CHALLENGING ISSUES FOR THE CLINICIAN
| OUTPATIENT ANTIMICROBIALS: ADVICE ON APPROPRIATE USE —B. Joseph Guglielmo, Pharm D, Professor and
Vice-Chair, Department of Clinical Pharmacy, University of California, San Francisco
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| Etiology of community-acquired pneumonia (CAP): order of association—Streptococcus pneumoniae (also
commonly associated with sinusitis and otitis); Mycoplasma pneumoniae (younger population at greater risk); Chlamydia
pneumoniae; viruses
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| Beta-lactams: pneumococcal resistance to penicillin 30%; amoxicillin does not show similar resistance; cephalosporins,
promoted because of extended spectrum of activity against β-lactamase–producing gram-negative bacteria, appear inferior
to amoxicillin in antipneumococcal activity; studies show surge in penicillin resistance in 1990s has plateaued
and may have decreased
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 | Cephalosporins: first generation—no role in outpatient management of respiratory tract infections (poor antipneumococcal
drugs); second generation—oral cefuroxime only drug used frequently in this setting; third generation—
cefixime (available only as suspension); cefpodoxime most used as effective drug in treatment of outpatient pneumococcal
respiratory tract infection
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| Amoxicillin vs penicillin: in vitro activity different; effectiveness increases with length of time β-lactam remains in
bloodstream and tissue compartments; if time above minimum inhibitory concentration (MIC) >50%, efficacy optimal
(eg, organism that shows in vitro penicillin nonsusceptibility actually has amoxicillin susceptibility and clinical efficacy
with high dose [40 mg/kg per day in adult] because of optimal time over MIC); cefuroxime plus/minus drug
against pneumococcus with intermediate susceptibility; amoxicillin best β-lactam against pneumococcus
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| Amoxicillin and potassium clavulanate: new formulation (Augmentin XR) contains more amoxicillin and less clavulanic
acid than earlier preparation; increased amount of amoxicillin provides effectiveness against penicillin-nonsusceptible
pneumococci; lower dose of clavulanate decreases gastrointestinal (GI) side effects
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| Treatment of CAP: β-lactams limited by lack of coverage of atypical organisms; amoxicillin preferred β-lactam when
pneumococcus suspected organism; amoxicillin–clavulanate picks up β-lactamase producers (speaker argues these not
important); cephalosporins, while more active against other organisms, less than optimal when compared to amoxicillin
in their activity against pneumococcus
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| Beta-lactams in other upper respiratory infections (URIs): amoxicillin drug of choice for sinusitis and otitis;
delayed-prescription strategy—give parent amoxicillin prescription with instruction to fill it at 72 hr if child worse or
not better; high-dose amoxicillin—give to children in daycare or those who recently received antibiotics, particularly
amoxicillin
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| Streptococcus pyogenes: number one bacterial pathogen in pharyngitis; no cases of penicillin-resistant S pyogenes; controversial
in that meta-analyses show cephalosporins better than penicillin for bacteriologic and clinical cure of pharyngitis;
penicillin inexpensive, has narrow spectrum of activity, and well studied in prevention of rheumatic fever; meta-analysis
data show absolute difference between cephalosporins and penicillin 5.4% (19 number needed to treat to get 1 additional
bacteriologic cure); speaker believes penicillin still drug of choice; mechanism—study of 40 children with recurrent tonsillitis
treated with penicillin or cefdinir found S pyogenes isolated from 11 penicillin-treated and 3 cefdinir-treated patients
at conclusion of therapy; β-lactamase–producing bacteria (Staphylococcus aureus, Haemophilus influenza, and Moraxella
catarrhalis) recovered from significantly more patients treated with penicillin than with cefdinir; conclusion that
cephalosporins kill β-lactamase–producing organisms while penicillin does not, and these organisms degrade penicillin
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| Allergy: cross-reactivity between penicillin and cephalosporins different for each cephalosporin; American Academy of
Pediatrics recommends cephalosporins in patients who have IgE-mediated reaction to penicillins; speaker does not recommend
any cephalosporin in patients who have had anaphylactic reaction to penicillin because of potential cross-reactivity;
sulfonamide allergy—study looked at patients with history of sulfonamide antibiotic allergy vs those without this
history; patients with history who got sulfonamide nonantibiotic significantly more likely to have reaction; patients with
history of sulfonamide antibiotic reaction significantly more likely to have allergy to penicillin after receiving penicillin
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| Macrolides: resistance—one quarter of all S pneumoniae isolates resistant to macrolides; erythromycin resistance has increased
significantly (≤40%); M–type resistance—concentration-dependent; easily overcome with high levels of drug;
macrolide-lincosamide-streptogramin (MLS)–type resistance—all or none; clinical relevance—case-control study
of patients with bacteremic pneumococcal infection; case group (organism grown out of bloodstream intermediate or resistant
to erythromycin) vs controls (susceptible to erythromycin); study found that case group patients actively taking macrolide
antibiotics orally at time blood cultures positive significantly more likely to have bacteremia than controls; M-type
resistance significantly more likely to show itself in patients taking macrolide at time of bacteremia, as opposed to those not
receiving macrolides; conclusion that in sicker patients, macrolide not drug of choice (especially if patient bacteremic);
study—trial looked at percentage of resistance, based on prior receipt of antibiotic; previous treatment with azithromycin
most associated with resistance to penicillin, ceftriaxone, trimethoprim–sulfamethoxazole (TMP–SMX), or erythromycin; if
coverage needed for H influenzae, azithromycin and clarithromycin better than erythromycin; all macrolides adequate
against Moraxella (not significant pathogen in most patients); coverage of atypical organisms—macrolides provide
good coverage for Mycoplasma, Chlamydia, and Legionella; fluoroquinolones and doxycycline offer comparable coverage;
adverse events—upper GI intolerance; ototoxicity (dose-related, reversible cochlear involvement; elderly at risk); cardiac
toxicity (prolonged QT interval and torsades de pointes); erythromycin and clarithromycin potent inhibitors of
cytochrome (CY)P450 isoenzymes, leading to interactions with drugs cleared by these enzymes; azithromycin microspheres
(Zmax oral suspension)—one-time, 2-g dose extended-release suspension; approved for sinusitis and mild-to-
moderate CAP; CAP—coverage of atypical organisms primary strength of macrolides; macrolides plus/minus in pneumococcal
coverage (contraindicated in elderly patients with spiking fevers and possiblity of bacteremia); widespread use of
macrolides for nonantibacterial indications contributing to decline in susceptibility
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| Nonantibacterial use of macrolides: macrolides have anti-inflammatory activity that reduces release of lipid mediators,
eg, cytokines, that damage lungs; study—mean number of colds significantly reduced when erythromycin taken for
12 mo; hospitalization for exacerbation of chronic obstructive pulmonary disease (COPD) not found in erythromycin
group (present in control group); cystic fibrosis—study showed significant increase in exacerbation-free periods in patients
receiving azithromycin; cardiovascular disease—association of antibodies against C pneumoniae with risk for
cardiovascular events; demonstration of C pneumoniae in atheromatous plaques; study—in patients who had suffered
myocardial infarction (MI) and had documented C pneumoniae titers, azithromycin had no effect; found increased incidence
of diarrhea and abdominal pain and significant reduction in incidence of respiratory tract infections in treated
group; conclusion that use of these drugs in cardiovascular disease not indicated
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| Telithromycin: pros—active against community-acquired pathogens (eg, penicillin-resistant and/or macrolide-resistant
pneumococcus, H influenzae, M catarrhalis, atypical organisms); long half-life; once-daily dosing; cons—
telithromycin similar to erythromycin and clarithromycin in inhibition of CYP450 isoenzymes; similar adverse-events
profile to erythromycin; causes reversible blurred vision; possible liver failure
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| Doxycycline: spectrum of activity against S pneumoniae, H influenzae, M catarrhalis, and atypical organisms equal or
superior to macrolides; good tolerability; twice-daily dosing; study on susceptibility of S pneumoniae shows doxycycline
at least as good as macrolides in CAP; food does not impair absorption, but iron and bismuth do; upper GI adverse
effects
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| Fluoroquinolones: those with adequate antipneumococcal activity include gatifloxacin, gemifloxacin, levofloxacin, and
moxifloxacin; rate of pneumococcal resistance <1%; adverse events—upper GI; not toxic to children; tendinitis and tendon
rupture (risk factors include age >60 yr and concomitant glucocorticoid use); prolonged QT (risk factors include patient
receiving drugs that prolong QT or history of prolonged QT); gatifloxacin more dangerous than other respiratory
fluoroquinolones in patients with diabetes; fluoroquinolone susceptibility—Pseudomonas aeruginosa resistance
50%; Escherichia coli resistance 30%
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| Outpatient treatment recommendations: professional societies—low-risk patient with CAP, give macrolide or
doxycycline; high-risk patient (eg, comorbidities, recent receipt of antibiotics, age >65 yr), give combination of β-lactam
plus macrolide or doxycycline; single-drug therapy includes antipneumococcal fluoroquinolone; important to know patient’s
antibiotic history; speaker recommends—in patient with no comorbidities and not recently exposed to antibacterials,
doxycycline first choice; amoxicillin has strong role; second choice azithromycin; third choice clarithromycin; in
high-risk patients, respiratory fluoroquinolone as first choice, combination of β-lactam and macrolide/doxycycline as
second choice, and telithromycin as third choice
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| HIV-ASSOCIATED PULMONARY DISEASE —Laurence Huang, MD, Associate Professor of Clinical Medicine, University
of California, San Francisco, School of Medicine, and Chief, AIDS Chest Clinic, San Francisco General Hospital
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| Bacterial pneumonia: most common HIV-associated pulmonary disease; HIV-infected individuals have 25-fold higher
rates of pneumonia than HIV-negative individuals; rates increase as CD4 cell counts decrease; rates of pneumococcal bacteremia
50- to 100-fold higher in HIV-positive patients (blood cultures important for patients with low CD4 cell count who
present with presumed CAP); pathogens—S pneumoniae, H influenzae, Staphylococcus aureus, and gram-negative
bacteria, including P aeruginosa; treatment and outcome—no difference in time to clinical stability, length of hospitalization,
or mortality, compared to HIV-negative people; preventive strategies—highly active antiretroviral therapy
(HAART); pneumococcal vaccine (especially if CD4 count high); TMP–SMX (if CD4 count low); risk factor modification
(eg, stopping use of cigarettes, injected and smoked illicit drugs)
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| Mycobacterium kansasii: clinical and radiographic presentation similar to Mycobacterium tuberculosis; M kansasii potential
colonizer (nonpathogen); recovery from single respiratory culture not diagnostic for M kansasii pneumonia;
guidelines for diagnosis include compatible symptoms and findings on x-ray or high-resolution computed tomography
(HRCT) and on respiratory specimens (eg, 3 positive cultures, 2 positive cultures and 1 positive smear, granuloma on
biopsy)
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| Tuberculosis (TB): with CD4 count <200 cells/µL, look for extrapulmonary manifestations in lymph nodes, liver, bone
marrow, genitourinary tract, and central nervous system; radiographic presentation depends on T cell count; high T cell
count, look for upper lung–zone disease, often with cavitation; low T cell count, look for diffuse disease (including
miliary), middle and/or lower lung zone; cavitation less common, hilar and mediastinal adenopathy more common; patients
with TB and low T cell count may have normal radiograph 1 in 10 times
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| Immune reconstitution syndrome (IRS): paradoxical worsening of opportunistic infection with concurrent treatment
of HIV and opportunistic infection; pulmonary diseases where IRS described include TB, Pneumocystis jirovecii
(formerly carinii) pneumonia (PCP), and cryptococcal pneumonia; diagnosis of exclusion (consider nonadherence,
drug resistance, and concurrent or superimposed process, eg, bacterial pneumonia); underlying mechanism related to
immune response to residual organism and/or antigen
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| P jirovecii pneumonia: classically presents with 2 to 4 wk of gradually progressive symptoms; often HIV-identifying
(and AIDS-defining) diagnosis; bronchoscopy with bronchoalveolar lavage (BAL) gold standard diagnostic procedure;
sputum induction initial diagnostic procedure (sensitivity decreasing); possible TMP–SMX resistance; PCP requiring intensive
care unit (ICU) care associated with high mortality rate; retrospective studies suggest use of HAART associated
with improved survival of HIV-positive patients with PCP in ICU
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| Kaposi’s sarcoma: pulmonary Kaposi’s sarcoma can present in absence of visible mucocutaneous disease; most patients
with Kaposi’s sarcoma have mucocutaneous disease; Kaposi’s sarcoma seen almost exclusively in gay or bisexual
men; many patients with pulmonary Kaposi’s sarcoma have concurrent opportunistic infection; understanding epidemiology
of disease and characteristic radiographic findings key to diagnosis
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| Lymphocytic interstitial pneumonitis: rare cause of pulmonary disease in HIV-infected adults; more common in
HIV-infected children; clinical and radiographic presentation often indistinguishable from opportunistic infection; characteristic
chest x-ray has bilateral reticular nodular infiltrates, often with lower lung-zone predominance; diagnosis requires
tissue biopsy; optimum treatment unclear
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| Concurrent diseases: HIV-infected patients may present with >1 concurrent disease; PCP and bacterial pneumonia
have clinical and radiographic presentations relatively distinguishable from one another; diagnosis difficult when concurrent
diseases have identical or overlapping clinical and radiographic features (eg, PCP and cryptococcal pneumonia)
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| Pulmonary arterial hypertension (PAH): HIV-infected patients may develop PAH that shares clinical and pathologic
features with primary PAH; HIV infection associated with increased prevalence of PAH; in HIV patients, PAH possibly
due to pulmonary venous hypertension, associated with hypoxemia, or chronic thrombotic and/or embolic disease
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Educational Objectives
| The goal of this program is to provide the listener with information on antimicrobials and the treatment of outpatient respiratory
infections and HIV-associated pulmonary diseases. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. Discuss the use of β-lactams in the treatment of community-acquired pneumonia (CAP).
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| 2. Explain the role of macrolides in the treatment of CAP and their nonantibacterial uses.
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| 3. Compare outpatient antimicrobials in treatment of CAP.
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| 4. Discuss the spectrum of pulmonary diseases that are associated with HIV infection.
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| 5. Describe the challenges of diagnosing concurrent pulmonary diseases in HIV-infected patients.
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Discussed on This Program
Amiodarone HCl [Cordarone, Pacerone]
Amoxicillin [several trade names]
Amoxicillin and potassium clavulanate (co-amoxiclav) [Augmentin, Augmentin ES-600, Augmentin XR]
Azithromycin [Zithromax, Zmax]
Cefdinir [Omnicef]
Cefixime [Suprax] (discontinued)
Cefpodoxime proxetil [Vantin]
Ceftriaxone sodium [Rocephin]
Cefuroxime [Ceftin, Kefurox, Zinacef]
Clarithromycin [Biaxin, Biaxin XL]
Doxycycline [several trade names]
Erythromycin [several trade names]
Gatifloxacin [Tequin, Zymar]
Gemifloxacin mesylate [Factive]
Ibutilide fumarate [Corvert]
Levofloxacin [Levaquin, Quixin]
Moxifloxacin HCl [Avelox, Avelox I.V., Vigamox]
Penicillin [several trade names]
Sotalol HCl [Betapace, Betapace AF]
Tetracycline HCl [Sumycin 𣝢’, Sumycin 𣡜’, Sumycin Syrup]
Telithromycin [Ketek]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ)[several trade names]
Suggested Reading
Barbaro G, et al: Highly active antiretroviral therapy compared with HAART and bosentan in combination in patients
with HIV-associated pulmonary hypertension. Heart 92:1164, 2006; Boyton RJ: Infectious lung complications
in patients with HIV/AIDS. Curr Opin Pulm Med 11:203, 2005; Carrie AG, Kozyrskyj AL: Outpatient
treatment of community-acquired pneumonia: evolving trends and a focus on fluoroquinolones. Can J Clin
Pharmacol13:e102, 2006; Daneman N, et al: Macrolide resistance in bacteremic pneumococcal disease: implications
for patient management. Clin Infect Dis 43:432, 2006; Dean NC, et al: Comparing gatifloxacin and clarithromycin
in pneumonia symptom resolution and process of care. Antimicrob Agents Chemother 50:1164, 2006; File
Tm Jr.: Clinical implications and treatment of multiresistant Streptococcus pneumoniae pneumonia. Clin Microbiol
Infect 12 Suppl 3:31, 2006; Goossens H, Little P: Community acquired pneumonia in primary care. BMJ
332:1045, 2006; Innes Al, et al: Resolution of lymphocytic interstitial pneumonitis in an HIV infected adult after
treatment with HAART. Sex Transm Infect 80:417, 2004; Kabra S, et al: Antibiotics for community acquired
pneumonia in children. Cochrane Database Syst Rev 3:CD004874, 2006; Lesho E: Evidence base for using corticosteroids
to treat HIV-associated immune reconstitution syndrome. Expr Rev Anti Infect Ther 4:469, 2006; Lujan
M, et al: Optimal therapy for severe pneumococcal community-acquired pneumonia. Intensive Care Med 32:971,
2006; Marcetti F, Berti I: Pneumonia: macrolides or amoxicillin for community acquired pneumonia? BMJ
332:1213, 2006; Miguez-Burbano MJ, et al: Non-tuberculosis mycobacteria disease as a cause of hospitalization
in HIV-infected subjects. Int J Infect Dis 10:47, 2006; Narendran G, et al: Immune reconstitution syndrome in a
child with TB and HIV. Indian J Pediatr 73:627, 2006; Puthanakit T, et al: Immune reconstitution syndrome
from nontuberculous mycobacterial infection after initiation of antiretroviral therapy in children with HIV infection.
Pediatr Infect Dis J 25:645, 2006; Rice LB: Antimicrobial resistance in gram-positive bacteria. Am J Infect Control
34:s11, 2006; Waterer GW, et al: Delayed administration of antibiotics an atypical presentation in community-acquired
pneumonia. Chest 130:11, 2006.
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 issue,
the faculty reports nothing to report.
Dr. Guglielmo was recorded at the 27th Annual Advances in Infectious Diseases: New Directions for Primary Care,
held April 26-28, 2006, in San Francisco, CA, and sponsored by the Division of Infectious Diseases, Department of
Medicine, University of California, San Francisco, School of Medicine. Dr. Huang was recorded at The Medical
Management of AIDS A Comprehensive Review of HIV Management, held December 8-10, 2005, in San Francisco,
CA, and sponsored by the Department of Medicine, University of California, San Francisco, School of Medicine. The
Audio-Digest Foundation thanks the speakers and the UCSF School of Medicine for their cooperation in the production
of this program.
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