Internal Medicine Volume 67, Issue 17 | May 7, 2020

Antibiotics 101: Treating Outpatients with Upper Respiratory Infections

From Infectious Diseases in Clinical Practice: Update on Inpatient and Outpatient Infectious
Diseases, presented by the University of California, San Francisco, School of Medicine
B. Joseph Guglielmo, PharmD, Professor and Dean, University of California,
San Francisco, School of Pharmacy, San Francisco, CA

Acute bacterial vs viral rhinosinusitis: study of >2500 patients 2011 study evaluated high-dose amoxicillin-clavulanic acid;
reported that 15 patients with signs and symptoms of rhinosi- patients treated with antibiotics had significantly greater initial
nusitis must be treated for one patient to benefit; patients most and sustained resolution of symptoms; rate of clinical fail-
likely to benefit could not be identified; older patients and those ure (persistent signs of infection on otoscopy) significantly
with longer duration of symptoms or more severe symptoms less in antibiotic group at day 5 (4% vs 23%) and day 12
took longer to cure but were no more likely to benefit from (16% vs 51%); one child in placebo group developed mas-
antibiotics than other patients; in randomized, placebo-con- toiditis; diarrhea and diaper rash more common in children
trolled trial of adults with acute rhinosinusitis, amoxicillin or on antibiotics
placebo given for 10 days; no difference in symptoms between β-lactams for AOM: Streptococcus pneumoniae must be
groups on day 3; amoxicillin group demonstrated benefit at adequately covered; rates of resistance to S pneumoniae lower
7 days but not at 10 days for amoxicillin than penicillin because minimum inhibitory con-
Guidelines from Infectious Diseases Society of America centration of amoxicillin stays higher for longer after treatment;
(IDSA) for acute sinusitis (2012): list clinical presentations cefuroxime, cefpodoxime, and cefdinir often recommended by
most helpful in identifying patients with bacterial illness; anti- American Academy of Pediatrics (AAP) as alternatives, but for
biotics recommended if patient has persistent symptoms for S pneumoniae these drugs inferior to amoxicillin
≥10 days, severe symptoms (fever ≥39°C, purulent nasal dis- Macrolides for AOM: commonly recommended for children;
charge, or facial pain lasting at least 3 to 4 consecutive days), study evaluated S pneumoniae in cultures from middle ear
or “double sickening” (patient feels better after few days, then or mastoid and treatment with erythromycin, clarithromycin,
worsens); in children, moderate recommendation supported or azithromycin; one-fourth to one-third of isolates resistant to
amoxicillin-clavulanic acid; in adults, weak recommendation macrolides; meta-analysis of randomized controlled trials stud-
supported amoxicillin-clavulanic acid; high-dose amoxicillin- ied clinical failure at 10 to 16 days in ≈2700 children treated
clavulanic acid recommended for patients with severe infec- with amoxicillin or amoxicillin-clavulanic acid vs macrolides;
tion, children in daycare, children <2 yr of age, adults >65 yr compared with amoxicillin or amoxicillin-clavulanic acid,
of age, patients previously treated with antibiotics, and immu- macrolides associated with increased risk for clinical failure;
nocompromised patients; guidance did not recommend fluo- however, rate of adverse events (especially diarrhea) signifi-
roquinolones, macrolides, trimethoprim-sulfamethoxazole, or cantly lower in macrolides group
second- or third-generation oral cephalosporins; doxycycline, Guidelines from AAP for AOM: antibiotics indicated for children
however, considered alternative to amoxicillin-clavulanic acid ≥6 mo of age with severe AOM, defined as moderate to severe
Guidelines from IDSA for chronic sinusitis: based on meta- otalgia, otalgia for ≥48 hr, or temperature ≥39C; antibiotics
analysis, preferred treatment high-volume irrigation with saline also indicated for children 6 to 23 mo of age with nonsevere but
plus nasal inhaled steroids; for patients with nasal polyps, bilateral AOM; antibiotics optional for children 6 to 23 mo with
options include short burst of oral prednisone (1 to 3 wk), dox- nonsevere, unilateral AOM and for older children with nonse-
ycycline (≤3 wk), or leukotriene antagonist; for patient without vere AOM (unilateral or bilateral); for optional (observational)
polyps, prolonged course of macrolides (ie, for 3 mo) may be cases, clinician may provide prescription for amoxicillin but
considered instruct parent to first try treating pain with acetaminophen for
Acute otitis media (AOM): severe infections uncommon except few days; AAP regards high-dose amoxicillin (90 mg/kg per
in underserved children; previous studies limited by varying day) as drug of choice; however, if child has been treated with
diagnostic criteria and inappropriate antibiotics and doses; amoxicillin in last 30 days or has history of recurrent AOM
recent key studies restricted to children diagnosed with AOM unresponsive to amoxicillin, coverage should incorporate Hae-
used validated criteria; inclusion criteria effusion in middle ear mophilus influenzae and Moraxella catarrhalis; child should
and either moderate to marked bulging of tympanic membrane be treated with amoxicillin-clavulanic acid, cefdinir, cefuroxime,
(TM) or slight bulging of TM plus otalgia or marked erythema; or cefpodoxime

Educational Objectives Faculty Disclosure

The goal of this program is to improve diagnosis and treatment In adherence to ACCME Standards for Commercial Support,
of upper respiratory infections. After hearing and assimilating Audio Digest requires all faculty and members of the planning
this program, the clinician will be better able to: committee to disclose relevant financial relationships within
1. Identify patients who need antibiotic treatment for upper the past 12 months that might create any personal conflicts
respiratory infections. of interest. Any identified conflicts were resolved to ensure
that this educational activity promotes quality in health care
2. Summarize the recommendations for treatment of upper
and not a proprietary business or commercial interest. For this
respiratory infections from the Infectious Diseases Society
program, Dr. Guglielmo and the planning committee reported
of America and the American Academy of Pediatrics.
nothing to disclose. Dr. Guglielmo presents information in his
3. Manage a patient with chronic sinusitis. lecture related of the off-label or investigational use of a therapy,
4. Compare the advantages and disadvantages of various product, or device.
classes of antibiotics for managing patients with community-
acquired pneumonia.
5. List some long-term adverse effects of antibiotics that
may be mediated by changes in the gut microbiome.

IM-67-17
 Audio Digest Internal Medicine 67:17
Duration of treatment: trial compared treatment with amoxicillin- heartburn, epigastric pain, vomiting, and esophageal ulceration;
clavulanic acid for 10 days and 5 days; found clinical failure drug should be taken with dinner, not at bedtime; deposition in
twice as likely in 5-day group; symptom scores higher in 5-day teeth and bones typical of tetracycline but may not be observed
group; reduction of pain score by 50% significantly more com- in children treated with doxycycline
mon in 10-day group; patients receiving longer course not Fluoroquinolones for CAP: advantages include broad coverage
more likely to develop nonsusceptible pathogens, diarrhea, or and once-daily dosing; however, resistance to some organisms
fungal overgrowth is appearing, and fluoroquinolones risk factor for hypervirulent
Streptococcal pharyngitis: penicillin drug of choice, and not Clostridium difficile; adverse events include upper gastro-
associated with resistance of Streptococcus pyogenes intestinal symptoms, prolonged QT interval, dysglycemia
Allergy to penicillin: often diagnosed early in life, and usually (drugs may increase or decrease blood glucose compared with
in child who receives β-lactam for viral infection; interaction β-lactams), tendon rupture or tendonitis (especially in patients
between virus and drug associated with maculopapular rash; >60 yr of age or on steroids), neuropathy (may occur rapidly
although 10% of patients in United States carry label of allergy and may be permanent), aortic dissection and aneurysm, aortic
to penicillin, <10% of these patients truly allergic; therefore, and mitral valve regurgitation, and carpal tunnel syndrome
only 1% of patients have allergy to penicillin; instead of clari- Omadacycline for CAP: effective against CAP and aerobic
fying whether patient has allergy, clinicians often simply pre- Gram-negative pathogens; side effects and pharmacokinetics
scribe another drug; key questions include history of shortness similar to those of doxycycline; drug available in oral and intra-
of breath and type of skin reaction noted (hives-like vs red and venous forms
raised) Lefamulin for CAP: semisynthetic antibiotic available in oral
Guidelines from IDSA for streptococcal pharyngitis: rapid and intravenous forms; 5 days of lefamulin as effective as
antigen detection test or culture should be performed because 7 days of moxifloxacin for CAP; however, drug metabolized by
clinical features cannot be used to make diagnosis; patient CYP3A4 and therefore associated with drug-drug interactions;
should be treated with penicillin or amoxicillin; alternatives lefamulin may prolong QT interval; omadacycline and lefamu-
include first-generation cephalosporins and some other agents lin are expensive
Acute bronchitis: although antibiotics not effective, 60% to 80% Summary of outpatient treatment of CAP: for patient with no
of patients receive antibiotic; urgent care centers most likely comorbidities and no recent exposure to antibiotics, amoxicil-
to give antibiotics; patients express greatest satisfaction with lin drug of choice; second choice doxycycline; for high-risk
clinicians who prescribe antibiotics; unless pneumonia sus- patient, β-lactam plus azithromycin preferred; alternative is
pected, clinician should not perform testing or give antibiotics respiratory fluoroquinolone
to patient with bronchitis Human microbiome: microbes of gastrointestinal tract and
Community-acquired pneumonia (CAP): azithromycin not mammalian cells evolved in interdependent fashion; contribu-
preferred agent for treating S pneumoniae (most important tions of microbiota include maturation and continued educa-
organism to cover); other causes include Mycoplasma, Chla- tion of host immune response, protection against overgrowth of
mydophila pneumoniae, and viruses; among patients with pathogens, influence on host cell proliferation and vasculariza-
pneumococcal CAP, 20% of cases of S pneumoniae show inter- tion, and regulation of intestinal endocrine function, neurologic
mediate resistance to penicillin, and 15% exhibit high-level signaling, and bone density; microbiota provide energy and bio-
resistance (35% of S pneumoniae not susceptible to penicillin); synthesize vitamins and neurotransmitters; antibiotics increase
30% of isolates resistant to erythromycin, and 20% exhibit risks for inflammatory bowel disease, especially when given
multidrug resistance; main strength of macrolides is coverage to children; risk for eczema increases by 40% when antibiotics
of atypical organisms such as Legionella, Mycoplasma, Chla- given; 7% increase in risk for eczema seen for each additional
mydophila, H influenzae, and M catarrhalis; resistance associated course of antibiotics received during first year of life; any course
with clinical failure of antibiotics doubles risk for juvenile idiopathic arthritis, and
CAP guidelines from American Thoracic Society and IDSA: >5 courses associated with tripling of risk; in Danish registry,
high-dose amoxicillin drug of choice; alternative doxycycline, antibiotics increased risk for diabetes by 50%; risk associated
or macrolide if local pneumococcal resistance <25%; however, with treatments given ≤15 yr before diagnosis of diabetes; in
many clinicians cannot access information on local patterns of Nurses’ Health Study, women who used antibiotics for ≥2 mo
resistance; because national average rate of resistance 30%, between 20 and 39 yr of age had increased risk for colorectal
macrolides may not be useful; for more severe disease, amoxi- adenoma; antibiotic exposure in children associated with sig-
cillin-clavulanic acid recommended; alternatives cefpodoxime nificant increase in weight; largest weight gain associated with
or cefuroxime plus macrolide or doxycycline to cover atypical macrolides; in preterm infants, antibiotics persistently enriched
organisms; another alternative is respiratory fluoroquinolone gastrointestinal antibiotic resistome and prolonged carriage of
such as levofloxacin, moxifloxacin, or gemifloxacin multidrug-resistant Enterobacteriaceae
Macrolides for CAP: side effects may include prolonged QT Zinc for common cold: if taken correctly, zinc shortens duration
interval and torsades de pointes; risk for cardiac toxicity higher of cold symptoms by 1.5 days; data from 3 randomized con-
in females and patients with underlying cardiac disease; some trolled trials showed that dose <75 mg/day of elemental zinc
drugs (eg, clarithromycin, erythromycin) inhibit enzymes in less likely to reduce symptoms; effective dose 80 to 92 mg/day
cytochrome P450 system; azithromycin does not exhibit this Camphor, eucalyptus oil, and menthol rub (eg, Good Sense
interaction; when given with calcium channel blockers, clar- Medicated Chest Rub, Vaporx Balm, Vicks VapoRub):
ithromycin (but not azithromycin) increases risks for hospi- study evaluated children with upper respiratory tract infection
talization for kidney injury, hypotension, and mortality; when and cough, congestion, or rhinorrhea lasting ≥7 days; patients
given with statin, clarithromycin or erythromycin increases randomized to camphor-eucalyptus-menthol rub, inert petrola-
risks for hospitalization due to rhabdomyolysis, kidney injury, tum, or no intervention; study found no significant differences
and mortality; clarithromycin associated with increased risks in cold symptoms among groups; however, camphor-eucalyptus-
for cardiac death and neuropsychiatric events menthol rub associated with increased ability of child and par-
Doxycycline for CAP: spectrum of activity against S pneumoniae ent to sleep
superior to that of macrolides; doxycycline as effective as Summary: except for treatment of CAP, benefit of antibiotics
macrolides against Haemophilus and Moraxella, and active in outpatient upper respiratory infections modest; when patient
against atypical organisms; twice-daily dosing regimen favor- reports allergy to penicillin or β-lactam, clinician should take
able; unlike tetracycline, doxycycline well absorbed orally and time to prove or disprove allergy; high rate of resistance of
not affected by presence of food; side effects include nausea, S pneumoniae to macrolides has decreased their utility for
 Audio Digest Internal Medicine 67:17
treating respiratory infections; emergence of fluoroquinolone- Zinc acetate lozenges may improve the recovery rate of common cold
resistant Escherichia coli, Pseudomonas, and other organisms patients: an individual patient data meta-analysis. Open Forum Infect Dis
has led to recommendation to use these drugs only as alterna- 2017;4(2):ofx059; Lieberthal AS et al: The diagnosis and management
tive agents for most outpatient respiratory tract infections (and of acute otitis media [published correction appears in Pediatrics 2014
not recommended for sinusitis); speaker believes clarithromycin Feb;133(2):346. Dosage error in article text]. Pediatrics 2013;131(3):
e964–e999; Lynch SV, Pedersen O: The human intestinal microbi-
has no utility for upper respiratory infection; antibiotics have ome in health and disease. N Engl J Med 2016;375(24):2369–2379;
significant effect on human microbiome and maybe on some Metlay JP et al: Diagnosis and treatment of adults with community-
noninfectious diseases acquired pneumonia. an official clinical practice guideline of the American
Elements of decision making: clinician must determine whether Thoracic Society and Infectious Diseases Society of America. Am J Respir
patient has infection that requires antibiotic; appropriate Crit Care Med 2019;200(7):e45–e67; Rudmik L, Soler ZM: Medical ther-
cultures should be ordered before starting antibiotic; when apies for adult chronic sinusitis: a systematic review. JAMA 2015;314(9):
antibiotic given, clinician must consider when to stop agent, 926–939; Schwartz BS et al: Antibiotic use and childhood body mass index
give drug with more narrow spectrum, or change from intrave- trajectory. Int J Obes (Lond) 2016;40(4):615–621; Shulman ST et al: Clini-
nous or oral therapy; duration of therapy should be tailored to cal practice guideline for the diagnosis and management of group A strepto-
diagnosis coccal pharyngitis: 2012 update by the Infectious Diseases Society of America
[published correction appears in Clin Infect Dis 2014 May;58(10):1496
Suggested Readings Dosage error in article text]. Clin Infect Dis 2012;55(10):e86–e102; Stets R
Chow AW et al: IDSA clinical practice guideline for acute bacterial et al: Omadacycline for community-acquired bacterial pneumonia. N Engl
rhinosinusitis in children and adults. Clin Infect Dis 2012;54(8):e72–e112; J Med 2019;380(6):517–527; Tamma PD et al: Rethinking how antibiotics
File TM et al: Efficacy and safety of intravenous-to-oral lefamulin, a are prescribed: incorporating the 4 moments of antibiotic decision making
pleuromutilin antibiotic, for the treatment of community-acquired bacte- into clinical practice. JAMA 2019;321(2):139–140; Young J et al: Antibiot-
rial pneumonia: the phase III lefamulin evaluation against pneumonia ics for adults with clinically diagnosed acute rhinosinusitis: a meta-analysis
(LEAP 1) trial. Clin Infect Dis 2019;69(11):1856–1867; Hemilä H et al: of individual patient data. Lancet 2008;371(9616):908–914.

Acknowledgments
Dr. Guglielmo was recorded at Infectious Diseases in Clinical Practice: Update on Inpatient and Outpatient Infectious Diseases, pre-
sented by the University of California, San Francisco, School of Medicine, Office of Continuing Medical Education, and held February
16-21, 2020, in Honolulu, HI. For information on upcoming CME activities presented by the UCSF School of Medicine, please visit
https://meded.ucsf.edu/cme/calendar. The Audio Digest Foundation thanks the Dr. Guglielmo and the University of California, San
Francisco, School of Medicine for their cooperation in the production of this program.

Accreditation: The ­Audio Digest Foundation is accredited by the Accredi- Commission on Accreditation. A ­ udio Digest designates each activity for
tation Council for Continuing Medical Education to provide continuing 2.0 CE contact hours.
medical education for physicians. ­Audio Digest Foundation is approved as a provider of nurse practitioner
Designation: The ­Audio Digest Foundation designates this enduring mate- continuing education by the American Academy of Nurse Practitioners
rial for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should (AANP Approved Provider number 030904). ­Audio Digest designates each
claim only the credit commensurate with the extent of their participation activity for 2.0 CE contact hours, including 0.5 pharmacology CE contact
in the activity. hours.
Successful completion of this CME activity, which includes participation in The California State Board of Registered Nursing (CA BRN) accepts
the evaluation component, enables the participant to earn up to 2.0 Medi- courses provided for AMA PRA Category 1 Credit™ as meeting the continu-
cal Knowledge MOC points in the American Board of Internal Medicine’s ing education requirements for license renewal.
(ABIM) Maintenance of Certification (MOC) program. Participants will Expiration: This CME activity qualifies for AMA PRA Category 1
earn MOC points equivalent to the amount of CME credits claimed for the Credit™ for 35 months from the date of publication.
activity. It is the CME activity provider’s responsibility to submit partici-
Cultural and linguistic resources: In compliance with California Assem-
pant completion information to ACCME for the purpose of granting ABIM
bly Bill 1195, Audio Digest Foundation offers selected cultural and lin-
MOC credit.
guistic resources on its website. Please visit this site: www.audiodigest.org/
The American Academy of Physician Assistants (AAPA) accepts certifi- CLCresources.
cates of participation for educational activities designated for AMA PRA
Category 1 Credits™ from organizations accredited by ACCME or a rec- Estimated time to complete the educational process:
ognized state medical society. Physician assistants may receive a maximum Review Educational Objectives on page 1 5 minutes
of 2 AAPA Category 1 CME credits for each ­Audio Digest activity com- Take pretest 10 minutes
pleted successfully. Listen to audio program 60 minutes
­Audio Digest Foundation is accredited as a provider of continuing nurs- Review written summary and suggested readings 35 minutes
ing education by the American Nurses Credentialing Center’s (ANCC’s) Take posttest 10 minutes
 Audio Digest Internal Medicine 67:17
Antibiotics 101: Treating Outpatients with Upper Respiratory Infections
To test online, go to www.audiodigest.org and sign in to online services.
To submit a test form by mail or fax, complete Pretest section before listening and Posttest section after listening.

1. A study of >2500 patients reported that 15 patients with complaints of acute rhinosinusitis would have to be treated with
antibiotics in order for one patient to benefit. Which of the following groups of patients was found to be more likely to
benefit from treatment with antibiotics?
(A) Older patients
(B) Patients with more severe symptoms
(C) Patients with longer duration of symptoms
(D) Patients most likely to benefit could not be identified **
2. For adults with acute bacterial rhinosinusitis and symptoms for ≥10 days, which of the following antibiotics are recom-
mended by the Infectious Diseases Society of America?
1. Fluoroquinolones
2. Macrolides
3. Amoxicillin-clavulanic acid
4. Second-generation cephalosporins
5. Third-generation cephalosporins
6. Doxycycline
(A) 1,3,4 (B) 2,6 (C) 3,4,5,6 (D) 3,6 **
3. Which of the following, combined with saline irrigation, is the preferred treatment for chronic sinusitis without polyps?
(A) Doxycycline (C) Inhaled steroid **
(B) Oral steroid (D) Leukotriene antagonist
4. Per the American Academy of Pediatrics, which of the following children with acute otitis media should be treated with
antibiotics?
(A) 18-mo-old with mild unilateral otalgia (C) 3-mo-old with temperature of 39.2°C
(B) 8-mo-old with mild bilateral otalgia ** (D) 12-mo-old with mild otalgia for 4 days
5. For a child who needs initial treatment for acute otitis media, which of the following antibiotics does the American Academy
of Pediatric consider the drug of choice?
(A) High-dose amoxicillin ** (C) Cefuroxime
(B) High-dose amoxicillin-clavulanic acid (D) Cefpodoxime
6. A patient presents with suspected streptococcal pharyngitis. Which of the following should the clinician do first?
(A) Perform a rapid antigen test before treating with antibiotics **
(B) Treat empirically with amoxicillin
(C) Treat empirically with penicillin
(D) Use clinical criteria to determine whether to treat with antibiotics
7. For a low-risk patient with community-acquired pneumonia, which of the following antibiotic agents does the Infectious
Diseases Society of America consider the drug of choice?
(A) Lefamulin (C) Amoxicillin **
(B) Levofloxacin (D) Doxycycline
8. Which of the following is a side effect of doxycycline?
(A) Esophageal ulceration ** (B) Hyperglycemia (C) Neuropsychiatric events
9. When given to children, which of the following categories of antibiotics is most strongly associated with weight gain from
effects on the intestinal microbiome?
(A) Macrolides ** (C) Cephalosporins
(B) Fluoroquinolones (D) Penicillins
10. In recent decades, the utility of macrolides for respiratory infections has decreased because _______ has developed a high
rate of resistance to these drugs.
(A) Legionella pneumophila (C) Mycoplasma pneumoniae
(B) Streptococcus pneumoniae ** (D) Haemophilus influenzae
Answers to Audio Digest Internal Medicine Volume 67, Issue 15: 1-C, 2-D, 3-A, 4-A, 5-D, 6-C, 7-A, 8-B, 9-B, 10-D

ⒸⓅ 2020 Audio Digest Foundation • ISSN 0271-1303 • www.audiodigest.org

Toll-Free Service Within the U.S. and Canada: 1-800-423-2308 • Service Outside the U.S. and Canada: 1-818-240-7500
Remarks represent viewpoints of the speakers, not necessarily those of the Audio Digest Foundation.