INFECTIOUS DISEASE: WHERE DO WE STAND?
From the American Academy of Family Physicians’ 2005 Scientific Assembly, San Francisco
| RATIONAL PRESCRIBING IN THE ERA OF ANTIBIOTIC RESISTANCE—George P. Kent, MD, Clinical Associate
Professor of Family and Community Medicine, Stanford University School of Medicine, and Associate Director, O’Connor
Family Medicine Residency Program, San Jose, California
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| Mechanisms of resistance: enzyme degradation— β-lactamase enables organism (eg, Staphylococcus) to degrade penicillin
and other β-lactams; extended-spectrum β-lactamase (ESBL) also degrades cephalosporins and agents that had previously
inhibited β-lactamase (eg, sulbactam, clavulanic acid, and tazobactam); structural modifications—alterations
in proteins of cell walls (as in pneumococcus) may inhibit binding of antibiotic; changes in structure of target enzymes
(eg, DNA gyrase and topoisomerase) confer resistance to quinolones; changes in shape of ribosome affect binding of macrolides;
antibiotic pumps—active pump pushes antibiotic out before it can bind to cellular target
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| Antibiotic use and resistance: penicillin and Streptococcus penumoniae (pneumococcus)—intermediate resistance (requiring
larger doses of penicillin) developed in 1990s; highly resistant strains followed; currently, 30% to 50% of isolates
resistant; quinolones and Pseudomonas—increased use of quinolones since 1994 led to increased resistance; 30% of
isolates resistant to ciprofloxacin (Cipro); use also has put pressure on other gram-negative bacteria to develop resistance
to fluoroquinolones; macrolides and pneumococcus—comparison among countries in European Union found heavy
use of macrolides correlates with increased resistance
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| Methicillin-resistant Staphylococcus aureus (MRSA): prevalence of community-associated MRSA increasing;
transmission—close physical contact; outbreaks have occurred in daycare centers, athletic teams, prisons, and military
barracks; risk factors—community-associated MRSA not associated with history of hospitalization or contact with
health care setting; risk increases with 5 Cs (crowding, contact [particularly, skin to skin], compromised skin, contaminated
surfaces, and cleanliness [poor hygiene]); resistance—nosocomial MRSA often resistant to multiple antibiotics;
most isolates of community-associated MRSA still susceptible to many drugs (eg, trimethoprim–sulfamethoxazole [TMP–
SMZ], clindamycin, rifampin); virulence—virulence factor (Panton-Valentine laukocidin; PVL) associated with development
of invasive infections in otherwise healthy individuals; prevalence—cases likely underreported; different studies
found varying rates of resistance (15%-74%)
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| Treatment of MRSA: outpatient treatment with cephalexin (Keflex) or dicloxacillin acceptable for patients with localized
infections (skin or soft tissue); nonresponsive infections increase index of suspicion for MRSA (culture specimen to confirm);
patients who do not respond to treatment may require hospitalization because of risk for invasive infection requiring
parenteral antibiotics; antibiotic options—TMP–SMZ (Bactrim, Septra) or clindamycin; adding rifampin may
enhance activity; minocycline or doxycycline sometimes useful; fluoroquinolones and monotherapy with rifampin not
recommended (may induce resistance); D test required to assess susceptibility before using clindamycin; nonmedical
options—in healthy patients, hygiene and local wound care more important than antibiotic therapy; patients who do not
respond may have virulent form of MRSA; preventing transmission—cover infections that drain; wash hands; avoid
sharing personal items; wash soiled linens in hot water and dry in hot dryer (do not air-dry); vancomycin—former treatment
of choice for serious infections, but treatment failures becoming more common; maintaining appropriate level in serum
sometimes difficult; problems with nephrotoxicity and ototoxicity; poor diffusion into meninges and lungs
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| New antibiotics: linezolid (Zyvox)—parenteral and oral formulations available; important drug for resistant gram-positive
infections, including MRSA, methicillin-resistant Staphylococcus epidermidis, vancomycin-intermediate and vancomycin-resistant
S aureus, penicillin-resistant pneumococcus, and vancomycin-resistant Enterococcus (VRE); problems include
potential for overuse and high cost; daptomycin (Cubicin)—new class of antibiotics that destabilizes cell
membranes; parenteral formulation only; poor efficacy against pneumococcal infections; tigecycline (Tygacil)—broad-
spectrum coverage for polymicrobial infections; bacteriostatic drug that attacks ribosomes; activity against MRSA, glycopeptide-intermediate
Staphylococcus, VRE, penicillin-resistant pneumococcus, many gram-negative organisms,
anaerobes, and atypical pathogens; Pseudomonas and Proteus not covered; for treatment of polymicrobial infections
(eg, decubitus ulcer, infected foot of diabetic patient, infected traumatic wounds, and intra-abdominal infections), especially
in patients allergic or intolerant to combination of β-lactam– β-lactamase inhibitor plus metronidazole
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| Community-acquired pneumonia: S pneumoniae primary concern; isolates commonly resistant to penicillin and other antibiotics;
up to 50% of isolates resistant to macrolides; diagnosis—recent guidelines by Infectious Disease Society of
America (IDSA) recommend chest radiographs to document pneumonia and follow progression; pattern on radiograph
may provide clues about pathogen (eg, atypical pathogens often cause diffuse pattern; lobar pattern with diffusion more
likely with bacterial pyogenic infection); culture and Gram stain of sputum helpful for directing therapy and selecting
antibiotic; urine antigen test for pneumococcus has low sensitivity, but aids in diagnosis when positive; resistance and
clinical failure—antibiotic resistance has not clearly affected mortality rate
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 | Treatment: high levels of macrolides (especially azithromycin and clarithromycin) within macrophages and neutrophils often
overwhelm efflux mechanisms of bacteria; guidelines continue to recommend macrolide therapy or doxycycline as
first-line treatment in healthy patients with uncomplicated community-acquired pneumonia; fluoroquinolone, high-dose
amoxicillin (up to 4 g), or amoxillin and potassium clavulanate (Augmentin) plus macrolide (to cover atypical pathogens)
recommended for patients who have recently taken antibiotics (ie, resistance suspected); quinolone or macrolide acceptable
treatment for patients with comorbid conditions that decrease overall health; follow-up especially important in these
patients to assess response to treatment
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| Spectrum of coverage: macrolides and doxycycline generally sufficient to treat many community-acquired infections, including
S pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, and many atypical infections; use of broad-
spectrum antibiotics (eg, fluoroquinolones and β-lactams) puts pressure on other organisms, not just target organism
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| Telithromycin (Ketek): coverage similar to that of macrolides, but higher activity against many pathogens; approved treatment
for acute exacerbations of chronic bronchitis, acute bacterial sinusitis, and mild-to-moderate community-acquired
pneumonia; drug interactions—discontinue lovastatin, simvastatin, and atorvastatin; monitor levels of midazolam, triazolam,
digoxin, theophylline, and some β-blockers; adverse effects—diarrhea, nausea, and dizzines; may prolong QT interval
in patients with myasthenia gravis; use—consensus statement recommends use in patients with comorbid conditions
who have not recently taken antibiotics; azithromycin remains first-line treatment for patients without comorbidities
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| Acute bronchitis: evidence does not support treatment with macrolides; most cases self-limited and often viral; antibiotics
do not affect clinical course; exceptions—macrolides recommended to treat documented pertussis; follow-up important
when pneumonia suspected; exacerbation of chronic bronchitis in patients with chronic obstructive pulmonary disease
(COPD) warrants treatment
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| Sinusitis: pneumococcus and H influenzae responsible for 66% of cases of bacterial rhinosinusitis; 50% of isolates of H influenzae
produce β-lactamase; most cases caused by viral infections; secondary overgrowth of bacteria may result from
prolonged congestion; treatment—topical decongestant or antihistamine (if allergic etiology suspected) generally sufficient
for otherwise healthy patients; secondary worsening may occur in patients with bacterial infections; clinical judgment
may affect decision to treat; Augmentin recommended for treatment of documented bacterial infections;
amoxicillin alone may not overcome organisms that produce β-lactamase; cephalosporins also effective; quinolone or
Augmentin recommended for patients who have recently taken antibiotics; fluoroquinolone or clindamycin, plus
rifampin, acceptable for patients allergic to β-lactams
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| Pharyngitis: most cases not caused by group A Streptococcus; diagnostic and bacteriologic tests required for diagnosis;
presence of fever, exudate, or tender nodes increases suspicion for Streptococcus; presence of cough decreases suspicion
(negative predictor); rapid tests for Streptococcus have sensitivity of 95%; decision to treat—treat patients with positive
test findings; in face of negative findings, consider culture for patients with risk factors; withhold treatment until culture
results known; use clinical judgment in treating high-risk patients before results of culture known; antibiotics—
penicillin or cephalosporins; resistance increasing to macrolides (recommended only in patients allergic to penicillin)
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| Urinary tract infections (UTIs): local rate of resistance to TMP–SMZ directs choice of antibiotic; in communities where
>20% of isolates resistant, treat with quinolone or nitrofurantoin
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| Conclusions: antibiotic resistance requires constant surveillance; treatment recommendations change as new patterns of resistance
emerge; empiric therapy inherently imprecise; obtain bacterial specimens and cultures when possible; follow-up important
to identify failures in treatment; preventive measures (eg, immunizations, contact isolation) important; use of “comfort
measures” encouraged (avoid inappropriate use of antibiotics)
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| UPDATE ON PEDIATRIC IMMUNIZATIONS—Jonathan L. Temte, MD, Associate Professor of Family Medicine, University
of Wisconsin Medical School, Madison
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| Changes in recommendations: acellular pertussis vaccine and inactivated poliovirus vaccine replace earlier versions
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| Hepatitis B: birth dose important; most infants who develop hepatitis B contract infection through lateral transmission (ie,
not maternal transmission) during first month of life
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| Tetanus, diphtheria, and pertussis (DTaP and Tdap): combination vaccines have same antigens, but pertussis component
in Tdap only 25% of that contained in childhood series (sufficient to maintain immunity in adolescents and adults);
note—timing of vaccine (children 11-12 yr of age) facilitates implementation of preadolescent platform, including discussion
about lifestyle choices, substance abuse, and sexuality
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| Measles, mumps, rubella, and varicella (MMRV): combination vaccine recently licensed; use facilitates second dose of
varicella vaccine; recommendations forthcoming
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| Pneumococcal vaccine: use correlated with significant decrease in invasive pneumococcal disease; invasive disease caused
by pathogens covered by vaccine decreased by 94% between 1998 and 2003; all invasive pneumococcal disease decreased
by 75%
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| Influenza: B-level recommendation for children >6 mo of age; several neuromuscular conditions added to list of chronic
conditions that increase risk for complications from influenza
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| Hepatitis A: vaccine (inactivated; Vaqta) licensed for children 12 mo of age; A-level recommendation for people at high
risk; future recommendations for universal vaccination (with intention to eliminate disease) likely
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| Meningococcal disease: highest prevalence in early infancy (predominantly type B); components of new vaccine (MCV4;
Menactra) target secondary peak in adolescence; conjugate vaccine includes 4 serotypes; immunization recommended for
children 11 to 12 yr of age; new vaccine approved for use in patients 11 to 55 yr of age, but older polysaccharide vaccine
acceptable if Menactra unavailable; immunization strengthens argument for preadolescent platform; note—patients who
did not receive vaccine as part of preadolescent visit encouraged to do so before entry to high school or college;
immunity—expected to last 8 to 10 yr
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| Pertussis: 8000 cases reported in 2004 (true burden likely much greater); infants at highest risk for death from acute respiratory
distress; incidence declined dramatically until recent years; waning immunity may explain resurgence; Tdap
vaccines—Boostrix (GlaxoSmithKline), single-dose vaccine, approved for use in patients 10 to 18 yr of age; Adacel
(Sanofi Pasteur), single-dose vaccine, approved for patients 11 to 64 yr of age; products considered equivalent in most
situations; Tdap preferred over tetanus and diphtheria (TD) vaccine because of protection against pertussis;
recommendations—patients 11 to 18 yr of age should receive single dose of Tdap instead of TD as booster after completion
of childhood immunization with DTaP; although recommendations suggest waiting 5 yr after administration of
TD vaccine before giving Tdap, studies found no increase in adverse effects with shorter intervals (2 yr); better to give
Tdap along with meningococcal vaccine
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| Varicella: second dose being considered; can improve overall coverage; first dose cost-effective
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| Rotavirus: association between vaccination and incidence of intussusception led to discontinuation of vaccine; new vaccine
in development does not appear to have same problem; importance of vaccination—diarrheal illnesses second most
important cause of lost life-years worldwide
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| Human papillomavirus (HPV): 2 vaccines in development, aimed at reducing incidence of cervical and anogenital cancers;
potential controversy involves administering vaccine to preadolescents
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| Pandemic influenza: case fatality rate 52%, primarily in young, healthy individuals; vaccine not immediately available;
maximum production 6 million doses weekly; 2 doses required for immunity; prioritization plan in development
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| Questions and answers: influenza vaccines in children and adults—options include inactivated trivalent vaccine and
live attenuated virus; latter approved for use in patients 5 to 49 yr of age; some products free of thimerosal (important to
some parents)
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Educational Objectives
| The goal of this activity is to provide an update on antibiotic resistance and review recommendations for childhood immunizations.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss mechanisms of antibiotic resistance.
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| 2. Discuss the relationships among antibiotic use, resistance, and clinical failure.
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| 3. Identify and treat patients with resistant infections.
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| 4. Discuss recent updates in recommendations for childhood immunizations.
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| 5. Implement preadolescent platform for immunizations and other health issues.
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Discussed on This Program
Amoxicillin [Amoxil, Amoxil Pediatric Drops, Trimox, Trimox Pediatric Drops]
Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600, Augmentin XR]
Atorvastatin calcium [Lipitor]
Azithromycin [Zithromax]
Cephalexin [Biocef, Keflex]
Ciprofloxacin [Ciloxan, Cipro, Cipro I.V., Cipro XR]
Clarithromycin [Biaxin, Biaxin XL]
Clindamycin [Cleocin, Cleocin Pediatric, Cleocin Phosphate, Cleocin T, Clinda-Derm, Clindagel, ClindaMax,
ClindaMax Lotion, Clindets, C/T/S]
Daptomycin [Cubicin]
Dicloxacillin sodium
Digoxin [Digitek, Lanoxicaps, Lanoxin]
Diptheria and tetanus toxoids and acellular pertussis vaccine, adsorbed (DTaP) [Boostrix, Daptacel, Infanrix, Tripedia]
Diptheria and tetanus toxoids and acellular pertussis vaccine, adsorbed (Tdap), adult [Adacel]
Doxycycline (several trade names)
Hepatitis A vaccine, inactivated Havrix, Vaqta]
Influenza virus vaccine [FluMist, FluShield, Fluvirin, Fluzone]
Linezolid [Zyvox]
Lovastatin (mevinolin) [Altocor, Mevacor]
Measles, mumps, and rubella virus vaccine, live [M-M-R II]
Metronidazole [Flagyl, Flagyl 375, Flagyl ER, Flagyl IV, Flagyl IV RTU, Metric 21, MetroCream, MetroGel,
MetroGel-Vaginal, MetroLotion, Noritate, Protostat]
Midazolam HCl [Versed]
Minocycline HCl (minomycin) [Arestin, Dynacin, Minocin, Minocin IV]
Nafcillin sodium
Oxacillin sodium
Penicillin (several formulations and trade names)
Pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein) [Prevnar] Pneumococcal vaccine, polyvalent
[Pneumovax 23, Pnu-Imune 23]
Rifampin (rifampicin) [Rifadin, Rimactane]
Simvastatin [Zocor]
Telithromycin [Ketek]
Theophylline (several trade names)
Tigecycline [Tygacil]
Triazolam [Halcion]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, Bactrim DS, Bactrim IV, Bactrim Pediatric,
Cotrim, Cotrim D.S., Cotrim Pediatric, Septra, Septra DS, Septra IV, Sulfatrim]
Vancomycin [Vancocin, Vancoled]
Suggested Reading
Bal AM, Gould IM: Antibiotic resistance in Staphylococcus aureus and its relevance in therapy. Expert Opin Pharmocother
6:2257, 2005; Dawson A: The determination of ‘best interests’ in relation to childhood vaccinations. Bioethics
19:188, 2005; Fogarty C, et al: Efficacy of moxifloxacin for treatment of penicillin-, macrolide, and multidrug-resistant
Streptococcus pneumoniae in community-acquired pneumonia. Int J Clin Pract 59:1253, 2005; Fritsche TR, et al: Antimicrobial
activity of tigecycline tested against organisms causing community-acquired respiratory tract infection and
nosocomial pneumonia. Diagn Microbiol Infect Dis 52:187, 2005; Hviid A, et al: Childhood vaccination and nontargeted
infectious disease hospitalization. JAMA 294:699, 2005; Jacobs RJ, et al: Hepatitis A immunization strategies:
universal versus targeted approaches. Clin Pediatr (Phila) 44:705, 2005; Jefferson T, et al: Efficacy and effectiveness of
influenza vaccines in elderly people: a systematic review. Lancet 366:1165, 2005; Johnston N: Reversing the evolution
of antibiotic resistance. Drug Discov Today 10:1267, 2005; Kennedy AM, et al: Vaccine beliefs of parents who oppose
compulsory vaccination. Public Health Rep 120:252. 2005; Kowalski TJ, et al: Epidemiology, treatment, and prevention
of community-acquired methicillin-resistant Staphylococcus aureus infections. Mayo Clin Proc 80:1201, 2005;
Lutter SA, et al: Antibiotic resistance patterns in children hospitalized for urinary tract infections. Arch Pediatr Adolesc
Med 159:924, 2005; Mackenzie FM, et al: Report of the Consensus Conference on Antibiotic Resistance, Prevention
and Control (ARPAC). Clin Microbiol Infect 11:938, 2005; Paterson DL, Bonomo RA: Extended-spectrum beta-lactamases:
a clinical update. Clin Microbiol Rev 18:657, 2005; Paule SM, et al: Real-time PCR can rapidly detect methicillin-susceptible
and methicillin-resistant Staphylococcus aureus directly from positive blood culture bottles. Am J Clin
Pathol 124:404, 2005; Toltzis P, Jacobs MR: The epidemiology of childhood pneumococcal disease in the United States
in the era of conjugate vaccine use. Infect Dis Clin North Am 19:629, 2005.
Faculty Disclosure
In adherence with 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 issue,
the faculty reported nothing to disclose.
Drs. Kent and Temte were recorded in San Francisco at the 2005 Scientific Assembly of the American Academy of
Family Physicians (AAFP), held September 28 to October 2, 2005. The Audio-Digest Foundation thanks Drs. Kent
and Temte and the AAFP for their cooperation in the production of this program.
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