Authors: Kristin E. Fontes, MD (Emergency Physician, Santa Barbara Cottage Hospital and Goleta Valley Cottage Hospital) and Oladoyin Liu, PharmD (Emergency Department Pharmacy Specialist, Santa Barbara Cottage Hospital) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW/Parkland Memorial Hospital) and Brit Long, MD (@long_brit)

Case 1:

A 3-year-old ex-term and otherwise healthy boy who is fully immunized presents to the Emergency Department with his parents for 3 days of right ear pain and subjective fevers. He also has had a runny nose and dry cough. His older sister is also ill with similar symptoms.

Vital signs are as follows: T 99.9 F, HR 110, BP 100/60, RR 24, O2 sat 100% on room air

On examination, the child is smiling and interactive. He has moderate clear rhinorrhea, but demonstrates no nasal flaring, tracheal tugging, retractions, or other signs of increased work of breathing. Breath sounds are clear bilaterally. His left tympanic membrane is clear, and the right tympanic membrane is dull, bulging, and erythematous. There is no perforation. His mastoid areas are non-tender and demonstrate no erythema. His parents request a course of antibiotics for his ear infection, stating that in the past his ear infections always resolved after his pediatrician prescribed amoxicillin.

Case 2:

An 84-year-old woman with atrial fibrillation who takes warfarin presents with epistaxis and spontaneous bruising to her arms. She denies trauma. She states that her medications have not recently changed, but that 2 days ago she started a course of trimethoprim/sulfamethoxazole for a urinary tract infection.

Vital signs are as follows: T 98.6 F, HR 90, BP 120/70, RR 16, O2 sat 98% on room air

On examination, she is slightly pale. She has moderate continuous bleeding from both nares and is also noted to have multiple areas of ecchymoses on her arms. The epistaxis is finally controlled with placement of bilateral nasal packs. Relevant labs demonstrate Hb/Hct of 8.0/24.0, platelet count of 200, and INR of 6.0.

Think back to your last week in the Emergency Department. How many patients with infectious symptoms did you see? How many of them did you diagnose with an infection? To how many of them did you prescribe a course of antibiotics? How did you select the drug to prescribe? How did you select the drug in patients who reported prior antibiotic allergies? How did you decide on the dosing frequency and length of course they received? For discharged patients, did they receive an initial parenteral (IV/IM) dose in the ED? Were there any complications related to their antibiotic therapy (e.g. adverse drug reactions, C. diff colitis)? If cultures were obtained, were there any that grew an organism that was resistant to your initially prescribed agent?

Introduction

Each year in the United States, physicians prescribe hundreds of millions of antibiotic courses in the outpatient setting (1), and we spend over 10 billion dollars in the process (2). According to 2013 data from the Centers for Disease Control and Prevention (CDC), amoxicillin and azithromycin remain the most commonly prescribed agents, and there is a tendency for more frequent prescribing in the South (3). Emergency medicine providers accounted for just over 5% of all prescriptions that year (3). Unfortunately, providers write a significant number of prescriptions for conditions that rarely require antibiotic therapy (4,5). Furthermore, while inappropriate antibiotic prescribing rates for acute respiratory tract infections in children may be decreasing (6), we seem to be prescribing more antibiotics for conditions like otitis media (7), which is commonly viral in origin. Probably the greatest threat to patients from antibiotic therapy is emerging antimicrobial resistance and complications such as Clostridium difficile colitis, and these two factors combined lead to at least 35 thousand deaths every year (8).

This article focuses on common errors related to antibiotic use in the Emergency Department, as well as suggestions for improving our practice in appropriately and safely managing acute infections.

Potential antibiotic errors to be mindful of…

Common errors: Ask your ED clinical pharmacist what antibiotic errors they commonly encounter in their daily operations. A few examples:

Error Example Inappropriate dosing/frequency: · Indication-based dosing · Weight-based dosing Cephalexin 500 mg QID (standard for skin/soft tissue infections) for UTI treatment (should be 500 mg BID or 250 mg QID) Vancomycin 1 g IV for adults with skin/soft tissue infections (rather than calculating accurate 15-20 mg/kg loading dose) Overlooking previous culture identification and susceptibilities Empiric ceftriaxone for UTI treatment in a patient with previously documented extended spectrum beta lactamase (ESBL)-producing E. coli Over-treatment of organisms demonstrating good antimicrobial susceptibility Empiric carbapenem for UTI treatment in a patient with pan-sensitive E. coli Inadequate dose adjustment in patients with renal disease Giving standard Zosyn 3.375 g IV dose; in most cases individual dose will be 2.25 g IV for patients with CrCl <40

The presence of an ED clinical pharmacist has a positive impact on antibiotic error reduction (9) and efficiency in administering appropriate antibiotics (10). However, there are still several other potential areas for error when it comes to medical decision making.

Despite mindfulness about proper antibiotic selection and administration, we are learning more about how much antibiotic prescribing is even appropriate. According to a recent review of antibiotic prescriptions given in ambulatory care visits in the United States, the estimated prescription rate was 506 per 1000 population, only 353 of which were deemed appropriate (11). The American College of Physicians and CDC also released guidelines this year on appropriate antibiotic use for acute respiratory infection in adults, of which the general advice is to avoid testing/treating conditions that are likely viral (e.g. bronchitis, rhinosinusitis), and reserving antibiotics only for confirmed bacterial infections (e.g. group A streptococcal (GAS) pharyngitis) or persistent severe symptoms (in the case of rhinosinusitis) (12). However, antibiotic treatment for even confirmed cases of GAS is controversial, especially given the incidence of acute rheumatic fever in the United States is now extremely low (13).

While much of the current literature focuses on inappropriate antibiotic use, some recent data are challenging traditional teaching regarding management of uncomplicated cutaneous abscesses, for example. While the importance of adequate source control cannot be underestimated, a study examining trimethoprim-sulfamethoxazole (TMP/SMX) versus placebo when combined with typical incision and drainage found a small yet significant clinical cure benefit with antibiotic administration (14). However, note that in the study population there was a seemingly large amount of surrounding erythema (median length and width 6.5 cm and 5.0 cm, respectively), which suggests a greater degree of infection. Additionally, as we will discuss shortly, TMP/SMX therapy carries multiple risks.

The penicillin-allergic patient:

Penicillin is among the most commonly documented drug allergies (15). While a significant number of these are likely unreliable based on skin testing (16), it creates a challenge when selecting an antibiotic. A good example is the proposed cross reactivity with other beta lactam antibiotics, including cephalosporins and carbapenems. The most recent available data suggest that cefazolin (1st generation), as well as 3rd- and 4th- generation cephalosporins without a similar side chain to penicillin appear to carry a negligible risk of causing a cross allergy (17), and aztreonam and carbapenems appear to be well-tolerated even in patients with positive penicillin skin testing (18).

Drug-drug interactions with antibiotics:

Even when administered appropriately, we must consider the potential for serious drug-drug interactions when prescribing a course of antibiotics. This is of particular concern among elderly patients and those with comorbid medical conditions. Note, however, that the only antibiotic on the Beers Criteria (list for potentially inappropriate medications in geriatric patients) is nitrofurantoin (due to risk of pulmonary toxicity). Numerous case and population-based studies have documented the morbidity and mortality associated with drug-drug interactions, and we will highlight some of them here.

Warfarin: As illustrated in Case 2 above, antibiotics increase bleeding risk in patients taking warfarin. A recent analysis of Medicare Part D claims data illustrated the significant risk for bleeding associated with exposure to any antibiotic within 15 days, with the adjusted odds ratio (AOR) being highest for TMP/SMX (AOR 4.57, CI 1.90-11.03) and somewhat lower for cephalosporins (AOR 2.45, CI 1.52-3.95) and penicillins (AOR 1.92, CI 1.21-2.07) (19). The lowest (albeit not “low”) risk was seen with fluoroquinolones (AOR 1.69, CI 1.09-2.62).

Non-steroidal anti-inflammatory drugs (NSAIDs): While not widely reported in the literature, NSAID use may exacerbate rhabdomyolysis known to complicate TMP/SMX therapy (20).

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB): In a cohort of more than 4,000 patients taking ACE inhibitors or ARBs admitted to a Canadian hospital, TMP/SMX therapy was associated with a significantly increased risk of hyperkalemia-associated hospitalization when compared to amoxicillin (AOR 6.7, CI 4.5-10.0). The same study demonstrated no such effect from use of ciprofloxacin, norfloxacin, or nitrofurantoin (21).

Sulfonylureas: Antibiotic use can lead to profound hypoglycemia in patients concurrently taking a sulfonylurea. A recent review of Texas Medicare claims for patients taking glipizide or glyburide as well as a recently prescribed antibiotic assessed hypoglycemia events, and found significant risk (as calculated by odds ratio (OR)) with clarithromycin (OR 3.96, 95% CI 2.42-6.49), levofloxacin (OR 2.60, CI 2.18-3.10), TMP/SMX (OR 2.56, CI 2.12-3.10), metronidazole (OR 2.11, CI 1.28-3.47), and ciprofloxacin (OR 1.62, CI 1.33-1.97) (22). TMP/SMX by itself may also have a sulfonylurea-like effect by leading to increased serum insulin levels (23).

Take home point:

For patients concurrently taking warfarin, ACE inhibitors, ARBs, NSAIDs, or sulfonylureas, avoid use of trimethoprim/sulfamethoxazole (TMP/SMX), if possible.

Questions to ask yourself

Are there any diagnostic tests that can help guide the decision to start or stop antibiotic therapy?

While antibiotic stewardship programs and national objectives to reduce the number of antibiotic prescriptions (e.g. Healthy People 2020) have received significant attention recently, we know that antibiotics save lives when administered appropriately in patients with severe sepsis and septic shock (24). Hospitals commonly employ protocols to assess for the presence and severity of bacterial infection in patients presenting with the systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), an acute phase protein, is released by parenchymal cells in response to bacterial toxins, and may also downregulate in response to viral infections (25). One meta-analysis found a sensitivity of 77% and specificity of 79% for PCT in the diagnosis of sepsis, but also noted significant heterogeneity across individual studies (26). Recent Emergency Department studies examining community acquired pneumonia (CAP) demonstrate that PCT measurement may help reduce the duration of antibiotic therapy, whereas for acute exacerbations of chronic obstructive pulmonary disease (COPD), it may help reduce the number of prescriptions written (27). Some inpatient data suggests that the degree of elevation in PCT may predict the need for invasive respiratory or vasopressor support in patients with CAP (28). Regarding PCT and urinary tract infection (UTI), there is a paucity of literature from the United States, but there are a few studies from Europe. A study from Switzerland investigated a novel algorithm in which the value of the serum PCT guided the duration of antibiotic therapy in patients with clinical UTIs (uncomplicated and complicated). Overall, patients in the experimental group (clinical features of UTI + PCT/pyuria assessment) received a shorter duration of antibiotic therapy when compared to the control group (who had clinical features of UTI without PCT/pyuria assessment) (29). Another study found that PCT demonstrated reasonable diagnostic accuracy (as represented by the area-under-the-curve (AUC) of receiver operating characteristics (ROC), 0.71 for PCT, confidence interval (CI) 0.56-0.85) in predicting 30-day mortality in febrile UTIs, but did not perform as well as the plasma midregional pro-adrenomedullin (MR-proADM, 0.83, CI 0.71-0.94), a novel biomarker (30). Yet another study found that PCT achieved the greatest ROC-AUC for predicting the presence of bacteremia in patients with UTI (0.993, P<.001), which was better than both lactate (0.844) and CRP (0.534) (31). There is limited data on PCT measurement in skin and soft tissue infections, but one small study suggested that PCT successfully discriminated between lower limb erysipelas and deep vein thrombosis, whereas C-reactive protein and white blood cell count measurements did not (32).

Take home point:

Consider obtaining a serum procalcitonin level as part of your medical decision making for starting antibiotic therapy (may be more useful for respiratory and urinary tract infections).

Is an initial dose of parenteral antibiotics indicated prior to discharge from the ED?

Excluding sexually transmitted infections (33), there is a paucity of literature addressing this particular question. ED providers will often administer an initial dose of parenteral (intravenous or intramuscular) antibiotics in patients they project can be safely discharged once therapy is complete (e.g. uncomplicated skin/soft tissue infections, UTI/pyelonephritis), perhaps discrepant with established recommendations (34, 35). One concern is the risk of complications associated with parenteral antibiotics. A recent prospective cohort study of generally healthy ED patients with various infections who were discharged on antibiotics were evaluated for the development of antibiotic-associated diarrhea (AAD) as well as C. diff infection (CDI). Patients who were given an initial dose of IV antibiotics prior to discharge on oral antibiotics were at significantly increased risk for AAD compared to patients who received only oral treatment (relative risk 2.085, CI 1.206-3.606). Two patients in the AAD group (4.4%) developed CDI (36). In the same study, patients who took a longer course of antibiotics (mean 9.5 days), as well as those taking clindamycin as mono- or combination therapy, also had an increased rate of AAD (36).

Other ways to improve our practice

If there is only one reference from this post you read, review this recent article on ED antibiotic stewardship development recommendations (37). It goes into much greater detail regarding specific programs for reducing antibiotic errors than we will here, including physician and pharmacist leadership roles, educational interventions, and post-prescription reporting to providers.

It can be said without hyperbole that we live in an antibiotic-dependent society in the United States. The parents from Case 1 above represent an all-too-common scenario. Today’s healthcare providers are under constant scrutiny with regard to patient satisfaction, among other quality metrics. Unfortunately, unnecessary antibiotic therapy may be associated with increased patient satisfaction (38). However, in some cases patients may care more about having a better understanding of their illness than receiving a prescription (39). Despite established national guidelines, overuse of antibiotics remains prevalent (40).

Patient/parent shared decision making and education:

A survey of adults in Kentucky found that 61% of respondents believed antibiotics would be effective for treating a 5-day condition of cough, sore throat, and clear nasal discharge, and 79% believed in antibiotic efficacy if the nasal discharge was discolored (41). Perhaps, then, there is a role for enhancing patient/parent education in an effort to curtail antibiotic overuse. One study enrolled adults seen in the ED with acute respiratory infection (ARI) symptoms and implemented an interactive kiosk to assess knowledge about ARIs as well as desire for antibiotic therapy. Improved knowledge was associated with a decreased desire for antibiotics (p=0.001) (42). Another study randomized family physicians to either a training program designed to employ shared decision making (SDM) with regard to antibiotics for acute respiratory tract infections, or to a control group that did not receive training. They found that the training program positively influenced SDM as assessed by patients, but the actual decision to treat ARIs with or without antibiotics was not examined (43).

While education about antibiotic overuse/misuse is important, providers should also consider education patients/parents about judicious antibiotic use when they are actually prescribed an antibiotic course. A group in France randomized pediatric ED patients/parents receiving an antibiotic prescription to undergo therapeutic education, delivered by a clinical pharmacist, about either fever control or antibiotic use. At the 14-day follow up, parents in the antibiotic (intervention) group were more satisfied with the education they received than those in the fever control (control) group (96.9% vs 83%, P=0.002), and also performed better on a questionnaire about judicious antibiotic use (P=0.017) (44).

Take home point:

Consider using shared decision making or implementing patient/parent educational interventions to enhance judicious antibiotic use.

Antibiograms:

Do you use an antibiogram to guide your antibiotic treatment decisions? There are advantages to this approach, most importantly knowing specific resistance patterns within your institution and/or region. However, institution-specific antibiograms usually calculate antimicrobial susceptibility for organisms cultured from patients throughout the hospital (including the ED, wards, and ICU). Do these data accurately represent microbial isolates from the general ED population, where patients may not be as acutely ill or have as many comorbid conditions as patients in the inpatient setting? Most of the available literature is regarding UTI management. One group (cleverly!) capitalized on an error in their electronic medical record system in which all abnormal urinalysis samples from the ED were reflexively cultured. They found that, when comparing antimicrobial susceptibility of E. coli from ED cultures to the hospital-wide antibiogram, ED-specific susceptibility was significantly higher for common antibiotics including TMP/SMX (80% vs 71%), cefazolin (97% vs 87%), and ciprofloxacin (89% vs 73%) (p<0.05) (45). Another group obtained similar results with ciprofloxacin susceptibility within their institution (46).

Are ED-specific antibiograms even helpful, given we often do not send cultures on otherwise healthy patients with uncomplicated infections? One group found that, even when compared to their own ED antibiogram, women with uncomplicated E. coli UTIs (who otherwise would likely not have had a urine culture sent) had significantly lower resistance to ciprofloxacin (2% vs 42%, p<0.001), levofloxacin (2% vs 26%, p<0.001), and TMP/SMX (16% vs 33%, p=0.016) (47).

Take home point:

Use antibiograms with caution; they may underestimate antimicrobial susceptibility specific to ED patients, in particular those with uncomplicated infections.

Conclusion

Safe and appropriate antibiotic use requires education of both providers and patients. While medication errors are common and some are difficult to avoid, there are multiple areas for improvement. ED clinical pharmacist intervention for error prevention, thorough medical decision making in the management of acute infections, and efforts to improve patient and provider knowledge of the risks, benefits, and limitations of antibiotic use are only a few ways to address this important issue. Lastly, the ED is an important setting in which to implement programs that support antibiotic stewardship.

Take home point:

Harness the power of (and thank on a regular basis) your ED clinical pharmacists!

Takeaways…

For patients concurrently taking warfarin, ACE inhibitors / ARBs, NSAIDs, or sulfonylureas, avoid use of trimethoprim/sulfamethoxazole (TMP/SMX), if possible. Consider obtaining a serum procalcitonin level as part of your medical decision making for starting antibiotic therapy (may be more useful for respiratory and urinary tract infections). Consider using shared decision making or implementing patient/parent educational interventions to enhance judicious antibiotic use. Use antibiograms with caution; they may underestimate antimicrobial susceptibility specific to ED patients, in particular those with uncomplicated infections. Harness the power of (and thank on a regular basis) your ED clinical pharmacists!

References / Further Reading:

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Fleming-Dutra KE, Hersh AL, Shapiro DJ, Bartoces M, Enns EA, File TM Jr, Finkelstein JA, Gerber JS, Hyun DY, Linder JA, Lynfield R, Margolis JA, May LS, Merenstein D, Metlay JP, Newland JG, Piccirillo JF, Roberts RM, Sanchez GV, Suda KJ, Thomas A, Woo TM, Zetts RM, Hicks LA. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016 May 3;315(17):1864-73. Donnelly JP, Baddley JW, Wang HE. Antibiotic utilization for acute respiratory tract infections in U.S. emergency departments. Antimicrob Agents Chemother 2014;58(3):1451-7. Fischer T, Singer AJ, Lee C, Thode HC Jr. National trends in emergency department antibiotic prescribing for children with acute otitis media, 1996-2005. Acad Emerg Med 2007 Dec;14(12):1172-5. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. Available via the internet: http://www.cdc.gov/drugresistance/threat-report-2013/ DeWitt KM, Weiss SJ, Rankin S, Ernst A, Sarangarm P. Impact of an emergency medicine pharmacist on antibiotic dosing adjustment. Am J Emerg Med 2016 Jun;34(6):980-4. Moussavi K, Nikitenko V. Pharmacist impact on time to antibiotic administration in patients with sepsis in an ED. Am J Emerg Med 2016 Nov;34(11):2117-2121. Fleming-Dutra KE, Hersh AL, Shapiro DJ, Bartoces M, Enns EA, File TM Jr, Finkelstein JA, Gerber JS, Hyun DY, Linder JA, Lynfield R, Margolis DJ, May LS, Merenstein D, Metlay JP, Newland JG, Piccirillo JF, Roberts RM, Sanchez GV, Suda KJ, Thomas A, Woo TM, Zetts RM, Hicks LA. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA 2016 May 3;315(17):1864-73. Harris AM, Hicks LA, Qaseem A. 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