INFECTIOUS DISEASE CONSULT
From Clinical Pediatrics, presented February 16㪫, 2006, by the American Academy of Pediatrics, California
Chapter 2
John S. Bradley, MD, Director, Division of Infectious Diseases, Childrens Hospital San Diego; Committee on
Infectious Diseases, American Academy of Pediatrics; Anti-Infective Drug Advisory Committee, United States Food
and Drug Administration
| COMMUNITY-ACQUIRED MRSA: WHAT IT IS, WHAT IT DOES, WHAT YOU CAN DO ABOUT IT
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| Introduction: community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) started appearing ≈10 yr
ago, seen more frequently in last 5 yr; seen in South and Midwest before appearing in California; hospital-acquired
MRSA strains around for 40 yr but not viable in community
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| Resistance and antibiotics
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 | Resistance: CA-MRSA has genes for resistance to methicillin and other β-lactams but few other resistance genes; strains genetically
different, and most robust strain starting to take over
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| Epidemiology: organism highly viable and spreading quickly throughout United States; in San Diego in last 2 yr, CA-
MRSA has increased from 5% to >30% of strains isolated; in next 2 yr, speaker expects 70% to 80% of children admitted
with Staphylococcus infections to have CA-MRSA
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| Antibiotics: generally CA-MRSA resistant only to β-lactams, eg, penicillin, cephalosporins, carbapenems; ≈50% of strains
erythromycin-resistant; in southern California, ≈5% to 10% of strains resistant to clindamycin; confusion on mechanism
of clindamycin resistance
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| Mechanism of action: different from that of other Staphylococcus strains; causes deeper, more invasive infections; child
with wound like deep spider-bite classic presentation; seems to cause necrotizing fasciitis at greater rate than regular
strains; preliminary investigation of genetic structure suggests presence of gene for Panton-Valentine leukocidin (PVL),
which injures white blood cells (WBCs) that kill organism, allowing it to continue to grow; causes outbreaks in closed
populations (attachment factors probably involved); recurrent disease, formerly rare, occurring more frequently; does not
appear to cause bacteremic disease more frequently; has selective advantage in community; speaker believes methicillin-
susceptible strains (MSSA) will be replaced by CA-MRSA
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| Mechanism of resistance: CA-MRSA alters transpeptidase (penicillin-binding protein to which β-lactams attach), creating
different binding site to which β-lactam cannot attach; scientists working on tweaking β-lactam molecule so that it can
again bind to transpeptidase
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| Disease characteristics: reviews of children with MRSA and MSSA in hospitals in Texas show extended hospital stays
and increased numbers of days with positive blood cultures (in many instances due to inactive antibiotic therapy); complicated
pneumonia common; case—healthy 1-yr-old boy with no immune deficit developed flu-like illness; given
amoxicillin and potassium clavulanate (Augmentin) without improvement; presents to emergency department (ED); admitted
to intensive care unit (ICU) and intubated within 24 hr; widespread destructive lung disease; required high-frequency
ventilation and nitric oxide to increase gas diffusion; computed tomography (CT) after 1 mo in hospital shows
extensive lung damage with fibrosis and scarring
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| Abscess management: Houston study—clindamycin and vancomycin effective but do not play role in cure after surgical
incision and drainage; study retrospective, so may be selective for children with infections amenable to surgical drainage;
Dallas study—30% of abscesses in buttocks and 70% in thighs; typical spider-bite presentation; 90% of children admitted
had incision and drainage; abscesses seen more frequently than with old Staphylococcus; study—children managed
with ineffective antibiotics after drainage of cutaneous abscess improved on follow-up without changing antibiotic; appears
antibiotics not needed if drainage complete; in view of surgeons’ varying approach to incision and drainage,
speaker thinks antibiotics still have role
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| Vancomycin resistance: emerging problem; may be complete or partial resistance in which decreased response caused by
thickening of staphylococcal cell wall
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| Alternative drug therapies: other drugs may be as good as or better than β-lactams; linezolid (Zyvox) and daptomycin
(Cubicin; approved for adults, not yet studied in children)
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| Infant with necrotizing fasciitis: 7-day-old boy, recently discharged, presented to ED with irritability and rash spreading
superiorly and anteriorly from sacral area; red streaks on abdomen; neonatally jaundiced; admitted to ICU; thick indurated
skin, very poorly perfused; had histologically confirmed necrotizing fasciitis; surgical debridement performed;
blood pressure and organ function normal; mild respiratory distress syndrome present; skin grafts performed; 2 wk later,
new skin cells spread to cover defect
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| Treatment: most isolates susceptible to clindamycin; before treatment, check with local infectious disease specialist or
hospital antibiogram for susceptibility of strains; most isolates susceptible to vancomycin, but isolates with low susceptiblity
may be reported as susceptible because of time lag in laboratory reporting (takes ≈2 yr for laboratory standards
to incorporate new tests); most strains susceptible to trimethoprim-sulfamethoxazole (Bactrim, Septra) and to
tetracycline (for older children), but these drugs not studied in prospective comparative trials; susceptibility in laboratory
does not translate to people
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| Clinical experience: varying reports on use of Septra; no studies; exercise caution; use tetracycline cautiously also (only
bacteriostatic)
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| Moderate skin infections: in areas such as San Diego or Los Angeles, do not assume susceptibility to Augmentin or cephalexin
(Keflex); get cultures and start on clindamycin and if susceptible, switch back to β-lactam
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| Life-threatening infections: for past 4 yr, all children in ICU with suspected staphylococcal infection treated with vancomycin
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| Resistance to clindamycin and macrolides: erythromycin and other macrolides not effective against all strains of Staphylococcus
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| Two major mechanisms of erythromycin resistance: efflux pump—present in organism; recognizes macrolide antibiotic
and pumps it out immediately; inducible methylation—organism places methyl group on ribosomal binding site so
macrolide cannot bind and obstruct protein passage; clindamycin—if methylase already induced, clindamycin cannot
bind, but clindamycin cannot induce methylase; in most organisms, speed of methylation insufficient to prevent action
of clindamycin; however, some organisms have mutation in control genes, leading to continuous methylation and clindamycin
resistance
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| D-test: for inducible methylase-mediated resistance; some laboratories automatically report D-test, others require physician
to request D-test; request with cultures for all children; if organism D-test-positive and bacterial load >1 million
(eg, undrained abscess), vancomycin recommended; but if abscess drained, clindamycin should work because bacterial
load <1 million, and chance that organism mutant vanishingly small
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| Decolonization: not routinely used today; now we decrease colonization to decrease frequency of infections; chlorhexidine
soap—surgical scrub with residual antibiotic activity even after being washed off; use to bathe child daily for 5 to
7 days to decrease bacterial load, then every other day, then maybe every third day, until recurrent infection occurs; indicates
frequency of use required to prevent infection; chlorine bleach—one fourth cup per tub of bath water; has potential
for splashing into child’s eye; speaker waiting until data published before recommending; mupirocin (Bactroban)—
can also be used to reduce nasopharyngeal colonization, but reports of resistance after 3 or 4 courses; hygiene—do not
allow children to share towels, clothes, or bed linen; wash items in hot water; decrease exposures to other colonized children
(often not possible); alcohol-based hand gels kill bacteria
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| Linezolid: oxazolidinone active against almost all strains; well studied and works well; bacteriostatic, not bactericidal;
some hemotologic toxicity; high cost
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| Daptomycin: different mechanism of action; fifth-generation cephalosporin (“ceftriaxone on steroids”); effective against
same organisms as ceftriaxone and CA-MRSA
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| IMMUNIZATION OF ADOLESCENTS FOR PERTUSSIS
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| Immunization: 2 vaccines for adolescent pertussis now available; one vaccine can immunize adults also; older vaccines
too reactogenic
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| Epidemiology: vaccine approved by American Academy of Pediatrics (AAP) board and being integrated into practice; recent
data show alarming rate of increase in pertussis cases; may reflect actual increase or improved diagnosis due to, eg,
nasal swabs, polymerase chain reaction (PCR) antigen testing
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| Background: vaccine not 100% effective, despite being less reactogenic; no better than old vaccine at preventing disease;
improved pertussis vaccine still needed; even fully vaccinated children continue to circulate pertussis organisms; protection
from natural infection not expected beyond 10 yr, so vaccine given in early infancy cannot protect children for rest of
lives
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| Pertussis in adults: has relatively mild symptoms; adults often mistake for chronic cough and do not get tested; huge reservoir
of mild illness probably pertussis; case—nurse in pediatric clinic with chronic cough but no fever; developed post-
cough vomiting; no nausea, but cough accompanied by overwhelming urge to vomit; tested positive for pertussis; cocoon
theory—infants far less exposed if adults protected; greatest morbidity and mortality of pertussis in infants <6 mo of age
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| Adolescents: young adulthood brings susceptibility to pertussis again; pediatricians test young adults, but many internists
fail to do so; high rate of diagnosed disease in adolescent population; youngest babies have highest rates (not fully immunized
yet); one dose of vaccine “does nothing”; effectiveness improves with 2 doses, best with 3 doses
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| Adolescent vaccine platform: concept crystallizing; now have meningococcal and human papillomavirus (HPV) vaccines
for this age group; AAP supports adolescent immunization; pediatricians do better immunization programs than other
specialties; Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP)
urges pediatricians to start vaccinating adolescents
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| Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (TdaP) vaccine: single dose for adolescents; no
booster recommended for children; booster recommendations for adults and for health care workers expected from CDC
and ACIP; goal to replace tetanus and diphtheria toxoids (Td) vaccine with TdaP
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| FDA-licensed vaccines: similar efficacy and safety; components same as those in vaccines for infants, but proportions different;
TdaP—Boostrix (GlaxoSmithKline [GSK]) and Adacel (Sanofi Pasteur) for adolescents; antigen content—in
infants and young children, 23 to 25 µg of pertussis toxin gives appropriate serologic response; antigen requirement for
adults reduced to 2.5 µg (still gives serologic response with acceptable adverse events)
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| Vaccine composition: companies’ preparation varies, so reaction rates differ; method of preparation proprietary information;
no fimbrial antigens in Boostrix, Sanofi Pasteur’s vaccines include them
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| Diptheria toxoid: amount varies from 25 units in infant vaccine to 2.5 units in adult vaccine (GSK), and from 15 units to
2 units in Sanofi Pasteur vaccines; meningococcal vaccine (Menactra) contains 48 units of diptheria toxoid as adjuvant,
so meningococcal vaccine provides huge boost in antidiptheria titer; Menactra and TdaP vaccine should be administered
at same time to minimize reaction at the injection site
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| Safety: goal to use vaccine that causes least reaction; Food and Drug Administration (FDA) works with companies on trials,
but each company designs own trial, so end points not comparable; FDA requires company to compare vaccine under
investigation with another vaccine for which FDA has data; study—Boostrix’s reaction rate compared to Td vaccine
produced by Massachusetts Public Health Department; reaction rates (eg, redness, swelling) same statistically; Adacel
compared to Sanofi-Pasteur’s Td vaccine for which FDA had data (similar statistically)
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| Systemic reactions: concern about fever; Boostrix showed 1.4% of children with temperature >102.2°F vs 1% with Td
from Massachusetts Public Health Department’s (same statistically); moderate fever (>102°F ) found in 0.9% of children
given Adacel vs 0.6% with other Sanofi-Pasteur Td vaccine; vaccines about equivalent; headache, general body aches,
and nausea equivalent to comparator vaccines; Boostrix licensed for 10 to 18 yr of age, Adacel for 11 to 64 yr of age
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| Recommendations: adolescents 11 to 12 yr of age immunized with DTP or DTaP should receive single booster dose of TdaP
instead of Td; adolescents not previously immunized should receive TdaP as one of 3 Td-containing vaccine injections; adolescents
13 to 18 yr of age should also receive single booster of TdaP if fully immunized with regular vaccines; if Td given
recently, interval of 5 yr recommended between Td and TdaP to reduce reactions; balance risk and benefit, eg, if adolescent
exposed to pertussis in high school, seriously consider giving TdaP rather than Td as booster, even if only 1 to 2 yr since Td
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| Pregnancy: CDC not recommending vaccine for any woman who might be pregnant because safety in pregnant women not
studied; however, history of pertussis vaccines in childhood shows no adverse events related to pregnancy; AAP believes
pregnancy not contraindication for TdaP, so no need to obtain pregnancy test in adolescent girls before vaccination
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| Availability: vaccine should be available on order; physicians should be able to integrate into immunization programs in
their practices; insurance companies should reimburse as contracts negotiated
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| Conclusion: both pertussis vaccines safe and effective for boosting immunity; no vaccine recommended officially; TdaP
can be used routinely instead of Td in adolescents; TdaP integral to the preadolescent vaccine platform
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Educational Objectives
| The goal of this program is to educate the listener about community-acquired methicillin resistant Staphylococcus aureus
(CA-MRSA) infection and immunization of adolescents for pertussis. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. Describe the signs and symptoms of CA-MRSA infection.
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| 2. Explain current management of CA-MRSA-infected abscesses in children.
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| 3. Choose appropriate drugs to treat CA-MRSA.
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| 4. Recognize the symptoms of pertussis in adults.
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| 5. Discuss current recommendations for pertussis vaccination in adolescents.
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Discussed on This Program
Amoxicillin [several trade names]
Cephalexin [Biocef, Keflex]
Clindamycin [several trade names]
Diphtheria and tetanus toxoids, combined (DT; Td)
Diphtheria and tetanus toxoids and acellular pertussis vaccine, adsorbed (DTaP) [Daptacel, Infanrix, Tripedia]
Erythromycin [several trade names]
Ibuprofen [many formulations and trade names]
Linezolid (Zyvox)
Meningococcal polysaccharide vaccine [Menomune-A/C/Y/W-135, Menactra]
Mupirocin (pseudomonic acid A) [Bactroban, Bactroban Cream, Bactroban Nasal]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [several trade names]
Vancomycin [Vancocin, Vancoled]
Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine, adsorbed (Tdap) [Boostrix, Adacel]
Suggested Reading
Alekshun MN et al: Commensals upon us. Biochem Pharmacol 71:89; Kluytmans-Vandenbergh MF et al: Community-acquired
methicillin-resistant Staphylococcus aureus infections. Int J Antimicrob Agents 27:87, 2006; Epub 2006 Jan 19. Aramburu
C et al: Clinical and Laboratory Features of Community-Associated Methicillin-Resistant Staphylococcus aureus: Is It
Really New? Infect Control Hosp Epidemiol 27:133, 2006; Epub 2006 Feb 8. Arnold FW et al: An analysis of a community-
acquired pathogen in a Kentucky community: methicillin-resistant Staphylococcus aureus. J Ky Med Assoc 103:206, 2005;
Bratu S et al: Community-associated methicillin-resistant Staphylococcus aureus in hospital nursery and maternity units.
Emerg Infect Dis 11:808, 2005; Buck JM et al: Community-associated methicillin-resistant Staphylococcus aureus, Minnesota,
2000-2003. Emerg Infect Dis 11:1532, 2005; Buck JM et al: The emergence of infections with community-associated
methicillin resistant Staphylococcus aureus. J Infect 52:157, 2006; Epub 2005 Nov 9.: Centers for Disease Control and Prevention
(CDC): Outbreaks of community-associated methicillin-resistant Staphylococcus aureus skin infections--Los Angeles
County, California, 2002-2003. MMWR Morb Mortal Wkly Rep 52:88, 2003; Chavez-Bueno S et al: Inducible clindamycin
resistance and molecular epidemiologic trends of pediatric community-acquired methicillin-resistant Staphylococcus aureus in
Dallas, Texas. Antimicrob Agents Chemother 49:2283, 2005; Diederen BM et al: The emergence of infections with community-associated
methicillin resistant Staphylococcus aureus. J Infect 52:157, 2006; Epub 2005 Nov 9. Fowler A et al: Community-acquired
methicillin-resistant Staphylococcus aureus pyomyositis in an intravenous drug user. J Med Microbiol 55:123,
2006; Frazee BW et al: Fatal community-associated methicillin-resistant Staphylococcus aureus pneumonia in an immunocompetent
young adult. Ann Emerg Med 46:401, 2005; Epub 2005 Aug 1. Fritsche TR et al: Importance of understanding
pharmacokinetic/pharmacodynamic principles in the emergence of resistances, including community-associated Staphylococcus
aureus. J Drugs Dermatol 4:s4, 2005; Johnigan RH et al: Community-acquired methicillin-resistant Staphylococcus aureus
in children and adolescents: changing trends. Arch Otolaryngol Head Neck Surg 129:1049, 2003; Kleinschmidt SL et al: In
vitro exposure of community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains to vancomycin: does vancomycin
resistance occur?. Int J Antimicrob Agents Feb;27(2):168-70. Epub 2006 Jan 18. Lee MC et al: Management and outcome
of children with skin and soft tissue abscesses caused by community-acquired methicillin-resistant Staphylococcus aureus.
Pediatr Infect Dis J 23:123, 2004; Lu D et al: Community-acquired methicillin-resistant Staphylococcus aureus, a new player
in sports medicine. Curr Sports Med Rep 4:265, 2005; Marcinak JF et al: Treatment of community-acquired methicillin-resistant
Staphylococcus aureus in children. Curr Opin Infect Dis 16:265, 2003; Martinez-Aguilar G et al: Clindamycin treatment
of invasive infections caused by community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus
aureus in children. Pediatr Infect Dis J 22:593, 2003; Ochoa TJ et al: Community-associated methicillin-resistant Staphylococcus
aureus in pediatric patients. Emerg Infect Dis 11:966, 2005; Purcell K et al: Epidemic of community-acquired methicillin-resistant
Staphylococcus aureus infections: a 14-year study at Driscoll Children's Hospital. Arch Pediatr Adolesc Med
159:980, 2005; Rybak MJ et al: Community-associated methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy
25:74, 2005; Sax H et al: Control of a cluster of community-associated, methicillin-resistant Staphylococcus aureus in
neonatology. J Hosp Infect [Epub ahead of print] Stevenson KB et al: Methicillin-resistant Staphylococcus aureus and vancomycin-resistant
Enterococci in rural communities, western United States. Emerg Infect Dis 11:895, 2005; Vandenesch F et al:
Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence.
Emerg Infect Dis 9:978, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this program, the following
has been disclosed: Dr. Bradley has received research support from Merck, Pfizer, AstraZeneca, and Elan.
Dr. Bradley spoke February 16㪫, 2006, in Palm Springs, California, at Clinical Pediatrics, presented by the American
Academy of Pediatrics, California Chapter 2. The Audio-Digest Foundation thanks Dr. Bradley and the AAP,
California Chapter 2 for their cooperation in the production of this program.
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