Essential Elements of Outpatient Antibiotic Stewardship

Educational Objectives

The goal of this program is to improve antibiotic prescribing practices. After hearing and assimilating this program, the clinician will be better able to:

1. Promote antibiotic stewardship in the dental setting.
2. Implement guideline-based recommendations for antibiotic prophylaxis.
3. Choose appropriate antibiotics for Clostridioides difficile infection (CDI) and recurrent CDI.
4. Optimize care for patients with allergic reactions to antibiotics.

Summary

Stewardship in the dental setting: dentists prescribe 10% of antibiotics (ABs) in the United States, 50% of which are for infection prevention in high-risk patients, and ≈85% of those are inappropriate or do not follow guidelines; dentists face significant barriers to implement stewardship, including a need for satisfied patients to return, limited access to full medical records, limited awareness of adverse effects (AEs) that occur in their patients, and patient expectations; recommendations — the American Heart Association (2021) outlines high-risk conditions (eg, prosthetic valves, endocarditis, cardiac transplants with valvulopathy, congenital heart defects) that require prophylaxis before invasive dental procedures; intermediate-risk conditions (eg, pacemakers, peripheral stents) do not require prophylaxis; the American Dental Association and American Academy of Orthopedic Surgeons recommend against prophylaxis for prosthetic joints

AB for dental prophylaxis: administer 30 to 60 min before the procedure or ≤2 hr after a procedure (oral amoxicillin [AMX] is preferred); patients with penicillin allergies may need alternatives (eg, cephalexin, azithromycin, doxycycline [DOX]); clindamycin is no longer recommended for AB prophylaxis; streptococci are showing increased resistance, and clindamycin is associated with more AEs

Risks: a single dose of AB can lead to Clostridioides difficile (C diff) infection (CDI); more likely with clindamycin than AMX; 15% of community-acquired CDI are attributable to ABs for dental procedures; 1.4% of patients who received oral prophylaxis against recommendations developed AEs, and 83% visited the emergency department

C diff infection: C diff, a spore-forming, anaerobic gram-positive rod, causes severe colitis in the setting of gut dysbiosis, infecting ≈500,000 patients annually; prevalence is shifting from predominantly hospital-acquired to community-acquired; AB exposure, extended hospitalizations, a history of C diff, serious immune compromise, and older age increase risk; ABs (eg, clindamycin, fluoroquinolones (FQ), broad-spectrum cephalosporins) are often associated with C diff; Infectious Diseases Society of America (IDSA) guidelines (2021) recommend fidaxomicin as the first-line treatment, followed by oral vancomycin as an alternative (metronidazole for patients who cannot take these); diagnosis — polymerase chain reaction (PCR) test is too sensitive and detects a gene that can produce toxin, not the active toxin itself; immunoassay can detect glutamate dehydrogenase antigen and toxin; a positive immunoassay most likely indicates presence of C diff; positive antigen and negative toxin may yield unclear results; clinical suspicion and combining immunoassay and PCR are often used to determine colonization or infection; avoid test of cure in patients with resolved symptoms

Fidaxomicin: a macrocyclic AB (a macrolide class) with a targeted spectrum of activity with C diff; the high cost is a treatment barrier; trials demonstrate no difference in clinical cure, drug-related AEs, or all-cause mortality between fidaxomicin and oral vancomycin; however, the difference in sustained response has led to the recommendation of using fidaxomicin; fidaxomicin is significantly better than vancomycin in preventing additional episodes of C diff; some cost-effectiveness models favor fidaxomicin over vancomycin; macrolide allergy — uncommon; anaphylaxis is rare; rechallenging non-anaphylactic reactions to macrolides is recommended; fidaxomicin has minimal systemic absorption (structural similarities with other macrolides) and is recommended for a non-anaphylactic macrolide allergy

Recurrent CDI: risk factors include age >65 yr, chronic hemodialysis, AB use, and recent hospitalization; ≤30% of patients with a single episode experience recurrence, with ≈5% experiencing multiple recurrences; recurrent CDI is associated with lower 6-mo survival; if vancomycin was the initial treatment, fidaxomicin (standard regimen or taper) or vancomycin (pulsed or tapered) can be used; extended dosing may help eradicate the spores; if fidaxomicin was the initial treatment, try tapering or switching to vancomycin pulsed or tapered; adjunctive treatments include bezlotoxumab and fecal microbiota transplant

Bezlotoxumab: a monoclonal antibody that binds to the C diff toxin B gene; used only as an adjunct as a single weight-based dosing; expensive; carries a warning of heart failure exacerbation and should be avoided in that patient population; recommended for patients at high risk for recurrence, with the strongest signal among patients with severe immune compromise; limited data show improved outcomes compared with fidaxomicin and vancomycin

Fecal microbiota transplant: an effective treatment for some patients; not approved by the US Food and Drug Administration; some concerns about infectious complications; an oral form (Vowst [4 oral capsules daily for 3 days]) and liquid suspension (Rebyota [enema]) were recently approved in 2023

Vancomycin as secondary prophylaxis: some meta-analyses support its efficacy; for patients with multiple recurrences or very severe initial and recurrent episodes, 125 mg oral vancomycin can be given once daily throughout and ≤5 days after the AB course

Treatment strategies for uncomplicated diverticulitis (UD): no ABs — ABs are unnecessary in patients with mild UD without significant comorbidities; improve metronidazole tolerance — adjust the dosing (traditionally every 8 hr or thrice daily); half-life is similar to ceftriaxone (once daily dose), and its active metabolite lasts ≈12 hr in the body; blood concentrations at 12 hr exceed the minimum inhibitory concentration for anaerobic organisms; 12-hr dosing improves tolerance, especially gastrointestinal; peripheral neuropathy and encephalopathy are rare and dose-related; easier for patients and decreases overall cost; exclude patients with unstudied conditions (eg, C diff, amoebic infections or conditions requiring higher concentrations) for 12-hr dosing; investigate the penicillin allergy — 9 of 10 patients with a listed allergy may not actually be allergic; intolerance, immunologic reaction to something else, or allergy waning over time should be considered; ≈80% of positive skin tests become negative after 10 yr

Management: penicillin allergy, need to use penicillin — AMX challenge (500 mg) for low-risk patients (benign skin reaction or remote unknown reaction; ≈90% of patients); penicillin allergy, need to use cephalosporin — for non-anaphylactic penicillin allergy, use any cephalosporin; for anaphylactic penicillin allergy, use a structurally different cephalosporin; cephalosporin allergy, need to use cephalosporin — for non-anaphylactic reaction, use a structurally different cephalosporin

Cephalosporin use in penicillin allergy: cross-reactivity rate between penicillin and cephalosporins is 0.7% or 1%; Sousa-Pinto et al (2021) — a study involving 220 patients with a history of anaphylaxis to penicillin found no severe reactions in any of the groups given clindamycin, vancomycin, or cefazolin, and similar rates of nonsevere reactions across groups; some patients may be more sensitive to ABs regardless of the treatment

β-lactam cross-sensitivity: cross-reactivity may be related to the structure of the β-lactam side chains; patients with penicillin allergies should avoid antimicrobials with similar side chains; first-generation oral cephalosporins (cephalexin and cefadroxil) are not suitable for patients with anaphylactic penicillin allergies; consider cefazolin and cefuroxime

Fluoroquinolones: not suitable for patients with resistant Escherichia coli; 30% to 40% of E coli in most US states are FQ-resistant; AEs — FQs have black box warnings for tendinitis, tendon rupture, and worsening myasthenia gravis; other warnings include psychiatric effects, blood glucose regulation, and increased risk for ruptures or tears in the aorta; avoid FQs in patients with a history of aortic aneurysm or strong risk factors

Oral ABs for urinary tract infection (UTI): IDSA recommends sulfamethoxazole-trimethoprim (SMX-TMP; eg, Bactrim, Cotrim, Septra), FQs, and nitrofurantoin (Macrobid, Macrodantin) over oral β-lactam ABs; urinary excretion is important for determining the concentration at the infection site; select an AB with high urinary excretion; first-generation oral cephalosporins are comparable to levofloxacin and SMX-TMP; third-generation oral cephalosporins have worsened pharmacokinetics; third-generation intravenous cephalosporins have expanded gram-negative coverage, but coverage is less clear for oral preparations; the Clinical and Laboratory Standards Institute recommends cefazolin as a marker for third-generation oral cephalosporin susceptibility; recommendations — do not use cefdinir for urinary source infections; AMX is better for AMX-susceptible organisms; AMX-clavulanic acid (CLA; Augmentin) is a good choice for broad coverage; DOX is useful for prostatitis (high tissue concentration); avoid tetracyclines, including DOX, for UTI or pyelonephritis

AB prostate concentration: Lipsky et al (2010) recommended FQs or SMX-TMP as first-line treatment for prostatitis; levofloxacin's tissue level is higher than its plasma level; β-lactams are now used more because of FQ-resistant E coli; cefuroxime is the best cephalosporin for prostate concentration followed by AMX-CLA and AMX; DOX is suitable for tetracycline-susceptible E coli or Enterococcus

FQ allergy: usually presents with delayed skin reactions that resolve with diphenhydramine (eg, Benadryl, Diphedryl, Tranquil) and cessation of FQ; occurs in 2% to 3% of patients; cross-reactivity between moxifloxacin, levofloxacin, and ciprofloxacin is low (limited data); consider using the same FQ for non-anaphylactic reaction that occurred >5 yr prior; consider a different FQ for a more severe or recent reaction

Tetracyclines against CDI: therapeutic concentrations of DOX inhibit C diff growth in vitro; cannot be used as a treatment option but helps prevent recurrent infections; studies show that ceftriaxone plus DOX results in a lower CDI rate vs ceftriaxone alone; DOX can cause phototoxicity

Linezolid and serotonin syndrome (SS): SS starts with mild symptoms, eg, tachycardia, shivering, diaphoresis; can progress to worsening conditions (rhabdomyolysis, seizures, and death) if the agent is not discontinued; linezolid has a low risk for SS (0.1%-0.5%), even when given with other serotonergic agents; SS is reversible if detected; linezolid penetrates well into multiple sites and is sometimes the only oral option for treatment; benefits usually outweigh risks; long-term linezolid use increases risk for cytopenia and peripheral and optic neuropathies; inform patients and check complete blood cell count weekly with long-term use beyond 2 to 3 wk; linezolid has shown some activity against C diff

Longer duration: in patients receiving ABs for pneumonia, risk for C diff infection increases by 9% each day; for each additional day of broad-spectrum AB use, risk for AB-related AEs increases by 5% and risk for broad-spectrum AB resistance increases by 8%

Readings

AHC Media. Clostridioides difficile infection: Guideline update. Internal Medicine Alert. 2021 October 15;43(376):p0. View Article; Evans CT, Fitzpatrick MA, Poggensee L, et al. High prescribing of antibiotics is associated with high prescribing of opioids in medical and dental providers. Pharmacotherapy: The Journal Of Human Pharmacology & Drug Therapy. 2022 September;42(9):p716–723. DOI: 10.1002/PHAR.2720. View Article; Johnson S, Lavergne V, Andrew M, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical Infectious Diseases. 2021 September 01;73(5):p755–757. DOI: 10.1093/CID/CIAB718. View Article; Khan DA, Banerji A, Blumenthal KG, et al. Drug allergy: A 2022 practice parameter update. Journal of Allergy & Clinical Immunology. 2022 December;150(6):p1333–1393. DOI: 10.1016/J.JACI.2022.08.028. View Article; Lipsky BA, Byren I, Hoey CT. Treatment of bacterial prostatitis. Clinical Infectious Diseases. 2010 June 15;50(12):p1641–1652. DOI: 10.1086/652861. View Article; Sousa-Pinto B, Blumenthal KG, Courtney L, et al. Assessment of the frequency of dual allergy to penicillins and cefazolin: A systematic review and meta-analysis. JAMA Surgery. 2021 April;156(4):pe210021. DOI: 10.1001/JAMASURG.2021.0021. View Article; Suda KJ, Hicks LA, Roberts RM, et al. A national evaluation of antibiotic expenditures by healthcare setting in the United States, 2009. Journal of Antimicrobial Chemotherapy. 2013 March;68(3):p715–718. DOI: 10.1093/JAC/DKS445. View Article; Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clinical Infectious Diseases. 2002 June 15;34(12):p1651–1652. DOI: 10.1086/340710. View Article; Wilson WR, Gewitz M, Lockhart PB, et al. Prevention of Viridans Group Streptococcal Infective Endocarditis: A Scientific Statement from the American Heart Association. Circulation. 2021 May 18;143(20):pe963–e978. DOI: 10.1161/CIR.0000000000000969. View Article.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Richardson was recorded at Primary Care in Paradise: Medical Specialties from the Primary Care Perspective, held April 1-4, 2024, on Maui, HI, and presented by Scripps Health. For information on future CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

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Lecture ID:

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