Antibiotic Update:
What’s Old?
Sunday July 25, 10:15 – 11:25 AM
Mark R. Schleiss, MD
American Legion Chair of Pediatrics
Director, Division of Pediatric Infectious Diseases
University of Minnesota, Amplatz Children’s Hospital
• Neither I nor any member of my immediate family
Disclosure
has a financial relationship or interest with any
proprietary entity producing health care goods
or services related to the content of this CME
activity.
• I do not intend to discuss an unapproved or
investigative use of commercial products or devices.
Objectives
• Review general classes of antimicrobials used in pediatric
practice
• Be familiar with the problem of antibiotic resistance
including its epidemiology and mechanisms
• Understand general classes of new antibiotics including
their spectrum and limitations
• Re-familiarize with older antibiotics that have fallen out
of favor in recent years but may have an important role in
the era of antimicrobial resistance
1970s
1980s
2000s
2010s
Ureidopenicillins
Cephalosporins
Betalactamase
Inhibitors
Carbapenems
Fluoroquinolones
Streptogramins and
Oxazolidinones
http://www.kent.ac.uk/secl/philosophy/jw/2009/macits/
http://biogetopics.files.wordpress.com/2008/11/horizontaltransfer.gif
http://www.microbiology.mtsinai.on.ca
• Rates are on the rise
(6.7/1000 in 2002 to
21.1/1000 in 2007)
• Median age 3 years
• Over 60% present as
skin or soft tissue infection
Factors Contributing to
Antimicrobial Resistance
• Resistance to antibiotics is a biological property of
microorganisms that can be accelerated by human practice
• Overuse of antibiotics in primary care for viral infections
• Noncompliance
• Over-reliance on new medications
• Self-medication and ease of access to OTC antibiotics
• Hospitals
• Agricultural practices
Solution:
Judicious Stewardship
• No antibiotics for URIs
• Use most narrow
spectrum agent
• “Watchful waiting” for
otitis media
• Reconsideration of
day care policies
http://www.lowdensitylifestyle.com/media/uploads/2010/03/antibiotic.jpg
Solution: Remove
Antibiotics from Agribusiness
• 70% of antibiotics used
in USA are for animals
• AMA, WHO, APHA have
called for removal
• EU has removed most
antibiotics from feed
http://www.foodrenegade.com
• FDA statement 6/29/10
called this an “urgent
public health issue”
Industry Reaction
• National Pork Producers
Council: “there is no
science that says
antibiotic use in livestock
leads to antibiotic
resistance in humans”
http://www.pewtrusts.org
• National Cattlemen's
Beef Association: “the
causes of antibiotic
resistance are complex
and should take into
consideration human
misuse of antibiotics”
Solution: Develop New Agents
Clinical Infectious Diseases 2010;50:1081-83
Solution: Develop New Vaccines
http://www.health.state.mn.us/divs/idepc/newsletters/dcn/sum07/spneumo.html
http://www.cdc.gov
Pneumococcal Vaccination Update
• PCV13 is replacing PCV7
• A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F
• A single supplemental dose of PCV13 is
recommended for all children 14 through 59 months
of age who have received 4 doses of PCV7 or other
age appropriate, complete PCV7 schedule
Polymyxin B
• Cyclic peptide
• Disrupts cell membrane via interaction with phospholipids
• Highly resistant Pseudomonas infections
• 15,000-25,000 U/kg/day (IM or IV)
• Intrathecal administration for resistant meningitis
• Neurotoxicity and nephrotoxicity
Colistin
• A member of polymyxin family
• Multidrug resistant gram negatives
• Two formulations:
•
Colistin sulfate (1-2 million units TID is an average dose)
•
Colistimethate sodium (2.5-5 mg/kg/day)
•
Nephrotoxicity and neurotoxicity
•
Inhalational form available
Macrolides
• First isolated from Saccharopolyspora erythraea
• Erythromycin, clarithromycin, azithromycin
• Active at ribosomal 70S rRNA complex
• Emergence of resistance has limited recent use in practice
particularly for S. aureus, GAHS, pneumococcus, H. flu
• Are there scenarios in pediatric practice where macrolides are
still useful?
Macrolides
• Nongonococcal urethritis/cervicitis
•
Azithromycin 1 g PO
•
Erythromycin base 500 mg QID for 7 days
•
Erythromycin ethylsuccinate 800 mg QID for 7 days
• Mycoplasma pneumoniae infection
• Legionella infection
• Bordetella pertussis (Whooping Cough)
•
Caution in neonates re: pyloric stenosis
Lincosamides
• Isolated from Streptomyces 1962
• Clindamycin is the prototype
• Protein synthesis inhibitor: binds to
the 23s portion of the 50S ribosomal subunit
• Activity against anaerobes; most MRSA (without inducible
clindamycin resistance); parasites (toxplasmosis, malaria);
no gram negative coverage; little CNS penetration
• Reduction of toxin production uniquely valuable for toxic
shock syndrome, invasive GAHS infections
http://www.health.state.mn.us
Clindamycin
•
•
•
•
A treatment of choice (with quinine) for babesiosis
Clindamycin/primaquine effective for Pneumocystis jirovecii
Effective for toxoplasmosis
Capsules (clindamycin hydrochloride) preferred over oral
suspension (clindamycin palmitate)
• The parenteral dose for clindamycin in children is 20 to 40
mg/kg/day divided every 8 hours
• The recommended oral dose of clindamycin in children with serious
infections is 8-20 mg/kg/day divided every 6-8 hours to a
maximum dose of 450 mg QID
• Clostridia difficile is intrinsically resistant to clindamycin
Tetracyclines
• First discovered in 1948 in soil sample
• Streptomyces aureofaciens
• Original tetracycline: aureomycin (still added to cattle feed)
• Works by binding the 30S ribosomal subunit and through
interaction with 16S rRNA prevents docking of aminoacylated tRNA
• Multiple formulations: rolitetracycline, minocycline and
doxycycline, and tigecycline
Take Two Beers and Call
Me in 1600 Years...
• Evidence from mummified
remains of Nubian people
that tetracycline had been
consumed
• Tetracycline extracted from
bone was shown to be
capable of killing bacteria
• Believed that brewed beer
was likely source
• First evidence of toxicity
to bones and teeth of
children
http://www.findarticles.com/p/articles/mi_m1134/is_4_109/ai_62324477
Tetracyclines
• First line therapy for:
•
•
•
•
Rocky Mountain Spotted Fever
Q Fever
Psittacosis
Anaplasma phagocytophilums
• Also useful for:
• Chlamydia
• MRSA
• Mycoplasma pneumoniae infection
http://www.bada-uk.org/images/buffycoatsmear.jpg
http://www.cdc.gov
Tetracycline: Toxicities and Cautions
• Complications:
Eosinophilia, leukopenia and thrombocytopenia (tetracycline)
Pseudotumor cerebri
Emesis and nausea,
Hepatitis
Photosensitivity
Hypersensitivity reaction (urticaria, asthma exacerbation, facial
edema, dermatitis)
• Systemic lupus erythematosus–like syndrome (minocycline)
•
•
•
•
•
•
• Avoid dairy products, antacids
Tetracycline: Cautions
• Children under 8 should not receive
tetracyclines
• Can cause permanent
discoloration of teeth
• Children as young as 4 years
of age can receive up to 4
courses of doxycycline with no evidence
of enamel discoloration (Volovitz, Clin Ped, 46:121, 2007)
http://www.toothmingle.com/healthy-smile/precaution-antibiotics-can-stain/
http://www.cdc.gov
http://www.ok.gov
Gerhard Domagk
• German physician and
chemist
• On sabbatical from
University of Munster
at I.G. Farbenindustrie
discovered prontosil
• Dramatic protection in
animal models but no
activity in cell culture
• Became the world’s first
commercial antibiotic
http://nobelprize.org/nobel_prizes/medicine/laureates/1939/domagk-bio.html
• Nobel Laureate 1939
Sulfonamides
• Protonsil metabolized to
Sulfanilamide in vivo
• Discovery paved way for many
sulfa drugs developed in 1940s-50s
• Co-trimoxazole (TMP-SFX) developed in 1960s
• Synergy derives from the fact that successive steps
in folic acid pathway are inhibited
TMP-SFX
• Folic acid dietary requirement
• Basis of selectivity for bacterial agent
TMP-SFX
• Combination of mechanisms discourages resistance
• Very broad spectrum agent
•
•
•
•
•
•
MSSA
MRSA
H. flu
E. coli
Listeria monocytogenes
Pneumocystis jirovecii
• Notably ineffective against GAHS
TMP-SFX: Side Effects
• GI side effects
• Hypersensitivity reactions (rash, urticaria)
• Hepatocellular injury
• Agranulocytosis
• Crystalluria/azotemia
• Stevens-Johnson Syndrome (1:1,000,000 prescriptions)
• Will all of these increase in the MRSA era?
FIGURE 2 Typical pattern of SJS: blisters develop on widespread atypical
targets
Levi, N. et al. Pediatrics 2009;123:e297-e304
Copyright ©2009 American Academy of Pediatrics
Summary
• Resistance to antibiotics continues at crisis levels in
medicine in 2010
• There are strategies that can help!
• New antimicrobials are on the horizon
• Older drugs – particularly the polymyxins, sulfonamides,
macrolides, lincosamides and tetracyclines – still play an
important role in the management of sick children
Research Opportunities
• Impact of PCV13 on DRSP and evolving patterns of disease
• Formulary committee: restriction of quinolones,
carbapenems and impact on GNR resistance
• CAP in children: RCT of macrolide or tetracycline versus
cephalosporin agents and impact on outcomes?
• Descriptive studies of tetracycline use and vector-borne
disease: regional variation, ICD-9 coding
• Cost-benefit analysis of TMP-SFX on management of MRSA
infections: are we over-treating or putting our children at risk?