353

Drug Update

AACN Advanced Critical CareVolume 27, Number 4, pp. 353-357

© 2016 AACN

A global crisis of antibiotic resistance is ongoing, especially with resistant gram-negative pathogens including Pseudomonas spp, carbapenemase-

producing Enterobacteriaceae, and extended-spectrum β-lactamase (ESBL)-producing organisms. The increasing rate of methicillin-resistant Staphylococcus aureus (MRSA) infections is also a concern.1 One newer intravenous cephalosporin (ceftaroline) was approved in 2010, and 2 new intravenous cephalosporin– β-lactamase inhibitor combinations (ceftolozane-tazobactam and ceftazidime-avibactam) have recently been approved to try to combat these resistant organisms in adult patients.

Although it is certainly exciting to have additional antibiotic options to treat severe or resistant infections, unfortunately none of these agents offers a new mechanism of action or a new class of antibiotic.2 Rather, they extend the spectrum of coverage against resistant organisms relative to other antibiotics. Although individual pricing will vary by institution, these agents generally cost more than older comparable antibiotics, which will most likely affect for-mulary inclusion and criteria for use. Use of these new antibiotics is also likely to be restricted to antimicrobial stewardship programs and clinicians trained in infectious diseases. Susceptibility testing should be done whenever possible when these agents are used.3,4 When using these newer antibiotics to treat severe, resistant infections off-label, especially when using higher doses or longer dura-tions of therapy, clinicians must be vigilant about closely monitoring for toxic effects. This article discusses the pharmacology, limitations, and role of these antibiotics in treating infections in critically ill adult patients. The Table sum-marizes the indications, dosing, and renal dose adjustments for each antibiotic.

CeftarolineCeftaroline (Teflaro) is a novel fifth-generation cephalosporin that was

approved by the US Food and Drug Administration (FDA) in October 2010. This agent is unique relative to previously approved cephalosporins because it offers expanded coverage of gram-positive organisms, including MRSA, and also maintains activity against many common gram-negative organisms.

Indications and Place in TherapyThe FDA-approved indications for ceftaroline include acute bacterial skin

and skin structure infections caused by susceptible strains of S aureus (including

Kathryn A. Connor is Associate Professor and Clinical Specialist, Critical Care, St John Fisher College of Pharmacy, 3690 East Ave, Rochester, NY 14618 (kaconnor@sjfc.edu).

The author declares no conflicts of interest.

Newer Intravenous Antibiotics in the Intensive Care Unit: Ceftaroline, Ceftolozane-Tazobactam, and Ceftazidime-Avibactam

Kathryn A. Connor, PharmD

DOI: http://dx.doi.org/10.4037/aacnacc2016612

Earnest Alexander, PharmD, and Gregory M. Susla, PharmD Department Editors

354

Drug Update WWW.AACNACCONLINE.ORG

methicillin-susceptible S aureus [MSSA] and MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneu-moniae, and Klebsiella oxytoca. This agent is also approved to treat community-acquired bacterial pneumonia caused by susceptible isolates of Streptococcus pneumoniae (includ-ing cases with concurrent bacteremia), S aureus (MSSA only because of the lack of adequate studies at this time to support MRSA pneu-monia treatment), Haemophilus influenzae, K pneumoniae, K oxytoca, and E coli.5

Beyond these FDA-approved uses, ceftaroline may be considered as an alternative therapy to treat serious MRSA infections or gram-negative pneumonia when more traditional agents are unable to be used because of clinical failure, resistance, or toxic effects. This agent may also be an option to consider for potential salvage therapy in patients with severe MRSA bacteremia, endocarditis, meningitis, osteomy-elitis, or other serious infections.3,8-12

SpectrumAs mentioned earlier, ceftaroline has a rela-

tively broad spectrum of activity, useful against staphylococci (MRSA and MSSA, including strains that are resistant to vancomycin), most streptococci, and common gram-negative

bacteria, including E coli, H influenzae, K pneumoniae, and K oxytoca. Of note, ceftaro-line does not have reliable activity against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Proteus vulgaris, Acinetobacter spp, or ESBL-producing organisms. Ceftaro-line also has minimal anaerobic activity and no activity against abdominal anaerobes like Bacteroides fragilis.1

Pharmacokinetics and Administration and Monitoring

The prodrug, ceftaroline fosamil, is con-verted to active ceftaroline in the plasma.1 Ceftaroline has a half-life of approximately 3 hours, which is prolonged in patients with renal dysfunction. This agent is primarily eliminated renally and requires dose adjust-ment in patients with renal insufficiency and patients undergoing hemodialysis, with a need to adjust dosages starting at a creatinine clear-ance (CrCl) of 50 mL/min or less. Ceftaroline is administered by intermittent intravenous infusion in 5 to 60 minutes.

A typical regimen for ceftaroline to treat community-acquired pneumonia is 600 mg intravenously every 12 hours for 5 to 7 days. Complicated skin and skin structure infections are usually treated with ceftaroline 600 mg

Antibiotic

Ceftaroline (Teflaro 5

Ceftolozane-tazobactam (Zerbaxa)6

Ceftazidime-avibactam (Avycaz)7

Dose

600 mg every 12 h

1.5 g every 8 h

2.5 g every 8 h

Indication

ABSSI, CABP

cIAI, cUTI

cIAI, cUTI

Renal Dose Adjustments

CrCl > 30 to < 50 mL/min: 400 mg every 12 hCrCl ≥ 15 to < 30 mL/min: 300 mg every 12 hCrCl < 15 mL/min: 200 mg every 12 hESRD on IHD: 200 mg every 12 h; given after HD on dialysis days

CrCl 30-50 mL/min: 750 mg every 8 hCrCl 15-29 mL/min: 375 mg every 8 hCrCl < 15 mL/min not on dialysis: no dose adjustments provided ESRD requiring IHD: 750 mg 1 time, then 150 mg every 8 h, given after HD on dialysis days

CrCl 31-50 mL/min: 1.25 g every 8 hCrCl 16-30 mL/min: 0.94 g every 12 hCrCl 6-15 mL/min: 0.94 g every 24 hCrCl < 5 mL/min: 0.94 g every 48 hESRD on IHD: Administer after HD on dialysis days; base dose on patient’s estimated renal function

Table: Summary of Newer Intravenous Antibiotics

Abbreviations: ABSSI, acute bacterial skin and skin structure infection; CABP, community-acquired bacterial pneumonia; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection; CrCl, creatinine clearance; ESRD, end-stage renal disease; IHD, intermittent hemodialysis; HD, hemodialysis.

355

Drug UpdateVOLUME 27 • NUMBER 4 • OCTOBER-DECEMBER 2016

intravenously every 12 hours for 5 to 14 days.5 More aggressive regimens (eg, 600 mg intrave-nously every 8 hours) may be considered to treat more severe, refractory MRSA infections.9,13

SafetyCeftaroline is a well-tolerated agent overall,

with an adverse effect profile similar to that for other cephalosporins.1 Of note, in phase 3 trials, patients receiving ceftaroline demon-strated a positive result on an antiglobulin test (an indicator of autoimmune hemolytic anemia) more frequently than did patients in the comparison group. If patients receiving ceftaroline are exhibiting signs or symptoms of anemia, drug-induced hemolytic anemia should be considered as a possible cause and ceftaroline should be discontinued with sup-portive care provided.5,14

Ceftolozane-TazobactamCeftolozane-tazobactam (Zerbaxa) is a

novel, fifth-generation cephalosporin and β-lactamase inhibitor combination product that was approved by the FDA in December 2014. This product was the first time that a β-lactamase inhibitor had been combined with a cephalosporin. Neither ceftolozane nor tazobactam is available as a stand-alone product, and tazobactam has been marketed as a combination product with piperacillin under the brand name Zosyn for years.

Indications and Place in TherapyCeftolozane-tazobactam is approved by the

FDA to treat complicated intra-abdominal infections, in combination with metronida-zole, caused by Enterobacter cloacae, E coli, K oxytoca, K pneumoniae, Proteus mirabilis, P aeruginosa, B fragilis, S anginosus, Strepto-coccus constellatus, and Streptococcus sali-varius. This agent is also approved to treat complicated urinary tract infections, including pyelonephritis, caused by E coli, K pneumoniae, P mirabilis, and P aeruginosa.6

Beyond these FDA-approved indications, ceftolozane-tazobactam may be considered as an alternative agent for directed therapy of multidrug-resistant, gram-negative organisms (eg, Pseudomonas) when more traditional agents cannot be used because of clinical failure, resistance, or toxic effects. This agent is an alternative to carbapenems and may be an attractive option to consider in place of colistin or aminoglycosides to use for salvage

therapy owing to the toxic effects associated with these antibiotics, especially the nephro-toxic effects.

SpectrumCeftolozane-tazobactam has expanded

gram-negative activity with the inclusion of tazobactam in this combination product. It has activity against gram-negative organisms including multidrug-resistant Pseudomonas spp and common ESBLs, but not carbapenemases. It also covers Streptococcus anginosus, Strep-tococcus constellatus, and Streptococcus sali-varius, but does not have reliable activity against gram-positive bacteria such as enterococci and Staphylococcus spp. Although ceftolozane-tazobactam covers B fragilis, other anaerobic activity may be variable, and the addition of metronidazole is recommended to treat com-plicated intra-abdominal infections.

Pharmacokinetics, Administration, and Monitoring

The ceftolozane component of this prod-uct has a half-life of approximately 3 hours, whereas the tazobactam component has a half-life of approximately 1 hour. The combi-nation drug is administered intermittently as a 60-minute intravenous infusion. Similar to other β-lactam antibiotics, ceftolozane-tazobactam is primarily eliminated unchanged in the urine and requires dose adjustments with CrCl of 50 mL/min or less, in patients with renal insuf-ficiency and patients undergoing hemodialysis.

To avoid medication errors, it is important to note that ceftolozane-tazobactam is a com-bination product, and dosage recommendations are expressed as grams of the ceftolozane-tazobactam combination. To treat complicated intra-abdominal infections, the typical regimen of ceftolozane-tazobactam is 1.5 g intrave-nously every 8 hours for 4 to 14 days in combi-nation with metronidazole. The usual regimen to treat complicated urinary tract infections, including pyelonephritis, is 1.5 g intravenously every 8 hours for 7 days.6 Serious infections may require 3 g intravenously every 8 hours; however, such dosing is not yet recommended in the prescribing information.15,16

SafetyCeftolozane-tazobactam appears to be

well-tolerated, and the adverse effect profile is comparable to that of other cephalosporins (eg, headache, fever, nausea, and diarrhea).4

356

Drug Update WWW.AACNACCONLINE.ORG

Renal function must be monitored at least daily, especially in dynamic critically ill patients, as doses will need to be adjusted accordingly. In clinical trials, ceftolozane-tazobactam was less effective in patients with a CrCl of 30 to 50 mL/min. Ceftolozane-tazobactam is listed as pregnancy risk factor B.6

Ceftazidime-AvibactamCeftazidime-avibactam (Avycaz) is a new

third-generation cephalosporin and novel β-lactamase inhibitor combination product that was approved by the FDA in February 2015. Ceftazidime has been a very well-known, widely used cephalosporin for decades, but, unfortunately, it is vulnerable to β-lactamases. Avibactam is a new β-lactamase inhibitor that has minimal antibacterial activity but works synergistically with ceftazidime to protect it and extend its activity. Avibactam is available only in this combination product.

Indications and Place in TherapyThe current FDA-approved indications for

ceftazidime-avibactam include the treatment of complicated intra-abdominal infections, in combination with metronidazole, caused by E cloacae, E coli, K oxytoca, K pneumoniae, P mirabilis, Providencia stuartii, and P aerug-inosa. Another FDA-approved indication is the treatment of urinary tract infections (including pyelonephritis) caused by Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, E cloacae, E coli, K pneumoniae, Proteus spp, and P aeruginosa.7

Beyond these FDA-approved indications, and like ceftolozane-tazobactam, ceftazidime-avibactam is reserved for patients with limited treatment options.17 Thus, ceftazidime-avibactam may be considered as an alternative agent for targeted therapy of resistant gram-negative organisms when more traditional agents can-not be used because of clinical failure, resist-ance, or toxic effects. This agent also offers an alternative to carbapenems, aminoglycosides, and colistin for serious infections.

SpectrumCeftazidime-avibactam is active against

most Enterobacteriaceae (including those that produce AmpC β-lactamase, some carbapene-mases, and ESBLs) and P aeruginosa. Of note, ceftazidime-avibactam is not active against Acinetobacter spp and does not have reliable anaerobic and gram-positive activity.

Pharmacokinetics and Administration and Monitoring

The ceftazidime component of this product has a half-life of approximately 3 hours, whereas the avibactam component has a half-life of approximately 2.5 hours. Ceftazidime-avibactam is administered by intermittent infusion in 2 hours. Similar to ceftaroline and ceftolozane-tazobactam, ceftazidime-avibactam is primarily eliminated unchanged in the urine and requires dose adjustments at a CrCl of 50 mL/min or less in patients with renal insufficiency and patients undergoing hemodialysis.

Dosage recommendations for ceftazidime-avibactam are expressed as total grams of combination product. Typical dosing of ceftazidime-avibactam to treat a complicated intra-abdominal infection is 2.5 g intrave-nously every 8 hours, in combination with metronidazole, for 5 to 14 days. Usual dosing for treating complicated urinary tract infec-tions (including pyelonephritis) is 2.5 g intra-venously every 8 hours for 7 to 14 days.7

SafetyReported adverse effects of ceftazidime-

avibactam include abdominal pain, constipa-tion, anxiety, and neurotoxic effects, including encephalopathy, coma, seizures, and myoclonus. Risk may be increased with renal insufficiency, so clinicians must ensure that doses are ade-quately adjusted for renal function. Of note, similar to ceftolozane-tazobactam, renal func-tion must be monitored at least daily when using ceftazidime-avibactam and doses should be adjusted accordingly.17 In clinical trials, ceftazidime-avibactam was less effective in patients with CrCl of 30 to 50 mL/min, but this lower effectiveness may have been due in part to subtherapeutic dosing. Ceftazidime-avibactam is also listed as pregnancy risk fac-tor B. In addition, a drug interaction is apparent between probenicid and ceftazidime–avibactam, and this combination should be avoided because of the potential for probenecid to increase serum concentrations of avibactam by decreasing its renal elimination.7,17

ConclusionResistant pathogens continue to cause

severe infections in the intensive care unit, leading to increased morbidity and mortality. Several new parenteral antibiotics have been approved to assist clinicians in treating these challenging infections, including ceftaroline,

357

Drug UpdateVOLUME 27 • NUMBER 4 • OCTOBER-DECEMBER 2016

ceftolozane-tazobactam, and ceftazidime- avibactam. All of these agents, however, have limitations and the potential to result in resist-ance, and none offers a new mechanism of action. Thus, the need for investigational agents and vigilant antimicrobial stewardship is ongo-ing in an effort to preserve these and other agents for current and future generations.

REFERENCES1. Lim L, Sutton E, Brown J. Ceftaroline: a new broad-

spectrum cephalosporin. Am J Health Syst Pharm. 2011; 68:491-498.

2. Theuretzbacher U. Recent FDA antibiotic approvals: good news and bad news. Center for Disease Dynam-ics, Economics & Policy website. http://cddep.org/blog /posts /recent_fda_antibiotic_approvals_good_news_and _bad_news.March 12, 2015. Accessed July 25, 2016.

3. Chahine EB. Ceftaroline: potential role and implications in an era of escalating antimicrobial resistance. Am J Health Syst Pharm. 2011;68:489.

4. Cluck D, Lewis P, Stayer B, et al. Ceftolozane-tazobactam: a new-generation cephalosporin. Am J Health Syst Pharm. 2015;72:2135-2146.

5. Teflaro (ceftaroline) [package insert]. Teramo, Italy: Facta Farmaceutici S.p.A.; August 2015.

6. Zerbaxa (ceftolozane-tazobactam) [package insert]. Syracuse, NY: Steri-Pharma LLC, July 2015.

7. Avycaz (ceftazidime-avibactam) [package insert]. Verona, Italy: GlaxoSmithKline Manufacturing S.p.A; September 2015.

8. Polenakovik HM, Pleiman CM. Ceftaroline for methicillin-resistant Staphylococcus aureus bacteraemia: case series and review of the literature. Int J Antimicrob Agents. 2013;42:450-455.

9. Ho TT, Cadena J, Childs LM, et al. Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis

treated with ceftaroline salvage therapy. J Antimicrob Chemother. 2012;67:1267-1270.

10. Tattevin P, Boutoille D, Vitrat V, et al. Salvage treatment of methicillin-resistant staphylococcal endocarditis with ceftaroline: a multicentre observational study. J Antimi-crob Chemother. 2014;69:2010-2013.

11. Balouch MA, Bajwa RJ, Hassoun A. Successful use of ceftaroline for the treatment of MRSA meningitis second-ary to an infectious complication of lumbar spine surgery. J Antimicrob Chemother. 2015;70: 624- 625.

12. Watkins RR. Successful treatment of osteomyelitis from methicillin-resistant Staphylococcus aureus with ceftaro-line. Infect Dis Clin Pract. 2013;21:48-49.

13. Canut A, Isla A, Rodríguez-Gascón A. Pharmacokinetic/ pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents. 2015; 45:399-405.

14. Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010;51:641-650.

15. Cubist Pharmaceuticals LLC. Safety and efficacy study of ceftolozane/tazobactam to treat ventilated nosocomial pneumonia (ASPECT-NP). ClinicalTrials.gov website. Bethesda, MD: National Library of Medicine (US); 2000-[2014 Dec 26]. www.clinicaltrials.gov/ct2/show /NCT02070757?term=ceftolozane&rank=1. NLM identifier: NCT02070757. Accessed July 25, 2016.

16. Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane /tazobactam pharmacokinetic/pharmaco-dynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Phar-macol. 2016;56:56-66.

17. Thompson CA. Ceftazidime with β-lactamase inhibitor approved for complicated infections. Am J Health Syst Pharm. 2015;72:511.

CE Test Instructions

This article has been designated for CE contact hour(s). The evaluation tests your knowledge of the following objectives:

1. Compare and contrast the spectrum of activity of newer intravenous (IV) antibiotics in the intensive care unit (ICU).2. Discuss the role, including indications and place in therapy, of newer IV antibiotics in the ICU.3. Summarize the safety implications associated with newer IV antibiotics in the ICU.

Contact hour: 1.0Pharmacology contact hour: 1.0Synergy CERP Category: A

To complete evaluation for CE contact hour(s) for test #ACC634, visit www.aacnacconline.org and click the “CE Articles” button. No CE test fee for AACN members. This test expires on October 1, 2019.

American Association of Critical-Care Nurses is an accredited provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. AACN has been approved as a provider of continuing education in nursing by the State Boards of Registered Nursing of California (#01036) and Louisiana (#LSBN12).