Open Forum Infectious Diseases MAJOR ARTICLE Outpatient Antibiotic Stewardship: A Growing Frontier—Combining Myxovirus Resistance Protein A With Other Biomarkers to Improve Antibiotic Use 1 2 Patrick Joseph and Eliot Godofsky 1 2 Private Practice to California Infection Control Consultants, San Ramon, California; University Hepatitis Center, Bradenton, Florida Background. e m Th ajority of oral antibiotics are prescribed in outpatient primary and urgent care clinics for acute respiratory infections. Effective antibiotic stewardship must include proper prescribing for outpatients as well as for those in a hospital or long- term care facility. Methods. Major databases, including MEDLINE and the Cochrane Library, were searched for prospective human clinical stud- ies, including children and/or adults published between January 1966 and November 2017 that evaluated Myxovirus resistance protein A (MxA) as a biomarker for diagnosing viral infections as well as both C-reactive protein (CRP) and procalcitonin (PCT) as potential biomarkers for identifying and differentiating true bacterial upper respiratory infection (URI) from colonization. Results. Ten prospective human studies, totaling 1683 patients, were identified that evaluated MxA as a viral biomarker in chil- dren and/or adults. Both systematic review articles, meta-analyses, and randomized controlled clinical trials that examined CRP and/or PCT as a biomarker for identifying clinically significant bacterial infections and supporting antibiotic stewardship were identified. Conclusions. Quick and accurate differentiation between a viral and bacterial respiratory infection is critical to effectively com- bat antibiotic misuse. MxA expression in peripheral blood is a highly specific marker for viral infection. Combining MxA with other inflammatory biomarkers to test for respiratory infections oer ff s enhanced sensitivity and specificity, forming an excellent tool for antibiotic stewardship in the outpatient setting. Keywords. C-reactive protein (CRP); diagnostic; FebriDx; myxovirus resistance protein A (MxA); point of care (POC); procal- citonin (PCT); upper respiratory infection (URI). Acute upper respiratory infections (URIs), inclusive of acute or family pressures, frequently facilitates the misuse of anti- pharyngitis, sinusitis, and tracheobronchitis, are the most com- biotics . Acute pharyngitis is primarily viral in adults, with mon reason for antibiotic therapy in primary care and urgent only about 10% of patients having a bacterial cause, most com- care settings and account for nearly 90% of the 41 million anti- monly a group A beta-hemolytic streptococcus (GABHS) . biotic prescriptions per year for acute respiratory infections None of the symptoms, physical findings, or the clinical criteria (ARI) in the United States . Unfortunately, viral respiratory scores are highly specific for differentiating GABHS from non- infections like influenza oen le ft ad to inappropriate prescrib- GABHS causes . Despite the relatively high frequency of viral ing of antibiotics, contributing to the expanding problem of pharyngitis in adults, physicians prescribe antibiotics for 78% to microbial resistance. In addition, routine antibiotic overuse can 98% of patients with clinical pharyngitis in an effort not to miss lead to unnecessary consultations, emergency room (ER) visits, bacterial GABHS pharyngitis [4, 5]. Furthermore, even though allergic reactions including anaphylaxis, Stevens Johnson syn- 90% of acute bronchitis is thought to be of viral etiology in the drome, and Clostridium difficile infection . United States, the rate of antibiotic prescribing was shown to be Clinical differentiation between a viral and bacterial URI can between 60% and 80% . be challenging. Diagnostic uncertainty, combined with patient Rapid antigen testing, cell culture, and newer molecular tests are limited by their cost, availability, and inability to differenti- ate microbial colonization or carrier states from clinical infec- Received 3 November 2017; editorial decision 14 January 2018; accepted 29 January 2018. tion . This may result in unnecessary antibiotic prescriptions, Correspondence: P. Joseph, MD, FIDSA, 5601 Norris Canyon Road, Suite 220, San Ramon, underscoring the importance of accurately defining a clinically CA 94583 (firstname.lastname@example.org). ® significant bacterial infection [3, 8, 9]. Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Confirmation of a clinically significant active infection Society of America. This is an Open Access article distributed under the terms of the Creative requires the identification of an infectious agent via antigen Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any detection, culture growth, or molecular techniques in associ- medium, provided the original work is not altered or transformed in any way, and that the work ation with a positive immune response, whereas the lack of a sys- is properly cited. For commercial re-use, please contact email@example.com temic immune response suggests a carrier state or colonization. DOI: 10.1093/ofid/ofy024 Outpatient Antibiotic Stewardship • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy024/4860205 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Traditionally, paired serology is performed, necessitating 2 the blood agar plate culture nor the rapid antigen tests can patient visits 2–4 weeks apart, and thus is impractical. Antigen accurately differentiate individuals with true GABHS pharyn- testing and molecular tests are more time efficient  but may gitis from GABHS carriers . Studies have shown that only overestimate the prevalence of true infection, leading to the pre- 40%–50% of the children with GABHS isolated from the upper scription of unnecessary antibiotics [7, 8]. respiratory tract who presented with symptoms of tonsillitis or Efficiently defining a clinically significant bacterial infection pharyngitis demonstrated a systemic immune response [16–18]. requiring antibiotic therapy is the rate-limiting step of anti- When Group A strep is cultured from the OP and associated biotic stewardship in the outpatient setting. Biomarkers such as with an antibody response characteristic of a true infection, CRP C-reactive protein (CRP) or procalcitonin (PCT) independently will elevate 80%–90% of the time [15, 17]. Conversely, patients may identify clinically significant infections, thereby reducing with a negative initial CRP test seldom show a rise in antibody the risk of missing a clinically significant bacterial infection. titer , and 96% have CRP <10 mg/mL . The high carrier However, these biomarkers lack adequate specificity to differ - rate of GABHS and false-positive diagnoses may contribute to entiate a viral from a bacterial infection and ultimately lead to the apparent “failure” rate of approximately 20% with penicillin antibiotic overtreatment of viral infections. Myxovirus resist- therapy . Valkenburg et al. have shown that an antistrepto- ance protein A (MxA), a protein induced by type I interferon, coccal antibody titer is more accurate than a throat culture in is selectively elevated in patients with viral infections and has predicting therapeutic outcome . the potential to greatly enhance the rapid distinction between Differentiation of infection from colonization requires the viral and bacterial respiratory infections [7, 8]. Combining CRP demonstration of an antibody response. However, proving or PCT with an elevated MxA will help identify patients who this immune response is time-consuming and may lead to most likely have viral infection, allowing physicians to consider false-negative results following appropriate antibiotic therapy reserving antibiotics in this patient population and proceed . A study by Ivaska et al.  showed that in 83 patients pre- with a watchful, waiting strategy. senting with pharyngitis, there was no significant difference in the mean initial serum antistreptolysin O (ASO) levels between METHODS the GABHS and non-GABHS patients and only 5 patients showed a 2-fold ASO increase in paired serum samples. Of the Major databases, including MEDLINE and the Cochrane 5 patients with an antibody response, 3 of them were GABHS Library, were searched for prospective human clinical studies, positive, 1 of them was GCBHS positive, and 1 was negative for including children and/or adults published between January streptococci by throat culture. Conversely, blood MxA levels 1966 and November 2017 that evaluated Myxovirus resistance were found to be elevated in 79% of patients with viral pharyn- protein A (MxA) as a biomarker for diagnosing viral infections gitis and remained low in 90% of patients with GABHS without as well as both C-reactive protein (CRP) and procalcitonin virus detection . (PCT) as potential biomarkers for identifying and differen- tiating true bacterial upper respiratory infection (URI) from Serological Biomarkers colonization. Myxovirus Resistance Protein A Colonization and the Carrier State MxA expression in peripheral blood is a highly specific marker Both viruses and bacteria may colonize the nasopharynx (NP) for viral infection [24–30]. MxA is an intracellular blood pro- and oropharynx (OP) without causing infection. Advances tein that mediates cellular resistance against a wide range of in molecular testing and microbial antigen detection with viruses and elevates in the presence of most acute active viral enhanced sensitivity may allow detection of colonization or infections including influenza A and B, respiratory syncytial postinfectious shedding of respiratory pathogens without clin- virus, parainfluenzaviruses, Epstein-Barrr, herpes simplex, ical significance . Respiratory viruses, such as the herpes cytomegalovirus, adenovirus, coronavirus, rhinovirus, and viruses, including Epstein-Barr (EBV) , herpes simplex metapneumovirus infections. However, it is not specific to a virus (HSV) , and cytomegalovirus (CMV) , are asso- particular type of virus [7, 25–27, 30]. ciated with chronic intermittent asymptomatic nucleic acid Interferons (IFNs) are naturally occurring proteins that are shedding. an important part of the host’s innate defense mechanisms Streptococcal carriers are at low risk to spread GABHS to and are released in response to viral infections [7, 31]. The close contacts. They do not require antibiotic treatment and MxA gene is expressed in blood mononuclear cells or locally are at minimal risk for development of rheumatic fever . in tissues, and expression is upregulated exclusively by type Streptococcal carriage may persist for many months and fre- I IFNs [25, 26]. The MxA gene does not respond to other quently poses diagnostic challenges when a symptomatic viral cytokines such as IL-1 or TNF-α. Neither type I IFN nor MxA URI develops in carriers. The low predictive value of throat elevates in healthy patients or those presenting with bacterial swabs relates to the prevalence of carrier rates , and neither infections . 2 • OFID • Joseph and Godofsky Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy024/4860205 by Ed 'DeepDyve' Gillespie user on 16 March 2018 In most cases of acute viral infections, type I IFN and MxA adults and children older than 72 hours are usually 0.15 ng/mL are released into the peripheral blood. Detection of interferons or less . In response to inflammation associated with bacter- in serum is difficult and unreliable, mainly due to their short ial endotoxin or inflammatory cytokines, PCT elevates within half-life . In contrast, MxA has a long half-life of 2.3 days, 2–6 hours, peaks at 12–24 hours, and has a half-life of 25–40 low baseline level of less than 15 ng/mL, and a fast induction hours [37, 40]. Higher procalcitonin levels in patients with bac- time of 1–2 hours aer inf ft ection . The low basal levels of terial sepsis are associated with a greater likelihood of severe MxA protein in tissues, its exclusive expression by type I IFNs, sepsis, septic shock, and decreased survival . Colonization and its relatively long half-life make it an excellent biomarker or carrier states without a systemic host response do not signif- for systemic IFN-α/β production in viral infections. icantly raise procalcitonin levels . Procalcitonin levels fall Recent studies show that other viral biomarkers, such as with successful treatment of either severe bacterial infection or TNF-related apoptosis-inducing ligand (TRAIL) and IP-10, are noninfectious inflammatory stimuli . less effective than MxA at differentiating viral infection. TRAIL URIs tend to cause modest elevations in PCT [42, 43]. Using and IP-10 show area under the curve (AUC) specifically for a lower PCT threshold of 0.1 ng/mL in association with poly- viral infection of 0.72 and IP-10 of 0.72 . Other studies fur- merase chain reaction–confirmed bacterial cultures of common ther support the superiority of MxA as a biomarker for identi- oral pathogens such as GABHS or atypical pathogens such as fying a viral infection, especially in URI [3, 24]. Chlamydophila or Mycoplasma, would suggest a true active bac- terial infection. Higher PCT cutoffs of 0.15–0.25 ng/mL could be C-Reactive Protein used in association with growth of typical bacterial colonizers or CRP is a nonspecific, acute-phase protein that increases during in association with a negative bacterial culture to suggest active an inflammatory process such as a severe infection. The normal bacterial infection in patients without another confirmed source CRP serum concentration is less than 1–3 mg/L and can rise above of infection, such as a viral infection [8, 40]. The PCT response 500 mg/L in the presence of severe inflammation or infection . to viral infections and noninfectious inflammatory stimuli such A high CRP level generally indicates bacterial rather than viral as autoimmune disease and chronic inflammatory processes infection and can also be used to assess disease severity. A sys- typically do not exceed 0.75 ng/mL [44, 45]. Branch et al. found tematic review of acute rhinosinusitis showed that a CRP of less that 17% of viral infections had a PCT >0.25 ng/mL . At low than 10 mg/L provided evidence against bacterial sinusitis and a concentrations (<1.0 ng/mL), PCT is inadequate by itself to dif- CRP greater than 20 mg/L showed evidence supporting bacter- ferentiate viral from bacterial etiology [8, 47, 48]. ial sinusitis . Calvino et al. showed that CRP elevated above RESULTS 20 mg/L in nearly all cases of GABHS, ensuring that a clinically Ten prospective human studies, totaling 1683 patients, were significant infection would less likely be missed, but could not identified that evaluated MxA as a viral biomarker in children differentiate viral from bacterial infection . Similarly, Putto and/or adults. Both systematic review articles, meta-analyses, et al. found that in examining 62 children with positive bacterial and randomized controlled clinical trials that examined CRP cultures, 89% showed a CRP elevated over 20 mg/L, consistent and/or PCT as a biomarker for identifying clinically significant with a clinically significant bacterial infection . bacterial infections and supporting antibiotic stewardship were Typically, bacterial infection stimulates/elevates CRP while identified. having no impact on MxA levels . CRP elevates within 4–6 hours of infection, doubles every 8 hours, and peaks at approxi- Clinical Outcomes Using Biomarker Guidance mately 36–50 hours . Although less common than bacterial CRP and PCT levels do not correlate consistently with each infection, viral pathogens such as adenovirus, parainfluenzavi- other, but in primary care patients with URI, each has moderate rus, influenza, respiratory syncytial virus, Epstein-Barr virus, predictive value for clinical outcome . Both CRP and PCT herpes simplex virus, and varicella zoster virus can raise CRP have been shown to elevate in infectious pharyngitis; however levels significantly over 20 mg/L [7, 24–27, 30, 38]. Therefore, a [42, 43], CRP is more sensitive and PCT is more specific for test system that utilizes both CRP and MxA simultaneously can detection of bacterial tonsillopharyngitis . In most acute potentially differentiate viral infections from bacterial disease respiratory infections, including URI, antibiotic therapy based as the elevated CRP from a viral infection would also be associ- on either biomarker alone has led to reduced antibiotic pre- ated with an elevation in MxA, whereas the MxA levels would scriptions without increased morbidity [50–54]. be normal in bacterial infection. Numerous studies have delineated the utility of CRP in anti- biotic stewardship, specifically decreasing antibiotic prescrip- Procalcitonin tions for patients with respiratory tract infections [50–53]. In PCT is the peptide precursor of calcitonin, a hormone that is Europe, a CRP >20 mg/L is recommended in the Pneumonia synthesized by the parafollicular C cells of the thyroid and regu- Guidelines by the National Institute for Health and Care lates calcium homeostasis. Standard reference values of PCT in Excellence (NICE) as a trigger for prescribing antibiotics . Outpatient Antibiotic Stewardship • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy024/4860205 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Using this CRP threshold, there was no statistically significant ratio of CRP/MxA would optimize differentiation between a increase in patient consultations, emergency visits, or adverse viral and bacterial infection . outcomes . In a recent systematic review and meta-analysis Rapid CRP tests are shown to promote more prudent use of 13 studies in primary care including 10 005 patients, CRP of antibiotics in primary care and have led to a 19% reduction testing led to significantly reduced antibiotic prescribing at the in antibiotic prescriptions . A prospective, multicenter, index consultation without increasing morbidity . cross-sectional study of adults and children with febrile URIs The effect of CRP testing on the outcome of patients in evaluated the diagnostic accuracy of a 15-minute, single-use general practice was evaluated in a recent randomized clin- disposable immunoassay that includes both CRP and MxA ical trial. A total of 179 patients were included, 101 in the (FebriDx; RPS Diagnostics, Sarasota, FL) . During a multi- CRP measurement group and 78 in the control group. Results center, US-based study that enrolled 370 patients, 205 sympto- suggested that CRP testing in patients with acute cough may matic patients with URI and 165 asymptomatic patients from reduce antibiotic prescribing and referral for radiography 10 clinical sites, including academic emergency departments without compromising outcome . Similar results have and community care centers, demonstrated a 97% negative pre- been demonstrated in identifying patients with chronic ob- dictive value (NPV) for bacterial infection. Also, the use of CRP structive pulmonary disease (COPD) exacerbations who do independent of MxA would have led to overtreatment of 38% not need antibiotic treatment . of viral infections . The pattern of results from test systems Clinical trials using PCT to guide antibiotic therapy for with CRP or PCT combined with MxA may assist health care patients with acute respiratory tract infections have shown that professionals to identify an immune response to a suspected a biomarker-driven algorithm can decrease antibiotic prescrib- viral and/or bacterial infection and greatly enhance antibiotic ing significantly and without an increase in adverse events or stewardship in the outpatient setting [7, 24]. This was recently treatment failures [57–62]. PCT-guided antibiotic stewardship demonstrated in a FebriDx study of 21 children and adults reduced initial antibiotic prescription rates by 40% to 50% in (mean age = 46 years) that evaluated the use of MxA plus CRP patients with lower respiratory infection (LRI) presenting to the as a guide for outpatient antibiotic management. Therapy was emergency departments , 70% to 80% in ambulatory patients altered in 48%, and unnecessary antibiotic prescriptions were presenting to their general physicians , and reduced total reduced by 80% without any adverse effects . antibiotic exposure in community-acquired pneumonia by 40% CONCLUSIONS to 50% . In a single-center randomized controlled study, a significant reduction in antibiotic use in patients hospitalized The value of inpatient antibiotic stewardship is embraced by with severe acute exacerbations of asthma was shown utilizing many professional societies such as the IDSA and the Center an algorithm of PCT measurements. In this study, withholding for Disease Control and Prevention (CDC). There are presently antibiotic treatment did not cause any apparent harm . several recommendations, guidelines, and requirements from some licensing organizations that continue to be updated as The Role for Combining Biomarkers to Guide Outpatient Antibiotic Prescribing diagnostics evolve and outcome measurements improve . Several clinical studies have verified that high MxA protein lev- The current focus on inpatients fits well with existing hos- els are strongly correlated with a systemic viral infection while pital surveillance programs and the ability to identify multiply elevated CRP levels are more closely associated with bacterial drug-resistant organisms. disease [3, 7, 8, 24–26]. Simultaneously performing CRP and Inpatient stewardship is driven in part by modern micro- MxA should predictably increase sensitivity and specificity for biology, which is oen n ft ot available or impractical in the out- identifying bacterial disease. patient setting. Outpatient stewardship is also critical, but more Combining MxA detection with a marker specific to bacter - difficult to implement. According to the CDC and American ial infection, such as CRP, could be of greater predictive value College of Physicians, up to 50% of antibiotic courses prescribed and allow more reliable differentiation between viral and bac- in the outpatient setting are inappropriate and completely un- terial infections than using a marker of bacterial infection alone necessary. This equates to more than $3 billion in direct costs. [7, 8, 24]. A high MxA with or without an elevated CRP would Additionally, billions of indirect costs include: (1) antibiotic-re- strongly suggest a viral infectious process and the absence of sistant illnesses, (2) antibiotic adverse events, and (3) secondary a bacterial infection . Unlike the common occurrence of infections with Clostridium difficile diarrhea . incidental identification of multiple pathogens in the OP or NP, A major obstacle to effective outpatient antibiotic stewardship true active co-infection that leads to a systemic viral and bac- and appropriate antibiotic prescribing is the difficulty in accur - terial immune response is not common in URI [1, 8]. If both ately defining the microbial cause of respiratory infections, espe- viral and bacterial pathogens are identified, an associated PCT cially distinguishing viral from bacterial etiology. This diagnosis ≥0.75 ng/mL or CRP ≥100 mg/L may support a diagnosis of a is even more challenging when rapid tests identify bacterial true co-infection result. Others have suggested that a defined pathogens present in the carrier state. Additionally, attempts to 4 • OFID • Joseph and Godofsky Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy024/4860205 by Ed 'DeepDyve' Gillespie user on 16 March 2018 differentiate bacterial from viral infections using only the history biomarkers such as CRP and MxA can be extremely useful as and physical findings are inaccurate about one-half of the time an important adjunct to traditional methods. Further studies . Patients may also have symptoms mimicking an infectious should be directed toward the delineation of biomarker utility process, which is actually caused by hypersensitivity, especially in the outpatient setting. rhinovirus and coronavirus acting directly as allergens, eliciting Acknowledgments an IgE elevated response. This may lead to low-grade fevers and Author contributions. P.J. wrote the paper. E.G. performed critical exacerbation of reactive airway disease in predisposed patients review. with a history of underlying allergies, atopy, asthma, or COPD Financial support. This study was unsponsored, and the authors [68, 69]. Lastly, patient expectations of therapy present another received no specific funding for this work. Potential conifl cts of interest. All authors: no reported conflicts of challenge to overcome in the outpatient setting. In 1 study, up to interest. All authors have submitted the ICMJE Form for Disclosure of 50% of parents had a previsit expectation of receiving an anti- Potential Conflicts of Interest. Conflicts that the editors consider relevant to biotic . 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Open Forum Infectious Diseases – Oxford University Press
Published: Feb 1, 2018
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