Implications for Emergency Medicine ,

American Journal of Emergency Medicine 35 (2017) 154–158

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American Journal of Emergency Medicine

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Review Newly approved antibiotics and antibiotics reserved for resistant ☆ ☆☆ ★ infections: Implications for emergency medicine , ,

Maryann Mazer-Amirshahi, PharmD, MD, MPH a,b,⁎, Ali Pourmand, MD, MPH c,d, Larissa May, MD, MS, MSPH e

a Department of Emergency Medicine, MedStar Washington Hospital Center, Washington, DC b Georgetown University School of Medicine, Washington, DC c Department of Emergency Medicine, The George Washington University, Washington, DC d The George Washington University, School of Medicine and Health Sciences, Washington, DC e Department of Emergency Medicine, UC Davis, Davis, CA

article info abstract

Article history: Millions of patients are evaluated every year in the emergency department (ED) for bacterial infections. Emer- Received 19 September 2016 gency physicians often diagnose and prescribe initial antibiotic therapy for a variety of bacterial infections, rang- Received in revised form 13 October 2016 ing from simple urinary tract infections to severe sepsis. In life-threatening infections, inappropriate choice of Accepted 13 October 2016 initial antibiotic has been shown to increase morbidity and mortality. As such, initiation of appropriate antibiotic therapy on the part of the emergency physician is critical. Increasing rates of antibiotic resistance, drug allergies, and antibiotic shortages further complicates the choice of antibiotics. Patients may have a history of prior resistant infections or culture data indicating that common ﬁrst-line antibiotics used in the ED may be ineffective. In recent years, there have been several new antibiotic approvals as well as renewed interest in second and third line antibiotics because of the aforementioned concerns. In addition, several newly approved antibiotics have the advantage of being administered once weekly or even as a single infusion, which has the potential to decrease hospitalizations and healthcare costs. This article reviews newly approved antibiotics and antibiotics used to treat resistant infections with a focus on implications for emergency medicine. © 2016 Elsevier Inc. All rights reserved.

1. Introduction later time. Occasionally, patients may present to the ED from healthcare facilities and/or with previous culture data indicating an infection with Every year, millions of patients present to the emergency depart- organisms that are resistant to first and second line antibiotics. ment (ED) with bacterial infections [1]. These infections can range in The overuse of antibiotics has had the unintended effect of contribut- etiology and severity from mild cystitis to life threatening septic ing to antibiotic resistance, which presents a major challenge in the cur- shock. Emergency physicians must recognize the signs and symptoms rent healthcare environment. The Centers for Disease Control and of bacterial infection and initiate appropriate antibiotic therapy in a Prevention estimates that over 2 million people annually are infected timely fashion in order to reduce morbidity and mortality. Kumar with bacteria that are resistant to antibiotics. Of these, approximately 23 et al. demonstrated that initiating appropriate antibiotic therapy within 000 will die from their infection [1]. Examples of clinically important re- an hour of presentation was the strongest predictor of mortality in sep- sistant organisms that may be encountered in the ED include extended sis patients [2]. They also showed that patients who were not given ap- spectrum beta-lactamase producing and colistin-resistant Escherichia propriate antibiotics had a five-fold increase in mortality [2].IntheED coli, Pseudomonas aeruginosa, vancomycin-resistant enterococcus, setting, microbiology results including susceptibility information may carbapenem-resistant Enterobacteriaceae (CRE), and methicillin- not be immediately available, making it necessary to initiate broad- resistant Staphylococcus aureus (MRSA). Patients with resistant infections spectrum antibiotics with the intention of narrowing the coverage at a have limited treatment options due to a relative paucity of new antibiotics in the drug development pipeline as well as drug shortages impacting approved antibiotics [3]. In the past few years there have been only a hand- ful of new antibiotics approved. It is important for emergency physicians ☆ Funding Support: No funding was provided for this study. to be cognizant of newly approved antibiotics, as well as current recom- ☆☆ Financial Disclosures: The authors have no financial relationships relevant to this arti- mendations for the treatment of resistant organisms as they are at the cle to disclose. frontlines of initiating appropriate antibiotic treatment for bacterial infec- ★ fl fl Con ict of Interest: The authors have no con icts of interest to disclose. tions in both hospitalized patients and those discharged to the communi- ⁎ Corresponding author at: 110 Irving Street NW, Washington, DC 20010. Tel.: +1 202 877 7385; fax: +1 202 877 7633. ty. This review will discuss newly approved antibiotics and older E-mail address: [email protected] (M. Mazer-Amirshahi). antibiotics used to treat resistant infections.

2. Cephalosporins a fifth generation cephalosporin, with expanded activity against P aeruginosa, including strains that are resistant to piperacillin, carbapen- 2.1. Ceftaroline ems, fluoroquinolones, aminoglycosides, and ceftazidime [17]. Tazobac- tam is a β-lactamase inhibitor that expands the activity of ceftolozane to Ceftaroline is a fifth-generation cephalosporin that was approved by include β-lactamase producing organisms, including ESBL producing or- the Food and Drug Administration (FDA) in 2010 for acute bacterial skin ganisms [18]. In addition to P aeruginosa, ceftolozane-tazobactam is and skin structure infections (ABSSSIs) and community acquired bacte- active against E coli, K pneumoniae, Streptococcus, and ESBL producing rial pneumonia (CABP) [4]. Fifth-generation cephalosporins differ from Enterobacteriaceae, and some anaerobes. Activity against Staphylococ- previous generations in that they have expanded Gram-positive cover- cus species and Cdifficile is limited [16]. age, particularly including MRSA, but retain broad-spectrum Gram- Ceftazidime-avibactam is dosed every 8 hours as an intravenous in- negative coverage [5]. Ceftaroline has activity against Saureus,including fusion. Dose reduction is recommended in patients with moderate to not only methicillin-resistant strains, but also vancomycin-intermediate severe renal impairment. Adverse effects include headache, gastrointes- and resistant S aureus [4]. In addition, it has coverage against several tinal disturbances, and pyrexia. Hypersensitivity reactions and Cdifficile strains of resistant Spneumoniaeand other clinically important Gram- colitis have rarely (b2%) been reported. There are limited data regarding positive organisms, such as S viridans, L monocytogenes, and E faecalis. the use of ceftolozane-tazobactam in the pediatric population [15,16]. Ceftaroline possesses broad Gram-negative coverage as well, including Enterobacter, M catarrhalis, and Hinfluenza. It also is active against 3. Lipoglycopeptides non-extended spectrum beta-lactamase (ESBL) Ecoliand K pneumoniae. Because other β-lactams generally lack activity against MRSA, 3.1. Dalbavancin Ceftaroline may obviate the need for combination antimicrobial therapy. Of note, ceftaroline is not active against P aeruginosa or anaerobic Dalbavancin was approved by the FDA in 2014 to treat ABSSSIs [19]. bacteria [6]. Lipoglycopeptides act in a similar manner to vancomycin, by inhibiting Ceftaroline is administered as an intravenous infusion over one hour. polymerization and cross-linkage in bacterial cell wall synthesis by The recommended adult dose is 600 mg every 12 hours; however, dose binding to the D-Ala-D-Ala peptidoglycan chain [20]. These antibiotics adjustments should be made for patients with moderate to severe renal have a similar spectrum of activity to vancomycin, including Streptococ- impairment and for patients receiving hemodialysis. The recommended cus species, S aureus (methicillin-sensitive and resistant), and treatment duration ranges from 5–14 days [7]. Ceftaroline is generally vancomycin-susceptible E faecalis [20]. The advantage of newer well tolerated and the most common adverse effects reported were gas- lipoglycopeptides lies in their lipophilic side chains, prolonging their trointestinal disturbances and headache. There was a low incidence half-lives, requiring less frequent dosing [20,21]. Dalbavancin, originally (b2%) of hypersensitivity reactions and C difficile colitis [7].Cross- approved to be administered as two infusions 1 week apart, has now reactivity in patients with penicillin allergy is similar to that of other been approved as a single dose agent which may shorten or completely advanced-generation cephalosporins. Rarely, ceftaroline has been asso- avoid hospitalization and decrease healthcare costs in patients with ciated with Coomb's positive hemolytic anemia [8,9]. Recently, moderately severe infections for whom intravenous antibiotics are ceftaroline was FDA approved for pediatric patients as young as 2 being considered without any other indication for hospitalization [21]. months of age [7]. Dalbavancin administration is most commonly associated with gastrointestinal distress and pruritus. Infusion reactions are often rate- 2.2. Ceftazidime-avibactam related and can be mitigated by slowing the infusion; however, hypersensitivity (b2%) reactions do occur [22]. It is unclear to what extent Approved by the FDA in 2015, ceftazidime-avibactam combines the dalbavancin and other new lipoglycopeptides cross-react with vanco- anti-pseudomonal third-generation cephalosporin ceftazidime with the mycin [22]. Rarely elevations in alanine aminotransferase and Cdifficile novel non-β lactam β-lactamase inhibitor avibactam. It is indicated for colitis (b2%) may occur [19,21,22]. complicated intra-abdominal infections (cIAIs) in combination with metronidazole and complicated urinary tract infections (cUTIs) [10].Be- 3.2. Oritavancin cause ceftazidime is a third-generation cephalosporin, it has activity primarily against Gram-negative organisms, with limited activity against In 2014 the FDA approved oritavancin as the first single dose product Gram-positive organisms and anerobes [11]. Avibactam has expanded to treat ABSSSIs [23]. In clinical trials, a single 1200 mg dose was non- β-lactamase inhibition compared to other molecules such as tazobac- inferior to a 7 to 10 day course of vancomycin for the treatment of tam or clavulanic acid [12]. As such, the addition of avibactam expands ABSSSIs [24]. It has a similar spectrum of activity to dalbavancin and the activity of ceftazidime to include ESBL-producing bacteria, including vancomycin [12,24]. It has the advantage of being administered as a sin- E coli, P aeruginosa, K pneumoniae, and CRE [13,14]. gle dose which may shorten or avoid hospitalization [23,24].Itisadmin- Ceftazidime-avibactam is administered over a 2-hour infusion every istered as a 3-hour infusion, which does not require dose adjustment for 8 hours with dose reduction recommended for patients with moderate renal impairment. Oritavancin is generally well tolerated with nausea to severe renal insufficiency. Treatment duration ranges from 5–14 days and infusion site and hypersensitivity reactions (b1.5%) being the [10]. It is generally well tolerated with the most common adverse effects most common adverse effect [23]. Caution should be used in patients reported being headache, gastrointestinal disturbances, and infusion taking warfarin as concomitant administration may increase bleeding site reactions. Renal failure and elevation of liver transaminases have risk. Also, oritavancin is contraindicated in patients who are being been reported [11]. Hypersensitivity reactions and Cdifficile colitis are administered heparin as it may artificially prolong activated partial rare (1–5%). Of note, combinations of avibactam with other antibiotics thromboplastin time (aPTT) (as well as prothrombin time [PT]). Cdiffi- are currently in clinical trials. cile colitis has been rarely reported [23].

2.3. Ceftolozane-tazobactam 3.3. Telavancin

Ceftolozane-tazobactam was approved for use in the United States in Telavancin was the ﬁrst lipoglycopeptide approved by the FDA in 2014 for the treatment of cIAIs in combination with metronidazole as 2009 and it is indicated for complicated bacterial skin and skin structure well as monotherapy for cUTIs [15]. It has also been used off-label for infections (cBSSSIs) and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (VABP) [16]. Ceftolozane is VABP [25]. It has a similar spectrum of activity compared to vancomycin

Daptomycin was approved by the FDA in 2003 for the treatment of 6. Implications for emergency medicine cBSSSIs and S aureus bacteremia, including right-sided endocarditis [32]. Of note, daptomycin is not recommended for the treatment of Emergency physicians are often the point of first contact for patients pneumonia because it because it binds to pulmonary surfactant [33]. presenting with resistant infections and are the providers that initiate Its mechanism of action is unique in that it causes rapid depolarization antibiotic therapy, which is often continued upon hospital admission of the bacterial cell membrane, leading to disruption of cellular process- [43]. This usually happens before consultation with an infectious disease es and ultimately death. Daptomycin acts primarily on Gram-positive specialist can occur. Patients can present with resistant infections that organisms, particularly S aureus, including MRSA, Streptococcus,and may not respond to the usual broad spectrum antibiotics initiated in Enterococci [32,34]. the ED and this can have an adverse effect on patient outcomes. As Daptomycin is administered intravenously once daily over 2 minutes. such, emergency physicians should have a basic understanding of new Higher doses are recommended for bacteremia. Dose adjustment is rec- antimicrobial agents as well as older second and third line agents. ommended for patients with moderate to severe renal insufficiency and They should also be able to identify patients at risk for resistant infec- daptomycin has been noted to be less effective in this patient population. tions, such as those with a prior hospitalization in the past 90 days (par- Several adverse effects have been associated with daptomycin adminis- ticularly in the intensive care unit), nursing home residents, patients on tration, including hypersensitivity reactions, eosinophilic pneumonia, hemodialysis, and those recently treated with antibiotics [44-47] rhabdomyolysis, peripheral neuropathy, and Cdifficile colitis [32,34]. (Table 2). These agents will likely be utilized in patients who have previous 5.2. Tigecycline culture data available from either a healthcare facility or prior hospitalization, those who are allergic to first-line agents, or in situations where Tigecycline was first approved by the FDA in 2005 and is indicated preferred antibiotics are impacted by drug shortages and may be un- for cBSSSIs, cIAIs, and CABP [35]. It is a glycylcycline that works by available. Another reason to optimize first-line therapy is the cost of inhibiting bacterial protein synthesis by binding to the bacterial 30s newly approved agents, which are considerably more expensive than

Table 1 Recently approved antibiotics and antibiotics for resistant infections

Medication Therapeutic category Indications Adult dose Toxicity (trade name)

GI disturbance Ceftaroline ABSSSI 600 mg IV q 12 h Cephalosporin hemolytic anemia (Teﬂaro) CABP renal adjustment hypersensitivity GI disturbance Ceftazidime-Avibactam cIAI 2.5 g IV q 8 h hypersensitivity Cephalosporin/β-lactamase inhibitor (Avycaz) cUTI renal adjustment renal failure transaminitis headache cIAI Ceftolozane-Tazobactam 1.5 g IV q 8 h hypersensitivity Cephalosporin/β-lactamase inhibitor cUTI (Zerbaxa) renal adjustment GI disturbance VABP pyrexia 1 g IV day 1, GI disturbance Dalbavancin (Dalvance) Lipoglycopeptide ABSSSI 500 mg IV day 8 infusion reactions renal adjustment transaminitis ↑ aPTT/PT Oritavancin (Orbactiv) Lipoglycopeptide ABSSSI 1200 mg IV × 1 GI disturbance infusion reactions ↑ aPTT/PT ↑QTc cBSSSI Telavancin fetal toxicity Lipoglycopeptide HABP 10 mg/kg IV q 24 (Vibativ) GI disturbance VABP infusion reactions renal toxicity GI distress Tedizolid (Sivextro) Oxazolidinone ABSSSI 200 mg IV/PO daily headache transaminitis GI distress Colistin 2.5-5 mg/kg per day IV in 2-4 doses Polymyxin Resistant Gram-negative infections neurotoxicity (Coly-mycin M) renal adjustment renal toxicity 4 mg/kg IV q 24 for cBSSSI eosinophilic pneumonia Daptomycin Lipopeptide cBSSSI 6 mg/kg IV q 24 peripheral neuropathy (Cubicin) for bacteremia rhabdomyolysis renal adjustment CABP 100 mg IV × 1 fetal toxicity ↑mortality Tigecycline Glycylcycline cBSSSI 50 mg IV q 12 h pancreatitis (Tygacil) cIAI hepatic adjustment transaminitis

HABP, hospital-acquired bacterial pneumonia. older antibiotics, that are often available in generic formulations [48]. the spread of resistant organisms. ASPs involve a multidisciplinary Emergency providers should review available culture and sensitivity team that reviews antibiotic use and advises physicians on how to use data when available, as well as institutional antibiograms when choos- antibiotics more effectively. While not typically implemented in the ing an antibiotic regimen and consult an infectious disease specialist. ED setting, ASPs have been shown to be very effective in optimizing an- Early consultation with an infectious disease specialist is also important tibiotic use and their expansion to the ED setting could help improve an- because many of the aforementioned antibiotics likely require approval tibiotic selection and patient outcomes. Studies have demonstrated that for use. In addition, an increasing number of EDs employ department- institutional implementation of ASPs has led to a decrease in patients based pharmacists who can assist with antibiotic selection, dosing, ad- being infected with both Cdifﬁcile and other resistant organisms as ministration, and monitoring. In institutions without a dedicated ED well as decreased costs associated with antibiotic therapy [51,52]. pharmacist, inpatient pharmacy services can be consulted to assist. In addition to treating resistant organisms, some of the newer Pharmacist involvement as part of an interdisciplinary team for the lipoglycopeptides may have a role in decreasing hospitalizations. management of pneumonia and sepsis has demonstrated improved pa- Dalbavancin is dosed once a week for 2 doses and oritavancin requires tient outcomes [49,50]. a single IV infusion. This may enable the outpatient treatment of ABSSSIs Emergency physicians should be cautious in using these new and in patients that are stable with appropriate follow up. This could help second line antibiotics without discretion to avoid promoting further decrease ED and hospital crowding as well as decrease healthcare antibiotic resistance. One resource in addition to infectious disease con- costs, although the drug costs compared to older agents are higher sultation is the hospital's antibiotic stewardship program (ASP), which [48]. However, data regarding the safety and efﬁcacy of this practice works to promote the appropriate use of antibiotics and to decrease are lacking and there may not be a mechanism for reimbursement of drug costs if administered in the ED. This remains an area of prospective study. Table 2 Risk factors for antibiotic-resistant bacteria. 7. Conclusion Diabetes mellitus Central venous catheter Liver disease Feeding tubes The growing problem of antibiotic resistance has multiple implica- Neoplastic disease Total parenteral nutrition End-stage renal disease Urinary tract catheterization tions for emergency medicine providers. The potential for negative pa- Cerebrovascular disease Urinary or fecal incontinence tient outcomes increases as antibiotic resistance becomes more Non-ambulatory status Long term oxygen therapy prevalent. It is critical that emergency physicians are cognizant of local Long term steroid therapy Nursing home patient resistance patterns as well as new and available effective therapies to Ongoing chemotherapy Active decubitus ulcer treat resistant organisms. This should be done in conjunction with

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