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New Antimicrobial Agents
New Antimicrobial Agents Catherine M. Oliphant, PharmD ABSTRACT
Infections caused by resistant pathogens are increasing and are a major threat to patient outcomes. A 2013 US Centers for Disease and Control and Prevention report on antibiotic resistance threats indicates that 2 million Americans acquire antibioticresistant infections annually and at least 23,000 die. Increasing resistance of bacterial pathogens to virtually all available antimicrobial classes signals the emergent need for new agents. Only 12 antibiotics were approved by the US Food and Drug Administration between 2000 and 2012. Initiatives to increase the number of effective antibiotics have been enacted. This study addresses the mechanism of action, microbiology, indications, dose, safety, drug interactions, and place in therapy of dalbavancin, tedizolid, oritavancin, ceftolozane/tazobactam, and ceftazidime/avibactam. Keywords: ceftazidime/avibactam, ceftolozane/tazobactam, dalbavancin, oritavancin, tedizolid Ó 2016 Elsevier, Inc. All rights reserved.
INTRODUCTION
D
espite increasing resistance among both Gram-positive and Gram-negative bacteria, antimicrobial agent development over the last 20 years has slowed dramatically—since 2000, only 12 antimicrobial agents have been approved. The increase in antibiotic-resistant pathogens has resulted in dwindling numbers of efficacious antimicrobial agents available to treat patients with resistant pathogens. According to the United States Centers for Disease Control (CDC) report, Antibiotic Resistance Threats in the United States, 2013, 2 million individuals acquire antibiotic-resistant infections each year and at least 23,000 of these patients die as a result. The CDC report states that developing new antibiotics is one of the four core actions needed to help fight resistant bacteria.1 Developing new antimicrobial agents is a challenging, timely, and costly process. The number of pharmaceutical companies involved in antibiotic research has decreased significantly. With regard to drug development, approximately 1 in 5 agents that reach the initial phase of testing receive approval from the US Food and Drug Administration (FDA).2 This is coupled with the fact that antibiotics are only used for a short period of time as compared with agents used for the management of chronic diseases www.npjournal.org
(ie, hypertension). In 2010, the Infectious Diseases Society of America proposed the 10 ’20 Initiative, in support of the development of 10 new systemic antimicrobial agents by 2020.3 To address these concerns, The US Congress enacted the Generating Antibiotic Incentives Now Act, under the FDA’s Safety and Innovation Act. The Generating Antibiotic Incentives Now Act provides drug manufacturers with an additional 5 years of exclusivity for qualifying new antimicrobial agents. The qualifying agents are referred to as a Qualified Infectious Disease Product and are defined as those antimicrobial agents that are intended to treat serious or life-threatening infections, including resistant pathogens (as defined by the FDA). These agents are eligible for priority review and fast track status. In 2015, President Obama proposed that the 2016 budget would include $1.2 billion for combating resistant infections.4 Since 2010, the FDA has approved 6 new systemic antimicrobial agents. These include ceftaroline, dalbavancin, tedizolid, oritavancin, ceftolozane/ tazobactam, and ceftazidime/avibactam. Five of these agents were granted priority review and approval as a Qualified Infectious Disease Product—dalbavancin, tedizolid, oritavancin, ceftolozane/tazobactam, and ceftazidime/avibactam. This article addresses the mechanism of action, clinical microbiology, The Journal for Nurse Practitioners - JNP
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indications, dose/administration/cost, adverse effects, drug interactions, and place in therapy for the agents approved in 2014 and the first half of 2015. CEFTOLOZANE/TAZOBACTAM Mechanism of Action
Ceftolozane (Zerbaxa, Cubist Pharmaceuticals, Lexington, Mass) is an extended spectrum cephalosporin in combination with tazobactam, a beta-lactamase inhibitor that was approved in December 2014. This is the first cephalosporin to be combined with a betalactamase inhibitor. Cephalosporins (a beta-lactam antibiotic) bind to penicillin-binding proteins and inhibit bacterial cell wall synthesis. Ceftolozane has greater affinity for penicillin-binding proteins than either ceftazidime or imipenem, making it more potent than these agents for certain pathogens. Tazobactam binds to some beta-lactamases (enzymes) and renders the enzyme unable to hydrolyze the beta-lactam ring, thus maintaining the antimicrobial activity of the antibiotic.5-7 Clinical Microbiology
Ceftolozane/tazobactam demonstrates activity against many Gram-negative bacteria, including Pseudomonas aeruginosa. In vitro data suggest that the addition of the beta-lactamase inhibitor enhances its Gram-negative activity against some extended spectrum betalactamase (ESBL)‒producing Enterobacteriaceae (including ceftazidime-resistant Enterobacteriaceae), as well as increased stability to AmpC beta-lactamases. However, ceftolozane/tazobactam does not have activity against metallo beta-lactamases or carbapenemase-producing bacteria. In the phase 3 intra-abdominal study, a small subset of patients (150 patients) had ESBL-producing Escherichia coli and Klebsiella pneumoniae. In the trial, patients treated with ceftolozane/tazobactam had clinical cure rates of 97% as compared with 85% of patients treated with meropenem. Ceftolozane alone has potent in vitro anti-pseudomonal activity, including multidrugresistant P aeruginosa. Ceftolozane/tazobactam has coverage against some Gram-positive bacteria as well. It has activity against some Streptococcus species, but has only limited coverage against Staphylococcus spp. In addition, it should not be used for infections secondary to Enterococcus spp. Data suggest limited e92
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anaerobic activity as well, but it should be used in combination with metronidazole for the treatment of complicated intra-abdominal infections (or other infections in which anaerobes are likely).5-10 Indications
Ceftolozane/tazobactam is FDA approved for the treatment of complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections, including pyelonephritis.6 A study evaluating its use in ventilator-associated pneumonia is currently underway. With regard to complicated intra-abdominal infections, ceftolozane/ tazobactam in combination with metronidazole was compared with meropenem for a duration of 4-14 days and was found to be noninferior (83% and 87.3%, respectively). In the complicated urinary tract infections trials, ceftolozane/tazobactam was compared with levofloxacin for a duration of 7 days. Levofloxacin resistance was noted in almost 27% of patients; however, when these patients were removed from the analysis, ceftolozane/tazobactam was also found to be noninferior (82.6% efficacy with ceftolozane/tazobactam vs. 79.7% with levofloxacin). Data from both the complicated intra-abdominal and urinary tract infections trials demonstrate that patients with a creatinine clearance (CrCl) of 30-49 mL/min had lower cure rates versus the comparator groups (meropenem and levofloxacin, respectively). In the intra-abdominal study, the clinical cure rate with CrCl 30-49 mL/min for ceftolozane/tazobactam was 47.8% and 69.2% for meropenem. These data come from a subgroup analysis of a small number of patients. It is important to note that all patients in the subgroup with CrCl 30-49 mL/min (regardless of treatment arm) had lower cure rates than the subgroup with CrCl 50 mL/min (with clinical cure rates of 85.2% and 87.9%, respectively, for ceftolozane/tazobactam and meropenem in the intra-abdominal study). In response, the FDA has recommended that additional studies be conducted evaluating outcomes in patients with CrCl of < 50 mL/min. In addition, in the intra-abdominal infections trials, clinical cure rates were noted to be lower in patients 65 years old who received ceftolozane/tazobactam compared with those given meropenem (69% vs. 82.4%). Again, the FDA has Volume 12, Issue 3, March 2016
recommended that additional studies be performed in this patient population.5-10 It is important to note that ceftolozane/tazobactam is not approved for ESBL-producing bacteria. In vitro data and minimal clinical data suggest activity against some of these pathogens, yet clinical outcomes have not been studied. Dose, Administration, Monitoring, and Cost
The recommended dose of ceftolozane/tazobactam is 1.5 g every 8 hours administered IV in patients with a CrCl > 50 mL/min. Duration of therapy ranged from 4 to 14 days in the intra-abdominal studies and was 7 days in the urinary tract infections trials. However, duration of therapy should be individualized and based on site of infection, severity, and the patient’s response to therapy. The drug is eliminated primarily unchanged in the urine. Therefore, in patients with reduced renal function (CrCl 50 mL/ min), the dose should be reduced based on the patient’s renal function. For patients with a CrCl of 30-50 mL/min, the recommended dose is 750 mg every 8 hours. If the CrCl is 15-29 mL/min, the recommended dose is 375 mg every 8 hours. For patients on hemodialysis, a single loading dose of 750 mg is recommended, followed by 150 mg every 8 hours.6 Renal function should be monitored before initiating therapy and during administration, especially if the patient has fluctuating renal function. The multiple daily dosing may be a disadvantage. In addition, it is more costly than the comparators used in the clinical trials—$249 per day, as compared with meropenem at $45/day and levofloxacin at $21/day [cost as of August 2015, based on wholesale acquisition cost (WAC), which is the manufacturer’s list price for a drug to wholesalers or direct purchasers]. Pregnancy Category/Breast-feeding Considerations
Ceftolozane/tazobactam is pregnancy category B. With regard to breast-feeding, it is unknown whether the agent is excreted into breast milk. Therefore, it is recommended to be used with caution.6 Adverse Effects
Data from trials indicate that ceftolozane/tazobactam is well tolerated and has adverse effects comparable to www.npjournal.org
those of other beta-lactam antimicrobial agents. The most common adverse effects were found to be constipation, nausea, insomnia, and headache. Phlebitis and infusion-site reactions did occur at lower rates than the aforementioned events. In addition, in phase 2 and 3 trials, ceftolozane/tazobactam was associated with higher rates of anemia than comparator agents (6.1% vs. 2.6% with meropenem in the complicated intra-abdominal study). Other betalactam antimicrobial agents have been reported to have hematologic abnormalities. Hypersensitivity reactions may occur as with other beta-lactam agents.5-10 Patients should be monitored for these adverse effects. Drug Interactions
Ceftolozane/tazobactam is not hepatically metabolized, so cytochrome P450 interactions are not expected to occur. No significant drug-drug or drug-food interactions have been noted.5-7 Place in Therapy
Ceftolozane/tazobactam is currently approved for the treatment of complicated intra-abdominal and urinary tract infections. However, because it is a novel agent with enhanced activity against drug-resistant pathogens, it should be reserved for use in patients with pathogens resistant to other available antibiotics or in those unable to tolerate other standard therapies for these indications. With its potent anti-pseudomonal activity, ceftolozane/tazobactam is an option for the treatment of infections caused by P aeruginosa, especially for those that are antibiotic-resistant. It may also be an alternative to carbapenems for the treatment of infections secondary to ESBL-producing bacteria. In vitro data demonstrate activity against select resistant Gram-negative pathogens. However, ceftolozane/tazobactam only has limited clinical data against these resistant pathogens and needs further evaluation. If this agent does prove to be useful against pathogens that dictate the use of carbapenems as standard therapy, it may reduce carbapenem use and potentially decrease the emergence of carbapenem-resistant bacteria. In the meantime, appropriate use of this important new agent is prudent to preserve its activity against resistant pathogens. The Journal for Nurse Practitioners - JNP
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CEFTAZIDIME/AVIBACTAM Mechanism of Action
Ceftazidime (Avycaz, Forest Pharmaceuticals, Cincinnati, OH) is a third-generation cephalosporin in combination with avibactam, a new beta-lactamase inhibitor, which was approved in February 2015. Avibactam is a more potent beta-lactamase inhibitor than tazobactam, clavulanate, or sulbactam.10-12 Clinical Microbiology
Ceftazidime/avibactam has activity predominantly against Gram-negative bacilli. The addition of avibactam greatly improves ceftazidime’s antimicrobial spectrum of activity against P aeruginosa and many Enterobacteriaceae, but not Acinetobacter spp. The addition of avibactam to ceftazidime adds activity against some bacteria producing ESBL (not metallo beta-lactamases) as well as some carbapenemaseproducing bacteria (not Acinetobacter OXA-type carbapenemase). In vitro data suggest that ceftazidime/avibactam is active against select resistant Gram-negative pathogens. Ceftazidime/avibactam is the first beta-lactam to have coverage against carbapenemases. This antimicrobial agent does not have activity against Gram-positive bacteria or most anaerobes (like ceftolozane/tazobactam, it must be used in combination with metronidazole for anaerobic infections).10-15 Indications
Ceftazidime/avibactam is FDA approved for complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections, including pyelonephritis.10 A study evaluating its use in hospital-acquired and ventilator-associated pneumonia is currently being conducted. In both the complicated intra-abdominal and urinary tract infections trials, ceftazidime/avibactam was found to be noninferior to the comparator agents (meropenem and imipenemcilastatin, respectively). Data from the complicated intra-abdominal infection trial indicate that patients with a CrCl of 30-50 mL/min who received ceftazidime/avibactam had a poorer outcome when compared with meropenem. Death occurred in approximately 26% of ceftazidime/avibactam patients as compared with 8.6% of those given meropenem (as compared with overall death of 2.5% of patients who e94
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received ceftazidime/avibactam and 1.5% of patients who received meropenem). Dosing of the ceftazidime/avibactam in this clinical trial was one third lower than what is currently recommended for this subgroup of patients with CrCl of 30-50 mL/min. The revised dosing is expected to provide adequate concentrations for this subgroup. A future trial is planned to evaluate dosing in patients with intra-abdominal infections and CrCl levels of 30-50 mL/min.10-15 It is important to note that ceftazidime/avibactam is not approved for ESBL- or carbapenemaseproducing bacteria. In vitro data and minimal clinical data suggest activity against some of these pathogens, yet clinical outcomes have not been evaluated.10,13,14 Dose, Administration, Monitoring, and Cost
The recommended dose for patients with a CrCl > 50 mL/min is 2.5 g every 8 hours administered IV. Duration of therapy has ranged from 5 to 14 days in the intra-abdominal studies and from 7 to 14 days in the urinary tract infections trials. However, duration of therapy should be individualized and based on site of infection, severity, and the patient’s response to therapy. Ceftazidime/avibactam is eliminated primarily unchanged in the urine, and therefore dosing adjustments must be made in patients with renal impairment. For patients with a CrCl of 31-50 mL/ min, the recommended dose is 1.25 g every 8 hours. If the CrCl is 16-30 mL/min, the recommended dose is 0.94 g every 12 hours. For a CrCl of 6-15 mL/min, the recommended dose is 0.94 g every 24 hours and, if the CrCl is < 5 mL/min, the recommended dose is 0.94 g every 48 hours. Renal function should be monitored before initiating therapy and during administration, especially if the patient has fluctuating renal function (adjust dose accordingly based on CrCl). Of note, this agent must be infused over 2 hours to maximize the time above the minimum inhibitory concentration—beta-lactams are timedependent antibiotics, and therefore optimizing time above MIC increases the efficacy of these agents.10-15 The daily cost for a patient receiving the recommended dose (2.5 g every 8 hours) for normal renal function is approximately $855 (cost as of August 2015, based on WAC). The comparators (meropenem and imipenem/cilastatin) in the clinical trials are approximately $45 per day. Volume 12, Issue 3, March 2016
Pregnancy Category/Breast-feeding Considerations
Ceftazidime/avibactam is pregnancy category B. With regard to breast-feeding, it is unknown whether the agent is excreted into breast milk. Therefore, it is recommended to be used with caution.15 Adverse Effects
Data from phase 1, 2, and 3 studies demonstrate that ceftazidime/avibactam is well tolerated. The most common adverse effects in the intra-abdominal trials were nausea, vomiting, and abdominal pain (likely due, at least in part, to metronidazole). In the urinary tract infections trials, constipation and anxiety were reported most commonly. As with other cephalosporins, gastrointestinal effects, hematologic abnormalities, and mild elevations in liver function tests may be expected. In addition, hypersensitivity reactions may occur as with other beta-lactam agents.10-15 Drug Interactions
There are no known significant drug interactions with regard to P450 enzymes, as ceftazidime/avibactam is not hepatically metabolized. Avibactam is a substrate of organic anion transporters 1 and 3 in the kidney; probenicid is an organic anion transporter inhibitor and therefore will reduce the elimination of avibactam. Administration of probenecid with ceftazidime/avibactam is not recommended.10-15 Place in Therapy
Ceftazidime/avibactam has demonstrated similar efficacy when compared with carbapenems in the treatment of complicated intra-abdominal (in combination with metronidazole) and complicated urinary tract infections. The addition of avibactam to ceftazidime improves P aeruginosa activity and broadens coverage to include ESBL-producing Gramnegative bacilli as well as certain carbapenemaseproducing Gram-negative bacilli. However, as with ceftolozane/tazobactam, this agent has not been clinically evaluated for use against these resistant pathogens and its efficacy remains to be seen. Practitioners should reserve this broad-spectrum agent for patients unable to tolerate currently available antibiotics. Future data will define the efficacy of this agent for infections caused by antibiotic-resistant Gramnegative pathogens. www.npjournal.org
DALBAVANCIN Mechanism of Action
Dalbavancin (Dalvance, Actavis, Inc, Parsippany, NJ) is a lipoglycopeptide that was approved in May 2014. Lipoglycopeptides inhibit bacterial cell wall synthesis by binding the peptidoglycan chain at the terminal D-alanyl‒D-alanine and interfere with cross-linking of the bacterial cell wall. As a result, the cell membrane is disrupted, which leads to cell death. Telavancin was the first lipoglycopeptide. Vancomycin is the prototype agent in the glycopeptide class of antimicrobial agents. Lipoglycopeptides differ from glycopeptides in that they have a lipophilic side chain that increases antibacterial potency while also prolonging the half-life.16-19 Clinical Microbiology
Dalbavancin’s spectrum of activity includes Grampositive aerobic and anaerobic bacteria. In vitro, it is a more potent antimicrobial agent than vancomycin against most pathogens due to the lipophilic side chain. MICs of dalbavancin are significantly lower than those of vancomycin.13 Dalbavancin’s coverage includes staphylococci [including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S aureus, and coagulase-negative staphylococci], streptococci (including penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae, viridans group streptococci), enterococci [including Enterococcus faecium and Enterococcus faecalis, vancomycin (van)‒ resistant enterococci—vanB and vanC strains (no activity against vanA enterococci)], Clostridium spp, and various other Gram-positive anaerobes.16-19 Of note, dalbavancin is FDA approved for the treatment of infections caused by S aureus [methicillin-susceptible (MSSA) and methicillin-resistant strains (MRSA)], Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus groups.19 Indications
Dalbavancin is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by the aforementioned pathogens. In phase 2 and 3 trials, the clinical efficacy rates were non-inferior to vancomycin (with the option to switch from vancomycin to oral linezolid). Future studies evaluating the efficacy of dalbavancin will The Journal for Nurse Practitioners - JNP
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include community-acquired bacterial pneumonia, osteomyelitis, and bacteremia.16-19 Dose, Administration, Monitoring, and Cost
Dalbavancin has a long half-life, which results in once-weekly dosing. It is only administered via the IV route. The FDA-recommended dose for ABSSSIs is 1,000 mg on day 1 followed by 500 mg on day 8, administered as a 30-minute infusion. In patients with CrCl < 30 mL/min (and not receiving regularly scheduled hemodialysis), the dose is reduced to 750 mg on day 1 followed by 375 mg on day 8.19 Monitoring of renal and liver function tests is suggested before initiation of therapy and during therapy. The cost for a course of therapy (2 doses) is approximately $4,500 (cost as of August 2015 based on WAC), which is significantly more expensive than vancomycin (approximately $20/day based on a 1-g dose every 12 hours for 7-14 days). Dalbavancin does not require pharmacokinetic monitoring of blood levels as compared with vancomycin, which does require monitoring (in addition to monitoring of serum creatinine). Pregnancy Category/Breast-feeding Considerations
Dalbavancin is pregnancy category C. Adverse effects were noted in animal reproductive studies. With regard to breast-feeding, it is unknown whether this agent is excreted in breast milk. Therefore, it is recommended to be used with caution.19 Adverse Effects
Dalbavancin was generally well tolerated in phase 2 and 3 trials. The most common adverse effects noted in these trials were nausea, vomiting, diarrhea, headache, rash, and pruritus. It is important to note that these adverse effects occurred in similar frequencies between both dalbavancin and the comparator agents (vancomycin linezolid). There are few data to demonstrate that dalbavancin is associated with either nephrotoxicity or hepatotoxicity. The nephrotoxicity rate in clinical trials was significantly lower for dalbavancin than for vancomycin. Alanine aminotransferase elevations were more common in patients receiving dalbavancin than comparator agents, but some of these patients had underlying liver abnormalities. Other liver enzyme e96
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abnormalities occurred at similar frequencies between dalbavancin and the comparator agents. Dalbavancin does not prolong the QTc interval.16-19 Like other glycopeptides, dalbavancin may be associated with an infusion reaction, referred to as red man syndrome (characterized by upper extremity/ face/neck redness/rash, pruritus, fever or chills, and hypotension). Therefore, the dose should be administered over 30 minutes to minimize the risk of infusion-related events.16-19 Patients should be monitored for these infusion-related reactions. Drug Interactions
Based on existing data, no significant drug-drug interactions have been identified. Dalbavancin is not a substrate, inhibitor, or inducer of the cytochrome P450 system.16-19 Place in Therapy
Dalbavancin is currently approved for the treatment of ABSSSIs. With regard to the use of dalbavancin, it is reasonable to state that it should not be considered a first-line agent for ABSSSIs because other efficacious and less costly alternative therapies exist. However, for nonadherent patients, outpatients, and those in whom venous access is an issue or if oral agents are not possible, this agent may have a role. In addition, this agent does not require pharmacokinetic monitoring, is well tolerated, and is patient-friendly in terms of dosing. Dalbavancin is a costly antimicrobial agent, but it has the potential to actually reduce health care costs if its use avoids or shortens the duration of hospitalization. Pharmacoeconomic analyses will provide further insight into the potential cost savings associated with this agent. Future clinical trials will provide data regarding dalbavancin’s use for additional indications, including coverage against multidrug-resistant bacteria. ORITAVANCIN Mechanism of Action
Oritavancin (Orbactiv, The Medicines Company, Parsippany, NJ) is a lipoglycopeptide that was approved in August 2014. Oritavancin’s mechanism of action is similar to that of dalbavancin. In addition, it may disrupt the bacteria cell membrane, increasing permeability. Oritavancin is also more potent than Volume 12, Issue 3, March 2016
vancomycin due to the structural modifications of the compound, which allow for improved ability to bind to the cell wall and thus increase the binding affinity to the target site. In addition, oritavancin has lower MICs against many Gram-positive pathogens when compared with vancomycin. Lipoglycopeptides are rapidly bactericidal (unlike vancomycin, which is slowly bactericidal). It also has a prolonged terminal half-life of 245 hours, allowing for novel dosing.18,20-23 Clinical Microbiology
Oritavancin is active against aerobic and anaerobic Gram-positive bacteria. In vitro, it is a more potent antimicrobial agent than vancomycin against most pathogens, due to the lipophilic side chain as well as the ability to cause cell membrane depolarization. It has excellent coverage against common Gram-positive pathogens, including S aureus (MSSA and MRSA), S pneumoniae (including penicillin-intermediate and penicillin-resistant strains), group A Streptococcus, S agalactiae, Enterococcus spp (both E faecalis and E faecium, including some vanA- and vanB-resistant strains), and some Gram-positive anaerobes (including select Clostridium spp). In vitro data suggest that oritavancin may have activity against both vancomycin intermediate and resistant S aureus (VISA and VRSA).20-23 Oritavancin is FDA approved for the treatment of infections caused by methicillinsusceptible and -resistant S aureus, Streptococcus pyogenes (group A Streptococcus), S agalactiae, S dysgalactiae, S anginosus group, and E faecalis (vancomycin-susceptible only).23 Indications
Oritavancin is FDA approved for the treatment of ABSSSIs caused by the aforementioned pathogens. In phase 2 and 3 trials, the clinical efficacy rates were noninferior to vancomycin. The phase 3 trials undertaken for the approval of oritavancin for ABSSSIs were the SOLO 1 and 2 trials. The primary efficacy endpoint in both of these trials was a composite endpoint that included the termination of spreading or a reduction in the size of the lesion, absence of fever, and no need for a rescue antibiotic. In the SOLO 1 trial, the primary efficacy endpoints were 82.3% and 78.9%, respectively, for oritavancin versus vancomycin. In the SOLO 2 trial, the composite www.npjournal.org
endpoint for oritavancin was 82.3% as compared with 78.9% for vancomycin.20-23 Dose, Administration, Monitoring, and Cost
Oritavancin is administered as a single IV dose of 1,200 mg administered over 3 hours. No dose adjustments are necessary for impaired renal or hepatic function.20-23 The cost for a course of therapy (1 dose) is $2,900 (cost as of August 2015, based on WAC). Like dalbavancin, oritavancin does not require pharmacokinetic monitoring of blood levels. Pregnancy Category/Breast-feeding Considerations
Oritavancin is pregnancy category C. With regard to breast-feeding, it is unknown whether this agent is excreted in breast milk. Therefore, it is recommended to be used with caution and only when the potential benefits outweigh the risks.18 Adverse Effects
Oritavancin has a long half-life and therefore resolution of adverse effects may be delayed. The most common adverse effects reported in phase 2 and 3 trials have included phlebitis, headache, diarrhea, nausea, vomiting, constipation, dizziness, and insomnia. Of note, the type and frequency of adverse reactions was similar to comparator agents. Patients receiving oritavancin in clinical trials had slightly higher rates of liver function test abnormalities than comparator agents. In addition, infusion-related reactions (pruritus, urticarial, flushing) may occur. Patients should be monitored for these infusion-related reactions. Hypersensitivity reactions have been reported. These reactions may persist for prolonged periods due to the long half-life of oritavancin. Clinicians should carefully monitor patients with a history of glycopeptide allergy. Oritavancin does not prolong the QTc interval.20-23 In clinical trials, an adverse reaction of osteomyelitis was noted to be more frequent in patients receiving oritavancin than comparator agents. The manufacturer recommends that patients be observed for findings of osteomyelitis during therapy.20,22,23 Drug Interactions
Oritavancin is a weak inhibitor and inducer of cytochrome P450 enzymes. It inhibits CYP2C19 and The Journal for Nurse Practitioners - JNP
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CYP2C9 and induces CYP3A4. Therefore, clinicians must monitor for drug-drug interactions with concomitant use of oritavancin and agents that are metabolized via these P450 enzymes. Of note, oritavancin may increase the serum concentrations and effects of vitamin K antagonists (ie, warfarin). Patients should be monitored and educated on the increased bleeding risk. Manufacturer labeling states that the average increase in the area under the curve for warfarin in patients receiving oritavancin is 31%.20-23 Oritavancin artificially prolongs coagulation tests. The activated partial thromboplastin time, a monitoring test for heparin, is artificially elevated for 48 hours. The use of unfractionated IV heparin is contraindicated for 48 hours after oritavancin administration due to the inability to appropriately monitor heparin, whereas the prothrombin time and international normalized ratio (both monitoring tests for warfarin) are artificially elevated for 24 hours. Thus, monitoring of these agents during these time frames leads to inaccurate test results.20-23 Place in Therapy
Oritavancin is currently only approved for the treatment of ABSSSIs. As with dalbavancin, it should not be considered a first-line agent for these infections, as other efficacious and less costly agents are available. It may have a niche for patients who do not need to be hospitalized and either need IV therapy or cannot take oral therapies. Additional clinical trials are needed to address its use for other indications.
Clinical Microbiology
Tedizolid is active against aerobic and certain anaerobic Gram-positive pathogens. In vitro data suggest it is a more potent antimicrobial than linezolid against many pathogens. Tedizolid’s coverage includes staphylococci (S aureus and coagulase-negative staphylococci, including methicillin-susceptible and methicillin-resistant strains as well as linezolidresistant strains), streptococci (including penicillinsusceptible and penicillin-resistant S pneumoniae, beta-hemolytic streptococci, viridans group), and enterococci (vancomycin-susceptible and vancomycin-resistant strains of E faecalis and E faecium). In addition, tedizolid has activity against select Gram-positive anaerobes.24-27 Of note, tedizolid is FDA approved for the treatment of infections caused by MSSA and MRSA, S pyogenes, S agalactiae, S anginosus group, and E faecalis.27 Indications
Tedizolid is FDA approved only for the treatment of ABSSSIs caused by the aforementioned FDAapproved pathogens. In phase 3 trials, tedizolid was noninferior to the comparator agent, linezolid, with regard to efficacy. The ESTABLISH-1 and -2 trials evaluated the efficacy and safety of 6 days of IV to oral tedizolid to 10 days of IV to oral linezolid for the treatment of ABSSSIs. Future studies will evaluate tedizolid’s use in complicated skin and skin structure infections, MRSA infections, and nosocomial pneumonia.24-27 Dose, Administration, Monitoring, and Cost
TEDIZOLID Mechanism of Action
Tedizolid (Sivextro, Cubist Pharmaceuticals, Lexington, Mass) is an oxazolidinone antimicrobial agent approved in June 2014. It is the second member in the oxazolidinone class, with linezolid being the first. Tedizolid is a protein synthesis inhibitor; it binds to the 23S ribosomal RNA of the 50S subunit of the ribosome. In contrast to linezolid, tedizolid has additional binding sites with a peptidyltransferase center that improves its antibacterial potency over linezolid. Tedizolid is a prodrug and must be converted to its active form by serum phosphatases in the body.24-27 e98
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The recommended dose for tedizolid for the treatment of ABSSSIs is 200 mg once daily, administered either orally (as a tablet) or IV for a total of 6 days of therapy. The once-daily dose is a benefit over the twice-daily dose required with linezolid. No dose adjustment is required in renal or hepatic impairment.24-27 A complete blood count should be done before initiating therapy. The daily cost for the tablet is $295 and for the IV dose is $235 as compared with linezolid’s daily cost of approximately $275 for both the oral or IV doses (cost as of August 2015, based on wholesale acquisition cost). Tedizolid may be a cheaper alternative to Volume 12, Issue 3, March 2016
linezolid for ABSSSIs if linezolid is administered for > 6 days. Of note, generic linezolid has been approved, which over time will likely result in a reduction in the price of linezolid. Pregnancy Category/Breast-feeding Considerations
Tedizolid is pregnancy category C. With regard to breast-feeding, it is unknown whether this agent is excreted in breast milk. Therefore, it is recommended to be used with caution.27 Adverse Effects
In phase 2 and 3 trials, gastrointestinal abnormalities (nausea, vomiting, and diarrhea) were most commonly observed but occurred less frequently in patients receiving tedizolid. Other common adverse effects included headache, dizziness, and fatigue (which were reported with similar frequency with the comparator agent, linezolid). Due to the fact that oxazolidinones may cause thrombocytopenia and optic and peripheral neuropathies (treatment with linezolid, particularly for > 14 days, has resulted in thrombocytopenia; neuropathies have been reported in patients taking linezolid for > 28 days), the propensity for tedizolid to also cause these effects was evaluated in clinical trials. Data from phase 3 trials demonstrate that 1.2% of patients who received 6 days of tedizolid reported peripheral neuropathy as compared with 0.6% of patients receiving linezolid. Optic nerve disorders were reported in 0.3% of patients given tedizolid and 0.2% in patients given linezolid. Patients should be monitored for optic and peripheral neuropathies. With regard to thrombocytopenia, the incidence of reduced platelet counts was significantly lower in patients treated with tedizolid 200 mg for 6 days as compared with linezolid for 10 days. The manufacturer states that tedizolid may have less effect than linezolid on hematologic parameters.24-27 It is important to note that adverse effect data exist only for the 6-day therapy of ABSSSIs—patients receiving longer courses of therapy may be at increased risk of adverse effects and should be closely monitored. Data from phase 1 studies demonstrate a potential for dose and duration effect on the hematologic parameters in healthy adults who received 21 days of therapy.27 www.npjournal.org
Drug Interactions
Although tedizolid is metabolized through the liver, it does not have affinity for the cytochrome P450 enzymes. The potential for P450 enzyme‒related drug-drug interactions is negligible. Tedizolid is a weak, reversible inhibitor of monoamine oxidase, similar to linezolid. Several studies have analyzed the potential for interactions and subsequent serotonergic effects (including serotonin syndrome) with the concomitant administration of tedizolid with tyramine and pseudoephedrine. With the concomitant use of tedizolid and tyramine or pseudoephedrine, there was no significant interaction identified with either agent. Data demonstrate a low potential for serotonergic effects with tedizolid. However, it is important to keep in mind that patients in the clinical trials did not receive agents (such as selective serotonin reuptake inhibitors or serotonin/ norepinephrine reuptake inhibitors) that are known to increase the risk of serotonergic effects, including serotonin syndrome. Clinicians should educate patients on the potential for adverse effects with concomitant use of tedizolid and other medications known to increase serotonergic effects.24-27 Information obtained from postmarketing use of tedizolid will shed further light on this important potential drug interaction. Place in Therapy
Tedizolid appears to be as efficacious as linezolid and demonstrates enhanced in vitro activity (against some pathogens) when compared with linezolid. Data to date show it is potentially safer than linezolid with regard to adverse effects and drug interactions, based on the 6-day duration of therapy in clinical trials. Use of this agent outside of currently recommended dosing and duration is not recommended. Tedizolid is a costly agent and its place in the treatment of ABSSSIs remains unknown. CONCLUSIONS
Ceftolozane/tazobactam, ceftazidime/avibactam, dalbavancin, oritavancin, and tedizolid are welcome additions to what has been a dwindling armamentarium of antimicrobial agents. These 5 new antimicrobial agents have been demonstrated to be as The Journal for Nurse Practitioners - JNP
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effective as their comparator agents in clinical trials. However, data to date with these drugs is limited as are approved indications. Additional clinical trials must be conducted to evaluate the use of these agents for the treatment of infections caused by resistant pathogens. These drugs should not be used as first-line treatment and should be reserved for use in patients who are unable to tolerate other standard therapies as overuse and misuse may lead to the emergence of antibiotic resistance. It is crucial that these new agents be used rationally to preserve their possible use in these difficult-to-treat infections secondary to highly resistant pathogens. Consultation with infectious disease specialists is recommended before prescribing any of these new antimicrobial therapies. Existing data indicate that the future of these new antimicrobial agents is promising with regard to the treatment of resistant pathogens. Clinicians must be prudent in prescribing of antibiotics to preserve the effectiveness of existing therapies and to avoid a post-antibiotic era (a time when antibiotics are unable treat infections). References 1. US Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. September 16, 2013. http://www.cdc.gov/ drugresistance/threat-report-2013/. Accessed June 24, 2015. 2. Hay M. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51. 3. Infectious Diseases Society of America. The 10 ’20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis. 2010;50:1081-1083. 4. US Food and Drug Administration. FDA Safety and Innovation Act. December 5, 2013. www.fda.gov/downloads/drugs/developmentapprovalprocess/ smallbusinessassistance/ucm361321.pdf/. Accessed June 24, 2015. 5. Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/b-lactamase inhibitor combination with activity against multidrug-resistant Gram-negative bacilli. Drugs. 2014;74:31-51. 6. Zerbaxa product information. Cubist Pharmaceuticals, Lexington, Mass. May 2015. 7. Sorbera M, Chung E, Ho CW, et al. Ceftolozane/tazobactam: a new option in the treatment of complicated Gram-negative infections. PT. 2014;39(12):825-832. 8. Sucher AJ, Chahine EB, Cogan P, et al. Ceftolozane/tazobactam: a new cephalosporin and b-lactamase inhibitor combination. Ann Pharmacother. 2015;49(9):1046-1056.
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9. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60(10):1462-1471. 10. Liscio JL, Mahoney MV, Hirsch EB. Ceftolozane/tazobactam and ceftazidime/ avibactam: two novel b-lactam/b-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. Int J Antimicrob Agents. 2015;46(3):266-271. 11. Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime/avibactam: a novel cephalosporin/b-lactamase inhibitor combination. Drugs. 2013;73:159-177. 12. Lagace-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014;9:13-25. 13. Zasowski EF, Rybak JM, Rybak MJ. The b-lactams strike back: ceftazidimeavibactam. Pharmacotherapy. 2015;35(8):755-770. 14. Pitart C, Marco F, Keating TA, et al. Activity of ceftazidime-avibactam against flouroquinolone-resistant Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59(6):3059-3065. 15. Avycaz product information. Forest Pharmaceuticals, Cincinnati, OH. February 2015. 16. Scott LJ. Dalbavancin: a review in acute bacterial skin and skin structure infections. Drugs. 2015;75(11):1281-1291. 17. Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014;370:2169-2179. 18. Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides—a comparative review of dalbavancin, oritavancin and telavancin. Drugs. 2010;70(7):859-886. 19. Dalvance product information. Durata Therapeutics, Chicago, III, May 2014. 20. Saravolatz LD, Stein GE. Oritavancin: a long half-life lipoglycopeptide. Clin Infect Dis. 2015;61(4):627-632. 21. Karaoui LR, El-Lababidi R, Chahine EB. Oritavancin: an investigational lipoglycopeptide antibiotic. Am J Health Syst Pharm. 2013;70:23-33. 22. Tice A. Oritavancin: a new opportunity for outpatient therapy of serious infections. Clin Infect Dis. 2012;54(Suppl. 3):S239-243. 23. Orbactiv product information. The Medicines Company, Parsippany, NJ. September 2014. 24. Kisgen JJ, Mansour H, Unger NR, et al. Tedizolid: a new oxazolidinone antimicrobial. Am J Health Syst Pharm. 2014;71:621-633. 25. Zhanel GG, Love R, Adam H, et al. Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant Gram-positive pathogens. Drugs. 2015;75:253-270. 26. Hall RG, Michaels HN. Profile of tedizolid phosphate and its potential in the treatment of acute bacterial skin and skin structure infections. Infect Drug Resist. 2015;8:75-82. 27. Sivextro product information. Cubist Pharmaceuticals, Lexington, Mass. March 2015.
Catherine M. Oliphant, PharmD, is an associate professor at the Idaho State University College of Pharmacy in Meridian, ID. She can be reached at [email protected]. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest. 1555-4155/15/$ see front matter © 2016 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2015.10.008
Volume 12, Issue 3, March 2016
Infections caused by resistant pathogens are increasing and are a major threat to patient outcomes. A 2013 US Centers for Disease and Control and Prevention report on antibiotic resistance threats indicates that 2 million Americans acquire antibioticresistant infections annually and at least 23,000 die. Increasing resistance of bacterial pathogens to virtually all available antimicrobial classes signals the emergent need for new agents. Only 12 antibiotics were approved by the US Food and Drug Administration between 2000 and 2012. Initiatives to increase the number of effective antibiotics have been enacted. This study addresses the mechanism of action, microbiology, indications, dose, safety, drug interactions, and place in therapy of dalbavancin, tedizolid, oritavancin, ceftolozane/tazobactam, and ceftazidime/avibactam. Keywords: ceftazidime/avibactam, ceftolozane/tazobactam, dalbavancin, oritavancin, tedizolid Ó 2016 Elsevier, Inc. All rights reserved.
INTRODUCTION
D
espite increasing resistance among both Gram-positive and Gram-negative bacteria, antimicrobial agent development over the last 20 years has slowed dramatically—since 2000, only 12 antimicrobial agents have been approved. The increase in antibiotic-resistant pathogens has resulted in dwindling numbers of efficacious antimicrobial agents available to treat patients with resistant pathogens. According to the United States Centers for Disease Control (CDC) report, Antibiotic Resistance Threats in the United States, 2013, 2 million individuals acquire antibiotic-resistant infections each year and at least 23,000 of these patients die as a result. The CDC report states that developing new antibiotics is one of the four core actions needed to help fight resistant bacteria.1 Developing new antimicrobial agents is a challenging, timely, and costly process. The number of pharmaceutical companies involved in antibiotic research has decreased significantly. With regard to drug development, approximately 1 in 5 agents that reach the initial phase of testing receive approval from the US Food and Drug Administration (FDA).2 This is coupled with the fact that antibiotics are only used for a short period of time as compared with agents used for the management of chronic diseases www.npjournal.org
(ie, hypertension). In 2010, the Infectious Diseases Society of America proposed the 10 ’20 Initiative, in support of the development of 10 new systemic antimicrobial agents by 2020.3 To address these concerns, The US Congress enacted the Generating Antibiotic Incentives Now Act, under the FDA’s Safety and Innovation Act. The Generating Antibiotic Incentives Now Act provides drug manufacturers with an additional 5 years of exclusivity for qualifying new antimicrobial agents. The qualifying agents are referred to as a Qualified Infectious Disease Product and are defined as those antimicrobial agents that are intended to treat serious or life-threatening infections, including resistant pathogens (as defined by the FDA). These agents are eligible for priority review and fast track status. In 2015, President Obama proposed that the 2016 budget would include $1.2 billion for combating resistant infections.4 Since 2010, the FDA has approved 6 new systemic antimicrobial agents. These include ceftaroline, dalbavancin, tedizolid, oritavancin, ceftolozane/ tazobactam, and ceftazidime/avibactam. Five of these agents were granted priority review and approval as a Qualified Infectious Disease Product—dalbavancin, tedizolid, oritavancin, ceftolozane/tazobactam, and ceftazidime/avibactam. This article addresses the mechanism of action, clinical microbiology, The Journal for Nurse Practitioners - JNP
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indications, dose/administration/cost, adverse effects, drug interactions, and place in therapy for the agents approved in 2014 and the first half of 2015. CEFTOLOZANE/TAZOBACTAM Mechanism of Action
Ceftolozane (Zerbaxa, Cubist Pharmaceuticals, Lexington, Mass) is an extended spectrum cephalosporin in combination with tazobactam, a beta-lactamase inhibitor that was approved in December 2014. This is the first cephalosporin to be combined with a betalactamase inhibitor. Cephalosporins (a beta-lactam antibiotic) bind to penicillin-binding proteins and inhibit bacterial cell wall synthesis. Ceftolozane has greater affinity for penicillin-binding proteins than either ceftazidime or imipenem, making it more potent than these agents for certain pathogens. Tazobactam binds to some beta-lactamases (enzymes) and renders the enzyme unable to hydrolyze the beta-lactam ring, thus maintaining the antimicrobial activity of the antibiotic.5-7 Clinical Microbiology
Ceftolozane/tazobactam demonstrates activity against many Gram-negative bacteria, including Pseudomonas aeruginosa. In vitro data suggest that the addition of the beta-lactamase inhibitor enhances its Gram-negative activity against some extended spectrum betalactamase (ESBL)‒producing Enterobacteriaceae (including ceftazidime-resistant Enterobacteriaceae), as well as increased stability to AmpC beta-lactamases. However, ceftolozane/tazobactam does not have activity against metallo beta-lactamases or carbapenemase-producing bacteria. In the phase 3 intra-abdominal study, a small subset of patients (150 patients) had ESBL-producing Escherichia coli and Klebsiella pneumoniae. In the trial, patients treated with ceftolozane/tazobactam had clinical cure rates of 97% as compared with 85% of patients treated with meropenem. Ceftolozane alone has potent in vitro anti-pseudomonal activity, including multidrugresistant P aeruginosa. Ceftolozane/tazobactam has coverage against some Gram-positive bacteria as well. It has activity against some Streptococcus species, but has only limited coverage against Staphylococcus spp. In addition, it should not be used for infections secondary to Enterococcus spp. Data suggest limited e92
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anaerobic activity as well, but it should be used in combination with metronidazole for the treatment of complicated intra-abdominal infections (or other infections in which anaerobes are likely).5-10 Indications
Ceftolozane/tazobactam is FDA approved for the treatment of complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections, including pyelonephritis.6 A study evaluating its use in ventilator-associated pneumonia is currently underway. With regard to complicated intra-abdominal infections, ceftolozane/ tazobactam in combination with metronidazole was compared with meropenem for a duration of 4-14 days and was found to be noninferior (83% and 87.3%, respectively). In the complicated urinary tract infections trials, ceftolozane/tazobactam was compared with levofloxacin for a duration of 7 days. Levofloxacin resistance was noted in almost 27% of patients; however, when these patients were removed from the analysis, ceftolozane/tazobactam was also found to be noninferior (82.6% efficacy with ceftolozane/tazobactam vs. 79.7% with levofloxacin). Data from both the complicated intra-abdominal and urinary tract infections trials demonstrate that patients with a creatinine clearance (CrCl) of 30-49 mL/min had lower cure rates versus the comparator groups (meropenem and levofloxacin, respectively). In the intra-abdominal study, the clinical cure rate with CrCl 30-49 mL/min for ceftolozane/tazobactam was 47.8% and 69.2% for meropenem. These data come from a subgroup analysis of a small number of patients. It is important to note that all patients in the subgroup with CrCl 30-49 mL/min (regardless of treatment arm) had lower cure rates than the subgroup with CrCl 50 mL/min (with clinical cure rates of 85.2% and 87.9%, respectively, for ceftolozane/tazobactam and meropenem in the intra-abdominal study). In response, the FDA has recommended that additional studies be conducted evaluating outcomes in patients with CrCl of < 50 mL/min. In addition, in the intra-abdominal infections trials, clinical cure rates were noted to be lower in patients 65 years old who received ceftolozane/tazobactam compared with those given meropenem (69% vs. 82.4%). Again, the FDA has Volume 12, Issue 3, March 2016
recommended that additional studies be performed in this patient population.5-10 It is important to note that ceftolozane/tazobactam is not approved for ESBL-producing bacteria. In vitro data and minimal clinical data suggest activity against some of these pathogens, yet clinical outcomes have not been studied. Dose, Administration, Monitoring, and Cost
The recommended dose of ceftolozane/tazobactam is 1.5 g every 8 hours administered IV in patients with a CrCl > 50 mL/min. Duration of therapy ranged from 4 to 14 days in the intra-abdominal studies and was 7 days in the urinary tract infections trials. However, duration of therapy should be individualized and based on site of infection, severity, and the patient’s response to therapy. The drug is eliminated primarily unchanged in the urine. Therefore, in patients with reduced renal function (CrCl 50 mL/ min), the dose should be reduced based on the patient’s renal function. For patients with a CrCl of 30-50 mL/min, the recommended dose is 750 mg every 8 hours. If the CrCl is 15-29 mL/min, the recommended dose is 375 mg every 8 hours. For patients on hemodialysis, a single loading dose of 750 mg is recommended, followed by 150 mg every 8 hours.6 Renal function should be monitored before initiating therapy and during administration, especially if the patient has fluctuating renal function. The multiple daily dosing may be a disadvantage. In addition, it is more costly than the comparators used in the clinical trials—$249 per day, as compared with meropenem at $45/day and levofloxacin at $21/day [cost as of August 2015, based on wholesale acquisition cost (WAC), which is the manufacturer’s list price for a drug to wholesalers or direct purchasers]. Pregnancy Category/Breast-feeding Considerations
Ceftolozane/tazobactam is pregnancy category B. With regard to breast-feeding, it is unknown whether the agent is excreted into breast milk. Therefore, it is recommended to be used with caution.6 Adverse Effects
Data from trials indicate that ceftolozane/tazobactam is well tolerated and has adverse effects comparable to www.npjournal.org
those of other beta-lactam antimicrobial agents. The most common adverse effects were found to be constipation, nausea, insomnia, and headache. Phlebitis and infusion-site reactions did occur at lower rates than the aforementioned events. In addition, in phase 2 and 3 trials, ceftolozane/tazobactam was associated with higher rates of anemia than comparator agents (6.1% vs. 2.6% with meropenem in the complicated intra-abdominal study). Other betalactam antimicrobial agents have been reported to have hematologic abnormalities. Hypersensitivity reactions may occur as with other beta-lactam agents.5-10 Patients should be monitored for these adverse effects. Drug Interactions
Ceftolozane/tazobactam is not hepatically metabolized, so cytochrome P450 interactions are not expected to occur. No significant drug-drug or drug-food interactions have been noted.5-7 Place in Therapy
Ceftolozane/tazobactam is currently approved for the treatment of complicated intra-abdominal and urinary tract infections. However, because it is a novel agent with enhanced activity against drug-resistant pathogens, it should be reserved for use in patients with pathogens resistant to other available antibiotics or in those unable to tolerate other standard therapies for these indications. With its potent anti-pseudomonal activity, ceftolozane/tazobactam is an option for the treatment of infections caused by P aeruginosa, especially for those that are antibiotic-resistant. It may also be an alternative to carbapenems for the treatment of infections secondary to ESBL-producing bacteria. In vitro data demonstrate activity against select resistant Gram-negative pathogens. However, ceftolozane/tazobactam only has limited clinical data against these resistant pathogens and needs further evaluation. If this agent does prove to be useful against pathogens that dictate the use of carbapenems as standard therapy, it may reduce carbapenem use and potentially decrease the emergence of carbapenem-resistant bacteria. In the meantime, appropriate use of this important new agent is prudent to preserve its activity against resistant pathogens. The Journal for Nurse Practitioners - JNP
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CEFTAZIDIME/AVIBACTAM Mechanism of Action
Ceftazidime (Avycaz, Forest Pharmaceuticals, Cincinnati, OH) is a third-generation cephalosporin in combination with avibactam, a new beta-lactamase inhibitor, which was approved in February 2015. Avibactam is a more potent beta-lactamase inhibitor than tazobactam, clavulanate, or sulbactam.10-12 Clinical Microbiology
Ceftazidime/avibactam has activity predominantly against Gram-negative bacilli. The addition of avibactam greatly improves ceftazidime’s antimicrobial spectrum of activity against P aeruginosa and many Enterobacteriaceae, but not Acinetobacter spp. The addition of avibactam to ceftazidime adds activity against some bacteria producing ESBL (not metallo beta-lactamases) as well as some carbapenemaseproducing bacteria (not Acinetobacter OXA-type carbapenemase). In vitro data suggest that ceftazidime/avibactam is active against select resistant Gram-negative pathogens. Ceftazidime/avibactam is the first beta-lactam to have coverage against carbapenemases. This antimicrobial agent does not have activity against Gram-positive bacteria or most anaerobes (like ceftolozane/tazobactam, it must be used in combination with metronidazole for anaerobic infections).10-15 Indications
Ceftazidime/avibactam is FDA approved for complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections, including pyelonephritis.10 A study evaluating its use in hospital-acquired and ventilator-associated pneumonia is currently being conducted. In both the complicated intra-abdominal and urinary tract infections trials, ceftazidime/avibactam was found to be noninferior to the comparator agents (meropenem and imipenemcilastatin, respectively). Data from the complicated intra-abdominal infection trial indicate that patients with a CrCl of 30-50 mL/min who received ceftazidime/avibactam had a poorer outcome when compared with meropenem. Death occurred in approximately 26% of ceftazidime/avibactam patients as compared with 8.6% of those given meropenem (as compared with overall death of 2.5% of patients who e94
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received ceftazidime/avibactam and 1.5% of patients who received meropenem). Dosing of the ceftazidime/avibactam in this clinical trial was one third lower than what is currently recommended for this subgroup of patients with CrCl of 30-50 mL/min. The revised dosing is expected to provide adequate concentrations for this subgroup. A future trial is planned to evaluate dosing in patients with intra-abdominal infections and CrCl levels of 30-50 mL/min.10-15 It is important to note that ceftazidime/avibactam is not approved for ESBL- or carbapenemaseproducing bacteria. In vitro data and minimal clinical data suggest activity against some of these pathogens, yet clinical outcomes have not been evaluated.10,13,14 Dose, Administration, Monitoring, and Cost
The recommended dose for patients with a CrCl > 50 mL/min is 2.5 g every 8 hours administered IV. Duration of therapy has ranged from 5 to 14 days in the intra-abdominal studies and from 7 to 14 days in the urinary tract infections trials. However, duration of therapy should be individualized and based on site of infection, severity, and the patient’s response to therapy. Ceftazidime/avibactam is eliminated primarily unchanged in the urine, and therefore dosing adjustments must be made in patients with renal impairment. For patients with a CrCl of 31-50 mL/ min, the recommended dose is 1.25 g every 8 hours. If the CrCl is 16-30 mL/min, the recommended dose is 0.94 g every 12 hours. For a CrCl of 6-15 mL/min, the recommended dose is 0.94 g every 24 hours and, if the CrCl is < 5 mL/min, the recommended dose is 0.94 g every 48 hours. Renal function should be monitored before initiating therapy and during administration, especially if the patient has fluctuating renal function (adjust dose accordingly based on CrCl). Of note, this agent must be infused over 2 hours to maximize the time above the minimum inhibitory concentration—beta-lactams are timedependent antibiotics, and therefore optimizing time above MIC increases the efficacy of these agents.10-15 The daily cost for a patient receiving the recommended dose (2.5 g every 8 hours) for normal renal function is approximately $855 (cost as of August 2015, based on WAC). The comparators (meropenem and imipenem/cilastatin) in the clinical trials are approximately $45 per day. Volume 12, Issue 3, March 2016
Pregnancy Category/Breast-feeding Considerations
Ceftazidime/avibactam is pregnancy category B. With regard to breast-feeding, it is unknown whether the agent is excreted into breast milk. Therefore, it is recommended to be used with caution.15 Adverse Effects
Data from phase 1, 2, and 3 studies demonstrate that ceftazidime/avibactam is well tolerated. The most common adverse effects in the intra-abdominal trials were nausea, vomiting, and abdominal pain (likely due, at least in part, to metronidazole). In the urinary tract infections trials, constipation and anxiety were reported most commonly. As with other cephalosporins, gastrointestinal effects, hematologic abnormalities, and mild elevations in liver function tests may be expected. In addition, hypersensitivity reactions may occur as with other beta-lactam agents.10-15 Drug Interactions
There are no known significant drug interactions with regard to P450 enzymes, as ceftazidime/avibactam is not hepatically metabolized. Avibactam is a substrate of organic anion transporters 1 and 3 in the kidney; probenicid is an organic anion transporter inhibitor and therefore will reduce the elimination of avibactam. Administration of probenecid with ceftazidime/avibactam is not recommended.10-15 Place in Therapy
Ceftazidime/avibactam has demonstrated similar efficacy when compared with carbapenems in the treatment of complicated intra-abdominal (in combination with metronidazole) and complicated urinary tract infections. The addition of avibactam to ceftazidime improves P aeruginosa activity and broadens coverage to include ESBL-producing Gramnegative bacilli as well as certain carbapenemaseproducing Gram-negative bacilli. However, as with ceftolozane/tazobactam, this agent has not been clinically evaluated for use against these resistant pathogens and its efficacy remains to be seen. Practitioners should reserve this broad-spectrum agent for patients unable to tolerate currently available antibiotics. Future data will define the efficacy of this agent for infections caused by antibiotic-resistant Gramnegative pathogens. www.npjournal.org
DALBAVANCIN Mechanism of Action
Dalbavancin (Dalvance, Actavis, Inc, Parsippany, NJ) is a lipoglycopeptide that was approved in May 2014. Lipoglycopeptides inhibit bacterial cell wall synthesis by binding the peptidoglycan chain at the terminal D-alanyl‒D-alanine and interfere with cross-linking of the bacterial cell wall. As a result, the cell membrane is disrupted, which leads to cell death. Telavancin was the first lipoglycopeptide. Vancomycin is the prototype agent in the glycopeptide class of antimicrobial agents. Lipoglycopeptides differ from glycopeptides in that they have a lipophilic side chain that increases antibacterial potency while also prolonging the half-life.16-19 Clinical Microbiology
Dalbavancin’s spectrum of activity includes Grampositive aerobic and anaerobic bacteria. In vitro, it is a more potent antimicrobial agent than vancomycin against most pathogens due to the lipophilic side chain. MICs of dalbavancin are significantly lower than those of vancomycin.13 Dalbavancin’s coverage includes staphylococci [including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S aureus, and coagulase-negative staphylococci], streptococci (including penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae, viridans group streptococci), enterococci [including Enterococcus faecium and Enterococcus faecalis, vancomycin (van)‒ resistant enterococci—vanB and vanC strains (no activity against vanA enterococci)], Clostridium spp, and various other Gram-positive anaerobes.16-19 Of note, dalbavancin is FDA approved for the treatment of infections caused by S aureus [methicillin-susceptible (MSSA) and methicillin-resistant strains (MRSA)], Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus anginosus groups.19 Indications
Dalbavancin is FDA approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by the aforementioned pathogens. In phase 2 and 3 trials, the clinical efficacy rates were non-inferior to vancomycin (with the option to switch from vancomycin to oral linezolid). Future studies evaluating the efficacy of dalbavancin will The Journal for Nurse Practitioners - JNP
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include community-acquired bacterial pneumonia, osteomyelitis, and bacteremia.16-19 Dose, Administration, Monitoring, and Cost
Dalbavancin has a long half-life, which results in once-weekly dosing. It is only administered via the IV route. The FDA-recommended dose for ABSSSIs is 1,000 mg on day 1 followed by 500 mg on day 8, administered as a 30-minute infusion. In patients with CrCl < 30 mL/min (and not receiving regularly scheduled hemodialysis), the dose is reduced to 750 mg on day 1 followed by 375 mg on day 8.19 Monitoring of renal and liver function tests is suggested before initiation of therapy and during therapy. The cost for a course of therapy (2 doses) is approximately $4,500 (cost as of August 2015 based on WAC), which is significantly more expensive than vancomycin (approximately $20/day based on a 1-g dose every 12 hours for 7-14 days). Dalbavancin does not require pharmacokinetic monitoring of blood levels as compared with vancomycin, which does require monitoring (in addition to monitoring of serum creatinine). Pregnancy Category/Breast-feeding Considerations
Dalbavancin is pregnancy category C. Adverse effects were noted in animal reproductive studies. With regard to breast-feeding, it is unknown whether this agent is excreted in breast milk. Therefore, it is recommended to be used with caution.19 Adverse Effects
Dalbavancin was generally well tolerated in phase 2 and 3 trials. The most common adverse effects noted in these trials were nausea, vomiting, diarrhea, headache, rash, and pruritus. It is important to note that these adverse effects occurred in similar frequencies between both dalbavancin and the comparator agents (vancomycin linezolid). There are few data to demonstrate that dalbavancin is associated with either nephrotoxicity or hepatotoxicity. The nephrotoxicity rate in clinical trials was significantly lower for dalbavancin than for vancomycin. Alanine aminotransferase elevations were more common in patients receiving dalbavancin than comparator agents, but some of these patients had underlying liver abnormalities. Other liver enzyme e96
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abnormalities occurred at similar frequencies between dalbavancin and the comparator agents. Dalbavancin does not prolong the QTc interval.16-19 Like other glycopeptides, dalbavancin may be associated with an infusion reaction, referred to as red man syndrome (characterized by upper extremity/ face/neck redness/rash, pruritus, fever or chills, and hypotension). Therefore, the dose should be administered over 30 minutes to minimize the risk of infusion-related events.16-19 Patients should be monitored for these infusion-related reactions. Drug Interactions
Based on existing data, no significant drug-drug interactions have been identified. Dalbavancin is not a substrate, inhibitor, or inducer of the cytochrome P450 system.16-19 Place in Therapy
Dalbavancin is currently approved for the treatment of ABSSSIs. With regard to the use of dalbavancin, it is reasonable to state that it should not be considered a first-line agent for ABSSSIs because other efficacious and less costly alternative therapies exist. However, for nonadherent patients, outpatients, and those in whom venous access is an issue or if oral agents are not possible, this agent may have a role. In addition, this agent does not require pharmacokinetic monitoring, is well tolerated, and is patient-friendly in terms of dosing. Dalbavancin is a costly antimicrobial agent, but it has the potential to actually reduce health care costs if its use avoids or shortens the duration of hospitalization. Pharmacoeconomic analyses will provide further insight into the potential cost savings associated with this agent. Future clinical trials will provide data regarding dalbavancin’s use for additional indications, including coverage against multidrug-resistant bacteria. ORITAVANCIN Mechanism of Action
Oritavancin (Orbactiv, The Medicines Company, Parsippany, NJ) is a lipoglycopeptide that was approved in August 2014. Oritavancin’s mechanism of action is similar to that of dalbavancin. In addition, it may disrupt the bacteria cell membrane, increasing permeability. Oritavancin is also more potent than Volume 12, Issue 3, March 2016
vancomycin due to the structural modifications of the compound, which allow for improved ability to bind to the cell wall and thus increase the binding affinity to the target site. In addition, oritavancin has lower MICs against many Gram-positive pathogens when compared with vancomycin. Lipoglycopeptides are rapidly bactericidal (unlike vancomycin, which is slowly bactericidal). It also has a prolonged terminal half-life of 245 hours, allowing for novel dosing.18,20-23 Clinical Microbiology
Oritavancin is active against aerobic and anaerobic Gram-positive bacteria. In vitro, it is a more potent antimicrobial agent than vancomycin against most pathogens, due to the lipophilic side chain as well as the ability to cause cell membrane depolarization. It has excellent coverage against common Gram-positive pathogens, including S aureus (MSSA and MRSA), S pneumoniae (including penicillin-intermediate and penicillin-resistant strains), group A Streptococcus, S agalactiae, Enterococcus spp (both E faecalis and E faecium, including some vanA- and vanB-resistant strains), and some Gram-positive anaerobes (including select Clostridium spp). In vitro data suggest that oritavancin may have activity against both vancomycin intermediate and resistant S aureus (VISA and VRSA).20-23 Oritavancin is FDA approved for the treatment of infections caused by methicillinsusceptible and -resistant S aureus, Streptococcus pyogenes (group A Streptococcus), S agalactiae, S dysgalactiae, S anginosus group, and E faecalis (vancomycin-susceptible only).23 Indications
Oritavancin is FDA approved for the treatment of ABSSSIs caused by the aforementioned pathogens. In phase 2 and 3 trials, the clinical efficacy rates were noninferior to vancomycin. The phase 3 trials undertaken for the approval of oritavancin for ABSSSIs were the SOLO 1 and 2 trials. The primary efficacy endpoint in both of these trials was a composite endpoint that included the termination of spreading or a reduction in the size of the lesion, absence of fever, and no need for a rescue antibiotic. In the SOLO 1 trial, the primary efficacy endpoints were 82.3% and 78.9%, respectively, for oritavancin versus vancomycin. In the SOLO 2 trial, the composite www.npjournal.org
endpoint for oritavancin was 82.3% as compared with 78.9% for vancomycin.20-23 Dose, Administration, Monitoring, and Cost
Oritavancin is administered as a single IV dose of 1,200 mg administered over 3 hours. No dose adjustments are necessary for impaired renal or hepatic function.20-23 The cost for a course of therapy (1 dose) is $2,900 (cost as of August 2015, based on WAC). Like dalbavancin, oritavancin does not require pharmacokinetic monitoring of blood levels. Pregnancy Category/Breast-feeding Considerations
Oritavancin is pregnancy category C. With regard to breast-feeding, it is unknown whether this agent is excreted in breast milk. Therefore, it is recommended to be used with caution and only when the potential benefits outweigh the risks.18 Adverse Effects
Oritavancin has a long half-life and therefore resolution of adverse effects may be delayed. The most common adverse effects reported in phase 2 and 3 trials have included phlebitis, headache, diarrhea, nausea, vomiting, constipation, dizziness, and insomnia. Of note, the type and frequency of adverse reactions was similar to comparator agents. Patients receiving oritavancin in clinical trials had slightly higher rates of liver function test abnormalities than comparator agents. In addition, infusion-related reactions (pruritus, urticarial, flushing) may occur. Patients should be monitored for these infusion-related reactions. Hypersensitivity reactions have been reported. These reactions may persist for prolonged periods due to the long half-life of oritavancin. Clinicians should carefully monitor patients with a history of glycopeptide allergy. Oritavancin does not prolong the QTc interval.20-23 In clinical trials, an adverse reaction of osteomyelitis was noted to be more frequent in patients receiving oritavancin than comparator agents. The manufacturer recommends that patients be observed for findings of osteomyelitis during therapy.20,22,23 Drug Interactions
Oritavancin is a weak inhibitor and inducer of cytochrome P450 enzymes. It inhibits CYP2C19 and The Journal for Nurse Practitioners - JNP
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CYP2C9 and induces CYP3A4. Therefore, clinicians must monitor for drug-drug interactions with concomitant use of oritavancin and agents that are metabolized via these P450 enzymes. Of note, oritavancin may increase the serum concentrations and effects of vitamin K antagonists (ie, warfarin). Patients should be monitored and educated on the increased bleeding risk. Manufacturer labeling states that the average increase in the area under the curve for warfarin in patients receiving oritavancin is 31%.20-23 Oritavancin artificially prolongs coagulation tests. The activated partial thromboplastin time, a monitoring test for heparin, is artificially elevated for 48 hours. The use of unfractionated IV heparin is contraindicated for 48 hours after oritavancin administration due to the inability to appropriately monitor heparin, whereas the prothrombin time and international normalized ratio (both monitoring tests for warfarin) are artificially elevated for 24 hours. Thus, monitoring of these agents during these time frames leads to inaccurate test results.20-23 Place in Therapy
Oritavancin is currently only approved for the treatment of ABSSSIs. As with dalbavancin, it should not be considered a first-line agent for these infections, as other efficacious and less costly agents are available. It may have a niche for patients who do not need to be hospitalized and either need IV therapy or cannot take oral therapies. Additional clinical trials are needed to address its use for other indications.
Clinical Microbiology
Tedizolid is active against aerobic and certain anaerobic Gram-positive pathogens. In vitro data suggest it is a more potent antimicrobial than linezolid against many pathogens. Tedizolid’s coverage includes staphylococci (S aureus and coagulase-negative staphylococci, including methicillin-susceptible and methicillin-resistant strains as well as linezolidresistant strains), streptococci (including penicillinsusceptible and penicillin-resistant S pneumoniae, beta-hemolytic streptococci, viridans group), and enterococci (vancomycin-susceptible and vancomycin-resistant strains of E faecalis and E faecium). In addition, tedizolid has activity against select Gram-positive anaerobes.24-27 Of note, tedizolid is FDA approved for the treatment of infections caused by MSSA and MRSA, S pyogenes, S agalactiae, S anginosus group, and E faecalis.27 Indications
Tedizolid is FDA approved only for the treatment of ABSSSIs caused by the aforementioned FDAapproved pathogens. In phase 3 trials, tedizolid was noninferior to the comparator agent, linezolid, with regard to efficacy. The ESTABLISH-1 and -2 trials evaluated the efficacy and safety of 6 days of IV to oral tedizolid to 10 days of IV to oral linezolid for the treatment of ABSSSIs. Future studies will evaluate tedizolid’s use in complicated skin and skin structure infections, MRSA infections, and nosocomial pneumonia.24-27 Dose, Administration, Monitoring, and Cost
TEDIZOLID Mechanism of Action
Tedizolid (Sivextro, Cubist Pharmaceuticals, Lexington, Mass) is an oxazolidinone antimicrobial agent approved in June 2014. It is the second member in the oxazolidinone class, with linezolid being the first. Tedizolid is a protein synthesis inhibitor; it binds to the 23S ribosomal RNA of the 50S subunit of the ribosome. In contrast to linezolid, tedizolid has additional binding sites with a peptidyltransferase center that improves its antibacterial potency over linezolid. Tedizolid is a prodrug and must be converted to its active form by serum phosphatases in the body.24-27 e98
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The recommended dose for tedizolid for the treatment of ABSSSIs is 200 mg once daily, administered either orally (as a tablet) or IV for a total of 6 days of therapy. The once-daily dose is a benefit over the twice-daily dose required with linezolid. No dose adjustment is required in renal or hepatic impairment.24-27 A complete blood count should be done before initiating therapy. The daily cost for the tablet is $295 and for the IV dose is $235 as compared with linezolid’s daily cost of approximately $275 for both the oral or IV doses (cost as of August 2015, based on wholesale acquisition cost). Tedizolid may be a cheaper alternative to Volume 12, Issue 3, March 2016
linezolid for ABSSSIs if linezolid is administered for > 6 days. Of note, generic linezolid has been approved, which over time will likely result in a reduction in the price of linezolid. Pregnancy Category/Breast-feeding Considerations
Tedizolid is pregnancy category C. With regard to breast-feeding, it is unknown whether this agent is excreted in breast milk. Therefore, it is recommended to be used with caution.27 Adverse Effects
In phase 2 and 3 trials, gastrointestinal abnormalities (nausea, vomiting, and diarrhea) were most commonly observed but occurred less frequently in patients receiving tedizolid. Other common adverse effects included headache, dizziness, and fatigue (which were reported with similar frequency with the comparator agent, linezolid). Due to the fact that oxazolidinones may cause thrombocytopenia and optic and peripheral neuropathies (treatment with linezolid, particularly for > 14 days, has resulted in thrombocytopenia; neuropathies have been reported in patients taking linezolid for > 28 days), the propensity for tedizolid to also cause these effects was evaluated in clinical trials. Data from phase 3 trials demonstrate that 1.2% of patients who received 6 days of tedizolid reported peripheral neuropathy as compared with 0.6% of patients receiving linezolid. Optic nerve disorders were reported in 0.3% of patients given tedizolid and 0.2% in patients given linezolid. Patients should be monitored for optic and peripheral neuropathies. With regard to thrombocytopenia, the incidence of reduced platelet counts was significantly lower in patients treated with tedizolid 200 mg for 6 days as compared with linezolid for 10 days. The manufacturer states that tedizolid may have less effect than linezolid on hematologic parameters.24-27 It is important to note that adverse effect data exist only for the 6-day therapy of ABSSSIs—patients receiving longer courses of therapy may be at increased risk of adverse effects and should be closely monitored. Data from phase 1 studies demonstrate a potential for dose and duration effect on the hematologic parameters in healthy adults who received 21 days of therapy.27 www.npjournal.org
Drug Interactions
Although tedizolid is metabolized through the liver, it does not have affinity for the cytochrome P450 enzymes. The potential for P450 enzyme‒related drug-drug interactions is negligible. Tedizolid is a weak, reversible inhibitor of monoamine oxidase, similar to linezolid. Several studies have analyzed the potential for interactions and subsequent serotonergic effects (including serotonin syndrome) with the concomitant administration of tedizolid with tyramine and pseudoephedrine. With the concomitant use of tedizolid and tyramine or pseudoephedrine, there was no significant interaction identified with either agent. Data demonstrate a low potential for serotonergic effects with tedizolid. However, it is important to keep in mind that patients in the clinical trials did not receive agents (such as selective serotonin reuptake inhibitors or serotonin/ norepinephrine reuptake inhibitors) that are known to increase the risk of serotonergic effects, including serotonin syndrome. Clinicians should educate patients on the potential for adverse effects with concomitant use of tedizolid and other medications known to increase serotonergic effects.24-27 Information obtained from postmarketing use of tedizolid will shed further light on this important potential drug interaction. Place in Therapy
Tedizolid appears to be as efficacious as linezolid and demonstrates enhanced in vitro activity (against some pathogens) when compared with linezolid. Data to date show it is potentially safer than linezolid with regard to adverse effects and drug interactions, based on the 6-day duration of therapy in clinical trials. Use of this agent outside of currently recommended dosing and duration is not recommended. Tedizolid is a costly agent and its place in the treatment of ABSSSIs remains unknown. CONCLUSIONS
Ceftolozane/tazobactam, ceftazidime/avibactam, dalbavancin, oritavancin, and tedizolid are welcome additions to what has been a dwindling armamentarium of antimicrobial agents. These 5 new antimicrobial agents have been demonstrated to be as The Journal for Nurse Practitioners - JNP
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effective as their comparator agents in clinical trials. However, data to date with these drugs is limited as are approved indications. Additional clinical trials must be conducted to evaluate the use of these agents for the treatment of infections caused by resistant pathogens. These drugs should not be used as first-line treatment and should be reserved for use in patients who are unable to tolerate other standard therapies as overuse and misuse may lead to the emergence of antibiotic resistance. It is crucial that these new agents be used rationally to preserve their possible use in these difficult-to-treat infections secondary to highly resistant pathogens. Consultation with infectious disease specialists is recommended before prescribing any of these new antimicrobial therapies. Existing data indicate that the future of these new antimicrobial agents is promising with regard to the treatment of resistant pathogens. Clinicians must be prudent in prescribing of antibiotics to preserve the effectiveness of existing therapies and to avoid a post-antibiotic era (a time when antibiotics are unable treat infections). References 1. US Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. September 16, 2013. http://www.cdc.gov/ drugresistance/threat-report-2013/. Accessed June 24, 2015. 2. Hay M. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40-51. 3. Infectious Diseases Society of America. The 10 ’20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis. 2010;50:1081-1083. 4. US Food and Drug Administration. FDA Safety and Innovation Act. December 5, 2013. www.fda.gov/downloads/drugs/developmentapprovalprocess/ smallbusinessassistance/ucm361321.pdf/. Accessed June 24, 2015. 5. Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/b-lactamase inhibitor combination with activity against multidrug-resistant Gram-negative bacilli. Drugs. 2014;74:31-51. 6. Zerbaxa product information. Cubist Pharmaceuticals, Lexington, Mass. May 2015. 7. Sorbera M, Chung E, Ho CW, et al. Ceftolozane/tazobactam: a new option in the treatment of complicated Gram-negative infections. PT. 2014;39(12):825-832. 8. Sucher AJ, Chahine EB, Cogan P, et al. Ceftolozane/tazobactam: a new cephalosporin and b-lactamase inhibitor combination. Ann Pharmacother. 2015;49(9):1046-1056.
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9. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60(10):1462-1471. 10. Liscio JL, Mahoney MV, Hirsch EB. Ceftolozane/tazobactam and ceftazidime/ avibactam: two novel b-lactam/b-lactamase inhibitor combination agents for the treatment of resistant Gram-negative bacterial infections. Int J Antimicrob Agents. 2015;46(3):266-271. 11. Zhanel GG, Lawson CD, Adam H, et al. Ceftazidime/avibactam: a novel cephalosporin/b-lactamase inhibitor combination. Drugs. 2013;73:159-177. 12. Lagace-Wiens P, Walkty A, Karlowsky JA. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014;9:13-25. 13. Zasowski EF, Rybak JM, Rybak MJ. The b-lactams strike back: ceftazidimeavibactam. Pharmacotherapy. 2015;35(8):755-770. 14. Pitart C, Marco F, Keating TA, et al. Activity of ceftazidime-avibactam against flouroquinolone-resistant Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59(6):3059-3065. 15. Avycaz product information. Forest Pharmaceuticals, Cincinnati, OH. February 2015. 16. Scott LJ. Dalbavancin: a review in acute bacterial skin and skin structure infections. Drugs. 2015;75(11):1281-1291. 17. Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014;370:2169-2179. 18. Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides—a comparative review of dalbavancin, oritavancin and telavancin. Drugs. 2010;70(7):859-886. 19. Dalvance product information. Durata Therapeutics, Chicago, III, May 2014. 20. Saravolatz LD, Stein GE. Oritavancin: a long half-life lipoglycopeptide. Clin Infect Dis. 2015;61(4):627-632. 21. Karaoui LR, El-Lababidi R, Chahine EB. Oritavancin: an investigational lipoglycopeptide antibiotic. Am J Health Syst Pharm. 2013;70:23-33. 22. Tice A. Oritavancin: a new opportunity for outpatient therapy of serious infections. Clin Infect Dis. 2012;54(Suppl. 3):S239-243. 23. Orbactiv product information. The Medicines Company, Parsippany, NJ. September 2014. 24. Kisgen JJ, Mansour H, Unger NR, et al. Tedizolid: a new oxazolidinone antimicrobial. Am J Health Syst Pharm. 2014;71:621-633. 25. Zhanel GG, Love R, Adam H, et al. Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant Gram-positive pathogens. Drugs. 2015;75:253-270. 26. Hall RG, Michaels HN. Profile of tedizolid phosphate and its potential in the treatment of acute bacterial skin and skin structure infections. Infect Drug Resist. 2015;8:75-82. 27. Sivextro product information. Cubist Pharmaceuticals, Lexington, Mass. March 2015.
Catherine M. Oliphant, PharmD, is an associate professor at the Idaho State University College of Pharmacy in Meridian, ID. She can be reached at [email protected]. In compliance with national ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest. 1555-4155/15/$ see front matter © 2016 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2015.10.008
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