children receiving 13 mg/kg amoxicillin; 3 patients (27%)
had no detectable amoxicillin, and 1 had very low level; all children with low levels were <1 yr of age; Seikel et
al, 1996—6 children treated with 35 mg/kg amoxicillin; 14 received 45 mg/kg; levels of concentration in middle
ear varied 5- to 7-fold, and 15% had no detectable level of amoxicillin in middle ear; Fonseca et al, 2003—5- to
52-mo-old children with pneumonia received 15 or 25 mg/kg per dose of amoxicillin (blood levels varied 5- to
30-fold)
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| Taste ratings for antibiotic suspensions (Steele et al, 2001): best-tasting antibiotic loracarbef (Lorabid); not
effective (no longer on market), but tastes great; cefdinir (Omnicef) best-tasting of guideline-recommended antibiotics
(amoxicillin equally good-tasting); bad taste barrier to use; among oral cephalosporins, cefpodoxime (Vantin)
closest to characteristics of ceftriaxone (tastes bad)
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| Dosing: several medications have once-daily indication
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| Duration of therapy: several medications have 5-day indication (speaker almost never gives 10 days of therapy)
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| Shortened (5-day) antibiotic treatment of AOM in children <36 mo of age (Casey and Pichichero, 2004, submitted):
end-of-therapy outcome—often, longer course performed better; by day 28 to 40, no difference (except one case in
which short-course better)
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| Observational study: (Pichichero et al, 2001): 2172 patients treated with 5, 7, or 10 days of therapy; higher cure
rates in children >2 yr of age; in general, duration made no difference; if ≥1 episode of ear infection occurred
within month preceding enrollment, 5- and 7-day regimens inferior to 10-day therapy
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| Problem of expired medications (paper by Pichichero): >70% of households store leftover antibiotics (average
household has 3 antibiotics); some families use these medications months or years after initial prescribing
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| Summary of treatment recommendations (AAP, American Academy of Family Physicians [AAFP]):
know epidemiology of AOM (otopathogens changing); amoxicillin current treatment of choice in guidelines (but
not speaker’s drug of choice); main pathogen β-lactamase–producing H influenzae; to cover pneumococci, speaker
uses high-dose Augmentin; other reasonable alternatives—consider Omnicef, Vantin, or Ceftin; factors that influence
compliance with antibiotic therapy—taste; ease of use; duration of therapy
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| PRESCRIBING CEPHALOSPORINS IN PENICILLIN-ALLERGIC CHILDREN
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| Introduction: cross-reactivity relates to side chain of molecule (not shared β-lactam ring); allergic reactions can
occur with first-generation cephalosporins (side chains similar to those of penicillin and ampicillin); because side
chains of second- and third-generation cephalosporins different, no problem of cross-allergenicity
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| Classification of adverse drug reactions (Gell and Coombs): “allergy” defined as type I reaction—also
called immediate reaction (onset within 1 hr); mediated by IgE; clinical signs include anaphylaxis, hypotension, and
urticaria; skin testing can identify these patients; reaction more likely after parenteral than oral administration; “non-
type I allergy” does not exist; type II—not IgE-mediated; skin tests not helpful; type III—immune complex (eg, serum
sickness); skin testing not useful; IgE not involved; type IV—delayed hypersensitivity; idiopathic—various
rashes
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| Types of allergic reactions to penicillins and cephalosporins: immediate—hives, bronchospasm, laryngeal
edema; hypotension; angioedema; anaphylaxis; late—morbilliform rash; serum sickness; urticaria
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| Percentage of patients with allergic reactions to cephalosporins (Pichichero, 2005): systematic review
suggested that if patient with history of penicillin allergy given first-generation cephalosporin (eg, cephalexin [Keflex]),
increased risk for allergic reaction, 0.5% (statistically significant); if given second- or third-generation cephalosporin,
risk “zero”
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| Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis (Pichichero et al,
2007):
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| Diagnosis by history alone: study—penicillin-allergic patients had increased risk for allergic reaction to cefazolin;
another study—if patients allergic to penicillin, likelihood of reacting to cephalothin (Keflin; discontinued)
increased; first-generation cephalosporins—significant increase in risk for allergic reaction to first-generation
cephalosporin if patient had history of penicillin allergy (P value significant); second- and third-generation
cephalosporins—no significant difference
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| Diagnosis by history and skin test: first-generation cephalosporins—almost achieved statistical significance; second-
and third-generation cephalosporins—no difference
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| Summary: data gathered on 47,000 patients; effect size suggested that first-generation cephalosporin (particularly
Keflex) had increased risk for cross-reactivity, but second- and third-generation agents had no evidence of cross-
reactivity
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| Cross-reactivity based on side chains of penicillins and cephalosporins
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| 7-position side chains: if patient reacts to penicillin—increased risk for reaction to intravenous (IV) cephalothin
(Keflin); reaction to ampicillin or amoxicillin—increased risk for reaction to cefaclor (Ceclor), Keflex, cefprozil
(Cefzil), and cefadroxil (Duricef); reaction to cefotaxime—increased risk for reaction to ceftriaxone or cefpodoxime;
reaction to cefdinir—side chain unique; no reason to expect reaction to other cephalosporin, penicillin,
or amoxicillin; possible separate reaction to (not cross-allergy between) amoxicillin and cefdinir
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| 3-position side chains: if patient allergic to cefdinir, avoid cefixime (no cross-reactivity to penicillin, amoxicillin, or
other cephalosporins); chance that child allergic to penicillin and all cephalosporins almost statistically impossible
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| Newest guidelines: acknowledge “tiny” increased risk for cross-reactivity between penicillin and first-generation
cephalosporins (eg, cephalexin); if patient had anaphylactic reaction to penicillin, then ampicillin and cephalexin
contraindicated (otherwise, medications permitted); generations of cephalosporins somewhat sort out by chemical
side chain; exception cefaclor (although second-generation drug, side chains mimic those of first-generation drugs)
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| PEDIATRIC AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH GROUP A STREPTOCOCCI
(PANDAS): FACT OR FICTION
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| Historical perspective (studies by Swedo): in 1989, Swedo described high prevalence of obsessive-compulsive
disorder (OCD) in children with Sydenham’s chorea (SC); significant evidence in literature supports notion that SC is
poststreptococcal event; in 1992, Swedo made association between group A streptococcal (GAS) infections and occurrence
of OCD or tic-like symptoms; in 1993, epidemiologic study in Rhode Island linked increase in tic disorders
in community to increase in streptococcal infections; Swedo’s hypothesis—significant overlap of symptoms between
SC, childhood-onset OCD, and Tourette’s syndrome (TS); each disorder has potential localization in basal ganglia;
comorbid symptoms—include separation anxiety; onset of symptoms abrupt; association based on circumstantial evidence
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| Research findings suggestive of genetic predisposition to PANDAS: 20% of patients with post-GAS tics
have first- or second-degree relatives with post-GAS autoimmune disorders; also, in patients with PANDAS, family history
of psychiatric and movement disorders seen in 39% of first-degree relatives; one paper has suggested that attention-
deficit/hyperactivity disorder (ADHD) predisposes patients to PANDAS
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| Neuroimaging in PANDAS: volumetric MRI shows enlargement of caudate nucleus and putamen of basal ganglia
during acute phase of SC and PANDAS; enlargement resolved during remission
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| Antineuronal antibodies: paper—antineuronal antibodies directed to basal ganglia identified in 46% of patients
with SC (rate 14% in patients with acute rheumatic fever and 2% in controls); antineuronal antibodies disappear
when chorea remits
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| Autoimmune etiology in pathogenesis of PANDAS: in patients with SC, Tourette’s syndrome, and PANDAS,
autoantibody cross-reacts with lysoganglioside GM1 (neuronal cell surface molecule), causing change in neuronal
signaling; antigen identified that mimics molecular structure of lysoganglioside; with disruption of specific pathway
of signaling by interacting with neuronal cell surface molecule, change in metabolism in cells of basal ganglia
might produce tic and OCD-type behaviors
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| Treatment: Perlmutter et al, 1999—in randomized controlled trial, patients with PANDAS given IV immune globulin
(IVIG), plasma exchange, or placebo; some decrease in OCD symptoms in IVIG and plasma-exchange groups;
significant reduction in tics with plasma exchange (but not IVIG) compared to controls; Snider et al, 2005—
prophylaxis with penicillin or azithromycin decreased neurologic or psychiatric symptoms in patients with suspected
PANDAS
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| Case report: one particular night, 5-yr-old boy experienced increased urinary frequency; no dysuria, fever, or nocturia;
behavior problem suspected (eg, acute separation anxiety); urinalysis negative; proposed diagnosis viral cystitis;
rapid Streptococcus test positive for GAS; cephalosporin prescribed; compulsive need to urinate ended within
1 wk, but 1 mo later, symptoms returned; sore throat suspected but throat looked normal and swab negative; 3 days
later, throat slightly red, and rapid Streptococcus test positive; condition improved on antibiotic therapy
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| Characterization of PANDAS cases (Murphy and Pichichero, 1999): in psychiatry literature, urinary frequency
common cause of obsession (eg, excessive hand-washing); children improved after antibiotic therapy; autoimmune
disease should not get better with antibiotics in absence of toxin-mediated disease caused by bacteria
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| Conclusions: primary care physician may see 1 to 3 children each year with first episode of PANDAS; diagnosis
requires 1) sudden onset of OCD and tics, 2) sore throat, and 3) positive culture, rapid Streptococcus test, or serologic
test (order antistreptolysin O and anti-DNase B tests); treat with antibiotics directed at GAS (do not wait for
test results); lack of response within 1 wk argues against PANDAS as diagnosis; Murphy and Pichichero (2002)—
rate of recurrence 50%; if recurrence occurs, disease should resolve with antibiotics; final words—if child presents
with urinary frequency, negative urinalysis, and absence of dysuria, nocturia, or fever, consider possibility of
PANDAS
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Suggested Reading
Casey JR, Pichichero ME: Metaanalysis of short course antibiotic treatment for group A streptococcal tonsillopharyngitis.
Pediatr Infect Dis J 24:909, 2005; Murphy ML, Pichichero, ME: Prospective identification and
treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection
(PANDAS). Arch Pediatr Adolesc Med 156:356, 2002; Perlmutter SJ et al: Therapeutic plasma exchange
and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 354:1153,
1999; Pichichero ME, Casey JR: Acute otitis media: making sense of recent guidelines on antimicrobial treatment.
J Fam Pract 54:313, 2005; Pichichero ME, Casey, JR: Emergence of a multiresistant serotype 19A pneumococcal
strain not included in the 7-valent conjugate vaccine as an otopathogen in children. JAMA 298:1772, 2007;
Pichichero ME, Casey JR: Safe use of selected cephalosporins in penicillin-allergic patients: a meta-analysis.
Otolaryngol Head Neck Surg 136:340, 2007; Pichichero ME, Poole MD: Comparison of performance by otolaryngologists,
pediatricians, and general practitioners on an otoendoscopic diagnostic video examination. Int J Pediatr
Otorhinolaryngol 69:361, 2005; Pichichero ME et al: A prospective observational study of 5-, 7-, and 10-day
antibiotic treatment for acute otitis media. Otolaryngol Head Neck Surg 124:381, 2001; Pichichero ME: A review
of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics
for penicillin-allergic patients. Pediatrics 115:1048, 2005; Pichichero ME: Cephalosporins can be prescribed
safely for penicillin-allergic patients. J Fam Pract 55:106, 2006; Pichichero ME: Use of selected cephalosporins in
penicillin-allergic patients: a paradigm shift. Diagn Microbiol Infect Dis 57:13S, 2007.
Educational Objectives
| The goal of this program is to improve the medical management of infectious disease in children. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Describe the changing epidemiology of acute otitis media (AOM) in children.
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| 2. Choose appropriate therapy for managing AOM.
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| 3. Evaluate the safety of prescribing cephalosporins in penicillin-allergic children.
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| 4. Describe recent research supporting the diagnosis of pediatric autoimmune neuropsychiatric disorders associated
with group A streptococci (PANDAS).
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| 5. Choose appropriate therapy for children who present with signs and symptoms of PANDAS.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Pichichero has received research grants
and/or honoraria from Abbott, Advancis, Innovia Medical, Medimmune, Merck, Sanofi Aventis, Sanofi Pasteur, and Welch Allyn.
The planning committee reported nothing to disclose.
Acknowledgments
Dr. Pichichero was recorded at the 49th Annual Pediatric Symposium, presented October 12-13, 2007, in Anaheim, CA, by
Kaiser Permanente. The Audio-Digest Foundation thanks Dr. Pichichero and Kaiser Permanente for their cooperation in the production
of this program.
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