Rational Drug Selection in Infectious Diseases

An Introduction to Rational Drug Selection in Infectious Diseases

Antimicrobial stewardship programs have demonstrated efficacy for reducing antibiotic use, antibiotic costs, antibiotic-associated adverse events, and antibiotic resistance without negative impact on patient outcomes

Rational antibiotic prescribing is one component of antimicrobial stewardship and is comprised of three major tenets

• determining the likelihood of bacterial infection
• weighing the benefits as compared to harms of antibiotic therapy for patients with very likely or confirmed bacterial infection
• choosing the appropriate narrow-spectrum agent, proper dosing, and duration of therapy:

Many bacterial infections in the outpatient setting share overlapping clinical features with viral infections and noninfectious disorders that make the diagnosis challenging

If bacterial infection is likely, consider the benefits versus harms of antibiotic therapy

When antibiotic treatment is likely to provide a net benefit, strategies for deciding the appropriate therapeutic regimen include:

• Choosing appropriate agent(s) for the most likely pathogens
• narrow-spectrum agent preferred over broad-spectrum agent
• choice must account for local resistance patterns
• Selecting the proper dose required for absorption and penetration to the site of infection
• Treating for the shortest duration required to prevent over-exposure that could lead to bacterial resistance

In some cases, observation and delayed prescribing (or the “wait-and-see” approach) may be useful. The observation approach may be considered for acute otitis media and sinusitis in patients without severe symptoms.

Healthcare providers may engage in shared decision making with patients and families to include a discussion on potential benefits and risks associated with immediate antibiotic therapy.

Now that you have been presented with an introduction to this assignment, please select each of the remaining sections by using the navigation pane. You will have a total of five questions to answer. Remember to select submit to post your answers. You will not be able to change your answers after you select submit.

Overview of Outpatient Antibiotic Prescribing

The majority of antibiotics prescribed in the outpatient setting are commonly used for respiratory tract infections, acute otitis media, urinary tract infections, and skin and mucosal conditions. The concept of rational antibiotic use (rational drug selection) refers to prescribing antibiotics only to patients who are expected to benefit from their use by:

1. Determining the likelihood of bacterial infection by:
• Weighing the benefits vs. harms of antibiotic therapy for patients with very likely or confirmed bacterial infection
• Choosing the appropriate narrow-spectrum agent and proper dosing, route, and duration of therapy
2. Benefits of rational antibiotic use include decreasing antimicrobial resistance, antimicrobial-associated adverse events, superinfection, and cost.

What has emerged in the literature is up to half of outpatient antibiotic prescriptions might be inappropriate and at least 30% of those reported are unnecessary likely due to:

• No established criteria exist to standardize definition of inappropriate antibiotic prescribing
• Most studies use expert opinion- or guideline-based definitions of appropriate therapy to assess appropriateness of antimicrobial use:
1. Inappropriate use is defined as:
• Use of antimicrobials not recommended in treatment guidelines or
• Use of antimicrobials to which organism is resistant
2. Unnecessary use defined as:
• Use of antimicrobials for noninfectious disorders
• Use of antibiotics for nonbacterial infections
• Prolonged duration of therapy beyond clinical utility
• Tedundant antimicrobial therapy (≥ 2 agents with activity against the same organism)
• Continuation of empiric broad-spectrum therapy after organism and susceptibility are known
3. Suboptimal use is defined as use of antimicrobials that could be improved in any of following aspects:
• Choice of drug (ex. medication with improved activity against the suspected or known organism)
• Route of administration (i.e. to allow for better penetration at the site of infection)
• drug dose

Please select Respiratory System Infection Rational Drug Selection from the navigation panel to continue.

Respiratory System Infection Rational Drug Selection

Infections of the respiratory system can be found in the nose, sinuses, or lungs, and their management can sometimes be a challenge. Many of these infections can be managed utilizing guideline-directed treatments which have been formulated over time based on clinical experience by experts. As with all infectious disease treatments, you should always keep in mind the concept of rational drug selection and the basics of antimicrobial stewardship to ensure safe and effective treatment of your patients. What follows is an example of guideline-directed recommendations for the management of acute bronchitis in both adults and children, as well as guideline-directed treatment rationales in acute sinusitis. It’s interesting to note the guidelines include many aspects of antimicrobial stewardship built in, and often recommend against the use of antibiotics. his may go against the wishes of some patients because they may expect to receive antibiotics when presenting for an infection. Understanding the guideline-based recommendations will make it easier for you as the provider to explain to your patients that pharmacologic treatment is not always the best course of action in all infectious states.

Acute Bronchitis Overview

Currently, there is no clear diagnostic criteria established for acute bronchitis

Patients with acute bronchitis commonly present with:²

• Productive or non-productive cough lasting up to six weeks
• Mild constitutional symptoms similar to patients with upper respiratory infection

Routine antibiotic treatment not recommended for uncomplicated acute bronchitis, regardless of duration of cough

Patients with acute bronchitis may benefit from symptom relief (cough suppression, fever control, bronchodilation)

National guidelines recommend against the use of antibiotics for acute bronchitis in adults or children:

• American College of Physicians/Centers for Disease Control and Prevention (ACP/CDC) do not recommend routine antibiotic treatment for uncomplicated acute bronchitis, regardless of duration of cough, unless pneumonia suspected²
• American Academy of Pediatrics (AAP) principles of judicious antibiotic prescribing for upper respiratory tract infections (URI) in pediatric patients do not recommend antibiotics for common colds, nonspecific upper respiratory infection, acute cough illness, nor acute bronchitis₁
• National Institute for Health and Care Excellence (NICE) recommends a no antibiotic strategy or a delayed antibiotic prescribing strategy for adults and children more than 3 months old with acute cough/acute bronchitis (Reference: BMJ 2008 Jul 23;337:a437, editorial can be found in BMJ 2008 Jul 23;337:a656).
• Canadian Association of Emergency Physicians recommends avoiding use of antibiotics in adults with bronchitis/asthma (Choosing Wisely Canada 2015 Jun 2)

If pertussis is suspected, perform diagnostic testing and initiate antimicrobial therapy:

• Antimicrobial therapy for suspected pertussis in adults recommended primarily to decrease shedding of pathogen and spread of disease
• Antibiotic treatment does not appear to hasten resolution of symptoms
• Reference: N Engl J Med 2006 Nov 16;355(20):2125full-text

Some guidelines suggest a role for antibiotics in children with "protracted bacterial bronchitis"

• British Thoracic Society (BTS) guidelines for assessment and management of cough in children
• Antibiotics generally not effective or recommended for treating acute coughs caused by simple "head colds"; supporting evidence for this conclusion included children with acute bronchitis and green-colored sputum in absence of signs of possible pneumonia
• Macrolide antibiotics recommended early (first 1-2 weeks) for children with pertussis
• For children with protracted bacterial bronchitis (more than 3 weeks)
• First rule out other underlying conditions and obtain sputum culture before making diagnosis of protracted bacterial bronchitis
• Trial of physical therapy and prolonged course (4-6 weeks) of antibiotics may be attempted

Please select Acute Sinusitis Antibiotic Recommendations from the navigation panel to continue.

Acute Sinusitis Antibiotic Recommendations

• Diagnosis of acute sinusitis typically made clinically
• No accurate diagnostic test to distinguish bacterial from viral sinusitis
• Clinical criteria associated with increased likelihood of bacterial infection include
• Persistent symptoms including nasal discharge or daytime cough not improving by 10 days
• Severe symptoms such as persistent fever (≥ 39 degrees C [102.2 degrees F]), purulent nasal discharge, or facial pain for ≥ 3 days
• Worsening or new onset fever, daytime cough, or nasal discharge after improvement of symptoms
• Antibiotics should be reserved for patients with clinical criteria for bacterial infection
• Observation with close follow-up may be considered for patients with persistent symptoms
• Over-the-counter and alternative therapies may be considered for symptomatic relief
• Antimicrobial agents (antibacterial or antiviral) are not recommended for acute viral rhinosinusitis and watchful waiting may be appropriate for patients with uncomplicated mild illness
• American Academy of Allergy, Asthma and Immunology recommends against indiscriminately prescribing antibiotics for uncomplicated acute rhinosinusitis
• American Academy of Pediatrics recommends against using antibiotics for apparent viral respiratory illnesses including sinusitis, pharyngitis, and bronchitis
• American College of Emergency Physicians recommends avoiding the prescription of antibiotics in the emergency department for uncomplicated sinusitis
• American Academy of Family Physicians recommends against routinely prescribing antibiotics for acute mild-to-moderate sinusitis unless symptoms last for ≥ 10 days, or symptoms worsen after initial clinical improvement

Start empiric antimicrobial therapy if a clinical diagnosis of acute bacterial rhinosinusitis established (Infectious Disease Society of America (IDSA) strong recommendation)

• Antibiotic recommendations for children and adolescents:
• Initial empiric therapy with amoxicillin or amoxicillin-clavulanate
• Amoxicillin 45 mg/kg/day in two divided doses for children ≥ 2 years old with mild-to-moderate uncomplicated acute bacterial sinusitis who do not attend childcare and who have not been treated with antibiotic within the previous four weeks
• Amoxicillin 80-90 mg/kg/day in two divided doses (maximum 2 g/dose) in community with > 10% prevalence of non-susceptible Streptococcus pneumoniae (including intermediate- and high-level resistance)
• Amoxicillin-clavulanate (80-90 mg/kg/day of amoxicillin component with 6.4 mg/kg/day of clavulanate in two divided doses with maximum amoxicillin 2 g/dose) if any of:
• Moderate-to-severe illness
• Age < 2 years
• Attending childcare
• Treatment with antibiotic within previous four weeks
• Amoxicillin-clavulanate preferred over:
• Amoxicillin alone (IDSA strong recommendation, moderate quality of evidence) based on high prevalence of beta-lactamase producing pathogens (Haemophilus influenzae and Moraxella catarrhalis) and in vitro susceptibility data
• Respiratory fluoroquinolone (IDSA weak recommendation, moderate quality of evidence)
• Alternatively, but also acceptable, are these less common antibiotic recommendations for children and adolescents:
• If vomiting is not allowing for oral antibiotics, one dose of ceftriaxone 50 mg/kg/day IV or intramuscularly followed by oral antibiotics 24 hours later
• If risk of antibiotic resistance or if failed initial therapy, use one of the following
• Hgh-dose amoxicillin-clavulanate 90 mg/kg/day orally intwo divided doses
• Levofloxacin 10-20 mg/kg orally once daily or in two divided doses
• For children from geographic regions with high-endemic rates of penicillin non-susceptible S. pneumoniae, consider combination therapy with third-generation oral cephalosporin (cefixime 8 mg/kg/day orally in two divided doses or cefpodoxime 10 mg/kg/day orally in two divided doses) plus clindamycin 30-40 mg/kg/day orally in 3 divided doses
• If beta-lactam allergy is present:
• Levofloxacin 10-20 mg/kg orally once daily or in two divided doses if history of type I hypersensitivity to penicillin
• Combination therapy with oral cephalosporin (cefixime 8 mg/kg/day orally in two divided doses or cefpodoxime 10 mg/kg/day orally in two divided doses) plus clindamycin 30-40 mg/kg/day orally in three divided doses if history of nontype I hypersensitivity to penicillin
• American Academy of Pediatrics (AAP) suggests cefdinir, cefuroxime, or cefpodoxime
• Treat uncomplicated acute bacterial rhinosinusitis for 10-14 days
• Antibiotic recommendations for adults:
• Initial empiric therapy with amoxicillin or amoxicillin-clavulanate
• Amoxicillin-clavulanate 500 mg/125 mg orally three times daily or 875 mg/125 mg orally twice daily
• Amoxicillin-clavulanate preferred over amoxicillin alone by Infectious Disease Society of America (IDSA) based on high prevalence of beta-lactamase producing pathogens (H. influenzae and M. catarrhalis) and in vitro susceptibility data
• Amoxicillin-clavulanate preferred over respiratory fluoroquinolone
• Alternatively, but also acceptable, are these less common antibiotic recommendations for adults:
• High-dose amoxicillin-clavulanate 2,000 mg/125 mg orally twice daily
• Doxycycline 100 mg orally twice daily or 200 mg orally once daily
• If risk of antibiotic resistance or if failed initial therapy, use one of the following
• High-dose amoxicillin-clavulanate 2,000 mg/125 mg orally twice daily
• Levofloxacin 500 mg orally once daily
• Moxifloxacin 400 mg orally once daily
• If beta-lactam allergy is present:
• Doxycycline 100 mg orally twice daily or 200 mg orally once daily
• Levofloxacin 500 mg orally once daily
• Moxifloxacin 400 mg orally once daily
• Treat uncomplicated acute bacterial rhinosinusitis for 5-7 days
• Antibiotics that are not recommended for initial empiric antimicrobial therapy of sinusitis
• Macrolides (clarithromycin and azithromycin)
• Trimethoprim-sulfamethoxazole
• Second- and third-generation oral cephalosporin monotherapy
• Routine antimicrobial coverage for Staphylococcus aureus or methicillin-resistant S. aureus during initial empiric therapy not recommended

Please select Rational Antibiotic Use in Urinary Tract Infections (UTI) from the navigation panel to continue.

Rational Antibiotic Use in Urinary Tract Infections (UTI)

Like respiratory infections, urinary tract infections (UTIs) are commonly encountered in daily practice. Providers should also utilize nationally-recognized guidelines to help in guiding treatment decisions. The fact UTIs are so common has made following treatment guidelines an important tool in fighting antibiotic resistance.

Treatment Overview in Urinary Tract Infections

• Uncomplicated UTI is formally defined as acute cystitis or pyelonephritis occurring in healthy premenopausal, nonpregnant women without underlying urinary tract abnormalities
• Escherichia coli causes majority of infections, followed by other enteric organisms
• Empiric antibiotic therapy for premenopausal women with strongly suspected uncomplicated cystitis is reasonable
• First-line empiric agents for acute uncomplicated cystitis include
• Nitrofurantoin 100 mg orally twice daily for five days
• Fosfomycin trometamol 3 g orally in single dose
• Bactrim (sulfamethoxazole/Trimethoprim)
• 160/800 mg (1 double-strength tablet) orally twice daily for three days
• If local resistance rates ≤ 20% or
• If infecting strain is known to be susceptible
• Not recommended if Bactrim used for UTI in previous three months
• Aminopenicillins or fluoroquinolones should not be used

• Treatment of acute uncomplicated pyelonephritis is based on culture and susceptibility testing
• First-line empiric agents for acute uncomplicated pyelonephritis include
• Fluoroquinolones such as
• Ciprofloxacin 500-750 mg orally twice daily for seven days
• Levofloxacin 750 mg orally once daily for five days
• A single IV dose may be considered before transition to oral therapy for patients appropriate for outpatient therapy, especially in absence of susceptibility testing results
• If rates of fluoroquinolone resistance in E. coli > 10%
• Consider IV ceftriaxone or IV consolidated single daily dose of aminoglycoside, especially if treating empirically
• If organism susceptible, consider
• Bactrim (trimethoprim-sulfamethoxazole [TMP-SMX]) 160 mg/800 mg orally twice daily for 14 days
• Cefpodoxime 200 mg orally twice daily for 10 days
• Ceftibuten 400 mg orally once daily for 10 days
• Do not use nitrofurantoin, oral fosfomycin, or pivmecillinam for uncomplicated pyelonephritis

Other considerations:

Phenazopyridine, a local anesthetic, can be given in addition to antibiotics for symptom relief

• 200 mg orally 3 times daily for maximum 2 days (take after meals)
• Contraindicated if renal disease or severe hepatitis

There is insufficient sufficient evidence to recommend cranberry juice for treatment of UTIs

Please select Summary from the navigation panel to continue.

Summary

References

• Hersh, A.L., Jackson, M.A., & Hicks, L.A. (2013). Principles of judicious antibiotic prescribing for upper respiratory tract infections in pediatrics. American Academy of Pediatrics Committee on Infectious Diseases. 132(6): 1146-54.
• Harris, A.M., Hicks, L.A., & Qaseem A. (2016). Appropriate antibiotic use for acute respiratory tract infection in adults: Advice for high-value care from the american college of physicians and the centers for disease control and prevention. High Value Care Task Force of the American College of Physicians and for the Centers for Disease Control and Prevention. 164(6):425-34.
• Sanchez, G.V., Fleming-Dutra KE, Roberts RM, & Hicks LA. (2016). Core elements of outpatient antibiotic stewardship. MMWR Recomm Rep. 65(6):1-12.
• Spivak, E.S., Cosgrove, S.E., & Srinivasan, A. (2016). Measuring appropriate antimicrobial use: Attempts at opening the black box. Oxford University Press for the Infectious Diseases Society of America. 15;63(12):1639-1644.
• Shields, M.D., Bush, A., Everard, M.L., McKenzie, S., & Primhak, R. (2007). BTS guidelines: Recommendations for the assessment and management of cough in children. British Thoracic Society Cough Guideline Group.
• Chow, A.W., Benninger, M.S., Brook, I., Brozek, J.L., Goldstein, E.J., Hicks, L.A., Pankey, G.A., Seleznick, M., Volturo, G., Wald, E.R., File, T.M.Jr. (2012). IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Infectious Diseases Society of America. 54(8):e72-e112
• Wald, E.R., Applegate, K.E., Bordley, C., Darrow, D.H., Glode, M.P., Marcy, S.M., Nelson, C.E., Rosenfeld, R.M., Shaikh, N., Smith, M.J., Williams, P.V., & Weinberg, S.T. (2013). Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. American Academy of Pediatrics. 132(1):e262-80.
• Rosenfeld, R.M., Piccirillo, J.F., Chandrasekhar, S.S., Brook, I., Ashok Kumar, K., Kramper, M., Orlandi, R.R., Palmer, J.N., Patel, Z.M., Peters, A., Walsh, S.A., & Corrigan, M.D. (2015). Clinical practice guideline (update): adult sinusitis. American Academy of Otolaryngology-Head and neck Surgery Foundation (AAO-HNSF). 152(2)S1-S39.
• Gupta, K., Hooton, T.M., Naber, K.G., Wullt, B., Colgan, R., Miller, L.G., Moran, G.J., Nicolle, L.E., Raz, R., Schaeffer, A.J., & Soper, D.E. (2011). International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the infectious diseases society of america and the european society for microbiology and infectious diseases. Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. 52(5): e103