CURBING INFECTIOUS DISEASE
From the 29th Annual Advances in Infectious Diseases: New Directions in Primary Care, presented by the University of
California, San Francisco, School of Medicine
Educational Objectives
| The goal of this program is to improve the management of common bacterial illnesses. After hearing and
assimilating this program, the clinician will be better able to:
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 | 1. Select appropriate antibiotic therapy for common respiratory tract infections.
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| 2. Identify patients with acute otitis media who should benefit from antibiotic therapy.
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| 3. Educate patients about the lack of benefit of antibiotics in some disease settings.
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| 4. Diagnose and treat patients with community-acquired pneumonia (CAP).
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| 5. Describe patterns of resistance to different classes of antibiotics relevant to the management of CAP.
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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 faculty and planning committee reported nothing to disclose.
Acknowledgments
Drs. Guglielmo and Sharpe were recorded at 29th Annual Advances in Infectious Diseases: New Directions in Primary
Care, presented by the University of California, San Francisco, School of Medicine, and held May 14-16, 2008,
in San Francisco, CA. The Audio-Digest Foundation thanks the speakers and the University of California, San Francisco,
for their cooperation in the production of this program.
| ANTIBIOTICS UPDATE —B. Joseph Guglielmo, PharmD, Professor and Chair, Department of Clinical Pharmacy, University
of California, San Francisco, School of Pharmacy
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Acute Bacterial Rhinosinusitis
| Etiology of acute rhinosinusitis: often nonbacterial (eg, viral or allergic); bacterial agents—pneumococci most
common; 20% to 30% of pneumococcal isolates have some degree of resistance to penicillin; Haemophilus second most
common pathogen; almost 40% produce β-lactamase; almost all isolates of Moraxella (third most common pathogen)
produce β-lactamase
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| Treatment effect: randomized double-blind trials show small benefit of antibiotics over placebo; symptoms resolve in
81% of patients receiving antibiotics, compared to 66% of those in control groups; study—randomized double-blind trial
compared responses to amoxicillin, nasal steroids, combination therapy, and double-placebo; proportions of patients with
symptoms lasting ≥10 days similar among all study groups; authors concluded that neither agent indicated for patients
with acute sinusitis; Cochrane review—meta-analysis of data from ≈2500 adults with acute rhinosinusitis showed that 15
patients need treatment with antibiotics to cure 1 additional patient, compared to placebo (ie, number needed to treat
[NNT], 15); common clinical signs and symptoms cannot identify patients with rhinosinusitis who benefit from antibiotic
therapy; antibiotics not justified, even among patients with symptoms lasting \>7 days; conclusions—previously, antibiotics
indicated for patients with symptoms lasting \>7 days; current evidence supports change in practice
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Acute Otitis Media (AOM)
| Diagnosis: joint statement by American Academy of Pediatrics (AAP) and American Academy of Family Physicians
(AAFP) lists requirements for diagnosis of AOM; diagnosis requires 1) acute onset of symptoms, 2) presence of middle
ear effusion, and 3) evidence of middle ear inflammation or distinct otalgia that interferes with normal activity or sleep
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| Management: decisions based on age of patient and diagnostic certainty; patients < 6 mo of age—antibiotics indicated,
regardless of diagnostic certainty; patients 6 mo to 2 yr of age—antibiotics indicated when diagnosis certain, or when
uncertain but symptoms severe; observation recommended for patients with uncertain nonsevere disease; patients \>2 yr
of age—antibiotics indicated for patients with severe certain disease; otherwise, observation recommended; observation
protocol—provide parent with prescription for amoxicillin; instruct parent to fill prescription and initiate antibiotic
therapy if child fails to improve or worsens despite appropriate use of analgesics
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| AAP/AAFP treatment recommendations: children—amoxicillin, 80 to 90 mg/kg daily; adults—amoxicillin, 40 mg/kg
daily; severe disease—amoxicillin plus clavulanate (for coverage of β-lactamase producers); mild penicillin allergy—
several options (eg, cephalosporins); speaker questions use of azithromycin and clarithromycin; amoxicillin failure—
amoxicillin plus clavulanate or intramuscular (IM) ceftriaxone
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| Pneumococcal resistance: ≈30% of isolates have intermediate to high resistance to penicillin, but amoxicillin resistance
relatively rare; resistance to cephalosporins relatively common
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| Pharmacokinetics and efficacy: efficacy of β-lactams largely determined by proportion of time that antibiotic exceeds
minimum inhibitory concentration (MIC) in target tissues; outcomes improved when concentration remains above
MIC for \>50% of dosing interval; amoxicillin remains above MIC for 55% to 80% of dosing interval; cefaclor and oral
cefuroxime remain above MICs for significantly less time and are clinically inferior
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| Amoxicillin preparations and dosing: original Augmentin contains 500 mg amoxicillin and 125 mg clavulanate; doubling
dose to achieve 1 g of amoxicillin (eg, when intermediate resistance suspected) associated with severe gastrointestinal
(GI) adverse effects, primarily due to clavulanate; new formulations—have less clavulanate (eg, Augmentin XR
[indicated for adults] has 62.5 mg clavulanate per 1 g of amoxicillin); sufficient coverage but fewer GI adverse effects
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| High-dose amoxicillin: study of children <7 yr of age with AOM showed ≈48% of pneumococcal isolates “nonsusceptible”
(but not “resistant”) to penicillin; only 7% of isolates “nonsusceptible” to usual doses of amoxicillin;
conclusion—high-dose amoxicillin recommended only for children at high risk for resistance (ie, those who attend
child care or have recently received antibiotics)
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Community-Acquired Pneumonia (CAP)
| Etiology of outpatient CAP: Streptococcus pneumoniae (most common); Mycoplasma (common in younger patients);
Chlamydia; viruses; Haemophilus and Staphylococcus aureus rare in outpatient setting
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| Standard empiric treatment of CAP in United Kingdom: fluoroquinolones not recommended; low rates of
penicillin resistance among pneumococcal isolates; inpatients—intravenous (IV) penicillin; additional coverage for
atypical pathogens in sicker patients; outpatients—amoxicillin for nonsevere cases; no additional coverage for atypical
pathogens; meta-analysis—expanded-coverage antibiotics (active against atypical organisms) found to have no overall
benefit; subgroup analysis showed benefit only among patients with Legionella (patients tended to be older, sicker, or immunocompromised)
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| β-lactams in CAP: lack coverage for atypical organisms, but typically sufficient for outpatient CAP; amoxicillin preferred
when pneumococcal agent suspected; increased doses recommended when intermediate resistance suspected;
amoxicillin clavulanate recommended for sicker patients (for coverage of atypical organisms); cephalosporins inferior to
amoxicillin against pneumococci
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Streptococcal Pharyngitis
| Streptococcus resistance: penicillin resistance not seen among isolates of group A Streptococcus; some resistance to
macrolides (6%-7%), clindamycin (0.5%), and levofloxacin (rare)
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| Choice of antibiotic: meta-analysis showed benefit of cephalosporins over penicillin; penicillin—inexpensive; narrow
spectrum of activity; well-studied; cephalosporins—NNT 19 to achieve 1 additional bacteriologic cure (vs penicillin);
core tonsillar cultures obtained from children with recurrent tonsillitis treated with extended spectrum cephalosporins are
less likely to harbor β-lactamase–producing bacteria and more likely to contain beneficial α-hemolytic streptococci,
compared to cultures taken from children treated with penicillin; conclusions—penicillin often preferred over cephalosporins;
small benefit of cephalosporins does not warrant practice change in many cases
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Role of Macrolides in CAP
| Pneumococcal resistance: has increased to ≈35% over past decade; macrolides—isolates resistant to erythromycin also
resistant to azithromycin and clarithromycin
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| Clinical relevance: case-control study showed resistance to erythromycin occurred in 18 of 76 cases (patients receiving
macrolides at time of bacteremia) but in no controls; types of resistance—M-type (ie, efflux pump) thought to result in
“relative” resistance, because higher concentrations of antibiotic overwhelm bacterial capacity to pump out antibiotic;
but bacteremia still may occur; other studies support conclusion that in vitro resistance increases rates of clinical failure
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| Other pathogens: azithromycin and clarithromycin superior to erythromycin against Haemophilus; all macrolides adequate
against Moraxella (rarely seen in outpatient CAP); atypical pathogens—macrolides provide good coverage, including
against Mycoplasma, Chlamydia, and Legionella; respiratory fluoroquinolones and doxycycline also have good
activity
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| Advantages and disadvantages of macrolides: primary strength—coverage of atypical organisms; problems—
unpredictable coverage of pneumococci; widespread use of macrolides for other indications (eg, management of peptic
ulcer disease) likely has contributed to increase in resistance; adverse effects—upper GI effects predominate; fewer
problems with sustained-release products (available for azithromycin and clarithromycin); ototoxicity reported, especially
among older patients receiving long-term therapy with azithromycin or clarithromycin; azithromycin
microspheres—extended-release formulation, approved for management of mild to moderate CAP; associated with
slightly lower rate of GI adverse effects; cardiac effects—QT prolongation and torsades de pointes associated with erythromycin
and clarithromycin; more common among women and patients with underlying cardiac disease; drug
interactions—erythromycin and clarithromycin inhibit cytochrome P450 (CYP450 ) system (ie, interfere with metabolism
of many drugs); azithromycin has little effect on CYP450 system
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| Patterns of resistance: study showed streptococcal resistance to macrolides significantly increased after treatment with
azithromycin (3 days) or clarithromycin (7 days); resistance rates remained elevated for ≥180 days; ribosomal methylase-
associated resistance (MLS-type isolates resistant to macrolides, lincosamides, eg, clindamycin, streptogramins, tetracyclines)
increased with clarithromycin but not azithromycin (persisted through 180 days)
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Telithromycin, Doxycycline, and Fluoroquinolones
| Telithromycin (Ketek): once-daily dosing results in concentrations similar to those achieved with macrolides; GI adverse
effects common; other adverse effects include blurred vision and diplopia (primarily among women <40 yr of age),
QT prolongation (rare), aggravation of myasthenia gravis, and liver toxicity (sometimes fatal); agent approved, despite
discovery of fraud during clinical trials; speaker asserts agent has no role in treatment of outpatient respiratory tract infections
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| Doxycycline: spectrum of activity—equal or superior to macrolides against many pathogens; dosing—bid; some suggest
once-daily dosing for older patients; advantages—well absorbed after oral administration; food does not impair absorption;
adverse effects—upper GI effects common; esophageal ulceration may occur (also associated with
minocycline; risk increases if dose taken at bedtime)
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| Fluoroquinolones: spectrum of activity—predictable against macrolides or β-lactamase-producing pneumococci; good
activity against Haemophilus and Moraxella; predictable against atypical pathogens; adverse effects—GI effects most
common; tendinitis or tendon rupture (more common among older patients; concomitant treatment with glucocorticoids increases
risk); QT prolongation (primarily with moxifloxacin; consider avoiding fluoroquinolones in patients receiving type
III antiarrhythmic agents and those with history of prolonged QT; ciprofloxacin does not appear to increase risk);
advantages—good coverage; once-daily dosing; disadvantages—questionable role in outpatient management of CAP; increasing
resistance, especially among isolates of Pseudomonas and Escherichia coli
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| Choice of antibiotics in CAP: cost varies widely, with doxycycline and amoxicillin being least costly and respiratory
fluoroquinolones being most expensive; doxycycline first choice for patients without comorbidities or recent exposure to
antibiotics (other options include azithromycin [preferred] and clarithromycin); respiratory fluoroquinolones first choice
for patients with comorbidities or recent exposure to antibiotics; combination therapy with β-lactam, eg, amoxicillin, plus
macrolide or doxycycline also good option
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| Questions and answers: doxycycline coverage of Legionella—active in vitro; clinical data show efficacy; no randomized
controlled trials comparing doxycycline to respiratory fluoroquinolones or macrolides; treatment of pertussis—
formerly, erythromycin estolate recommended; other macrolides (including azithromycin and clarithromycin) commonly
used; extended course typically required; fluoroquinolones in athletes—frank tendon rupture has occurred in athletes
taking fluoroquinolones; “weekend warriors” do not appear at increased risk for tendon rupture, compared to other patient
populations; informed consent unnecessary, but educate patients about risk, or consider different class of antibiotics;
treatment of group A streptococcal infections—amoxicillin equivalent to penicillin; maximum dose of amoxicillin—GI
effects not dependent on dose; dose based on weight
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| MORE ON PNEUMONIA —Bradley A. Sharpe, MD, Assistant Clinical Professor of Medicine, Division of Hospital Medicine,
University of California, San Francisco, School of Medicine
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| Epidemiology of CAP: 5 million cases annually in United States; 80% of cases treated in outpatient setting; sixth leading
cause of death in United States; inpatient mortality, 10% to 35%; in patients \>65 yr of age hospitalized for pneumonia, 1-yr
mortality rate 40%; outpatient mortality <1%; ethnicity as risk factor—whites have higher mortality than other populations
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| Presentation: classic symptoms include cough, fever, shortness of breath, and pleuritic chest pain; cough has high sensitivity
(90%) but low specificity (4%)
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| Typical vs atypical presentation: previously thought that classic symptoms (high spiking fever, rigors, rusty sputum, and
lobar infiltrate) indicated typical infectious organisms (S pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis
), whereas “walking pneumonia” (characterized by nonproductive cough, low-grade fever, and hazy bilateral
infiltrates) indicated atypical organisms (eg, Mycoplasma; Chlamydia); evidence shows no features from history, examination,
laboratory tests, or imaging predict etiology; severity of illness and treatment setting (eg, outpatient, inpatient,
intensive care unit) more useful for predicting pathogen; organisms—S pneumoniae most common agent among
inpatients and outpatients; Mycoplasma second most common agent among outpatients (responsible for ≤30% of
cases); clinical implications—narrowing list of infectious agents helps guide therapy
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| Staphylococcus aureus: may cause severe CAP; methicillin-resistant S aureus (MRSA) emerging as important pathogen;
during recent flu seasons (2003-2004 and 2006-2007), 25 cases of influenza-associated MRSA reported; patient
population—15 to 28 yr of age; most patients had no risk factors for MRSA; clinical features—rapid onset and progression
of symptoms; multilobar infiltrate; mortality rate almost 50%; clinical implications—for young patients with
rapidly progressing pneumonia with multilobar infiltrates, consider adding vancomycin to standard treatment regimen to
cover MRSA; increase index of suspicion during winter, when influenza-associated MRSA more common
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| Diagnosis: guidelines require combination of clinical features and imaging; clinical features and history not sensitive or
specific enough to make definitive diagnosis; radiographic evidence confirms or refutes clinical suspicion; if clinical
suspicion high, but imaging does not show infiltrate, acceptable to treat for pneumonia, but remain vigilant about other
diagnoses (eg, pulmonary embolism, chronic obstructive pulmonary disease)
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Suggested Reading
Brook I, Foote PA: Efficacy of penicillin versus cefdinir in eradication of Group A streptococci and tonsillar flora. Antimicrob
Agents Chemother 49:4787, 2005; Bukutu C, et al: Complementary, holistic, and integrative medicine: therapies
for acute otitis media. Pediatr Rev 29:193, 2008; Carbonara S et al: The correct approach to community-acquired
pneumonia in immunocompetent adults: review of current guidelines. New Microbiol 31:1, 2008; Casey JR, Pichichero
ME: Meta-analysis of cephalosporins versus penicillin for treatment of group A streptococcal tonsillopharyngitis in adults.
Clin Infect Dis 38:1526, 2004; Garbutt J et al: Developing community-specific recommendations for first-line treatment
of acute otitis media: is high-dose amoxicillin necessary? Pediatrics 114:342, 2004; Malhotra-Kumar S et al:
Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers:
a randomised, double-blind, placebo-controlled study. Lancet 369:482, 2007; Mandell LA et al: Infectious Diseases
Society of America/American Thoracic Society consensus guidelines on the management of community-acquired
pneumonia in adults. Clin Infect Dis 44 (Suppl 2):S27, 2007; Mills GD et al: Effectiveness of beta lactam antibiotics
compared with antibiotics active against atypical pathogens in non-severe community acquired pneumonia: meta-analysis.
BMJ 330:456, 2005; Prasad S, Ewigman B: Use anesthetic drops to relieve acute otitis media pain. J Fam Pract
57:370, 2008; Rosenfeld RM et al: Clinical practice guideline: adult sinusitis. Otolaryngol Head Neck Surg 137(3
Suppl):S1, 2007; Rubinstein E et al: Pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis
46(Suppl 5):S378, 2008; Williamson IG et al: Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis:
a randomized controlled trial. JAMA 298:2487, 2007; Young J et al: Antibiotics for adults with clinically diagnosed
acute rhinosinusitis: a meta-analysis of individual patient data. Lancet 371:908, 2008.
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