June 16, 2015
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It’s not novel, but it’s an addition: Zerbaxa

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It is a well-known fact that we are in a crisis, and we are running out of time. The reality is people are dying of multidrug-resistant pathogens, particularly gram-negative bacilli. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) are of notable concern. Their complex mechanisms of resistance make treatment of these organisms challenging. In addition, first-, second- and even third-line antibiotic treatments have been exhausted.

It was in 2002 that the Infectious Diseases Society of America (IDSA) expressed concerns over the available antibiotics on the market and the lack of new, novel agents in the pipeline. The 10 x ’20 initiative was developed with the focus of stimulating antibiotic research and development (R&D). The strategy is to develop global partnerships and provide financial incentives to support R&D. The challenge has been taken on by Big Pharma. Since 2009, seven new drugs are in clinical development for the treatment of resistant gram-negative bacteria.

Zerbaxa (ceftolozane/tazobactam, Cubist Pharmaceuticals) is one recently approved agent that has been added to our arsenal. While this agent does not exhibit a novel mechanism of action, it is the first of the cephalosporins to add a beta-lactamase inhibitor (tazobactam) to the chemical structure. Ceftolozane/tazobactam is a cephalosporin beta-lactam antibiotic, and the mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane’s chemical structure is most comparable to ceftazidime. Its chemical structure has a modified side-chain at the 3-position of the cephem nucleus, adding potent antipseudomonal activity by evading P. aeruginosa mechanisms of resistance, including efflux pumps, reduced uptake through porins and modification of PBPs. In addition, the beta-lactamase inhibitor extends its activity against most extended-spectrum beta-lactamase (ESBL) gram-negative pathogens.

Ceftolozane/tazobactam has been approved for two limited indications: complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections, including pyelonephritis. It must be used in combination with metronidazole for cIAI given its lack of anaerobic coverage. Ceftolozane exhibits linear (two-compartment model) kinetics and is unaffected by tazobactam. It is dosed as 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) intravenously every 8 hours. When compared with other cephalosporins, it has similar pharmacokinetics; administered over 1 hour, half-life of 2.3 hours, steady-state volume of distribution ranging from approximately 13 L to 17 L, a mean clearance of 102.4 mL/min, with more than 92% urinary excretion. It does require dose adjustments in patients with creatinine clearance (CrCl) of less than 50 mL/min. Dose reductions include 750 mg IV every 8 hours for an estimated CrCl of 30 mL/min to 50 mL/min, and 375 mg IV every 8 hours for an estimated CrCl of 15 mL/min to 29 mL/min. For patients receiving hemodialysis (HD), approximately two-thirds of the dose will be eliminated. A loading dose of 750 mg followed by 150 mg IV every 8 hours as a maintenance dose immediately following HD is recommended.

Kimberly D. Boeser

A recent safety alert from the FDA reported seven dose-related medication errors due to drug labeling. The labeling on the vials and cartons lists the strengths of the individual ingredients rather than the total grams of the two active ingredients. Other beta-lactam products list the sum of the ingredients. The confusion led to errors resulting in administration of 50% more drug than prescribed. Fortunately, no adverse events were associated with the error. The FDA is encouraging close attention be paid to the labeling of this antibiotic and extra vigilance of reported related errors. It is unknown if the FDA will require a change in the current labeling of the product by the manufacturer.

Like many of the cephalosporins, ceftolozane/tazobactam has a safe adverse event profile and limited drug interaction profile. The most commonly reported adverse events reported at more than 5% were nausea, headache, diarrhea and pyrexia. Other notable adverse events reported at less than 3% but higher than comparator agents meropenem and levofloxacin were transaminitis, abdominal pain and atrial fibrillation. No drug-drug interactions were observed with ceftolozane/tazobactam as it is not a substrate for cytochrome P450 enzymes (CYPs), therefore no clinically relevant adverse events involving inhibition or induction of CYPs will occur. One notable safety concern is the reported increased mortality in the cIAI trials, where various causes of death occurred in 2.5% of patients receiving ceftolozane/tazobactam compared with 1.5% of patients receiving meropenem.

So where is ceftolozane/tazobactam’s place in therapy? We need agents with novel mechanisms of action to treat the most difficult ESKAPE pathogens. It does add to our current available options for the treatment of multidrug-resistant pathogens, but it does not completely fill the gap. Currently, the drug has limited data to be evaluated for the treatment of other significant infections caused by these pathogens, although it is being investigated for the treatment of ventilator-associated bacterial pneumonia.

P. aeruginosa is particularly difficult given its multiple mechanisms of resistance in a single strain. Unlike other antipseudomonal cephalosporins on the market, ceftolozane has a pyrazole in the 3-position of the side chain, which adds to its ability to prevent hydrolysis and adds stability against AmpC beta-lactamase–producing P. aeruginosa. Additionally, it maintains activity against P. aeruginosa that expresses efflux pumps (MexXY and MexAB) and carbapenem-specific porins.

ESBL-producing gram-negative pathogens are another group of concerns. Ceftolozane/tazobactam can be considered an alternative treatment strategy to the available agents on the market (eg, carbapenems, colistin, tigecycline and cefepime). It has been shown to withstand the more narrow-spectrum beta-lactamases (TEM-1 and 2, SHV-1 and OXA-1), but reduced activity has been seen with ESBLs (TEM-3 through 9, SHV-2 through 4, OXA-2 and CTX-M-3 and 18). While this activity is promising, it still lacks much-needed coverage of gram-negative bacteria that produce carbapenemases (K. pneumoniae [KPC] and metallo-beta-lactamases [MBLs]).

Additionally, ceftolozane/tazobactam has a limited spectrum of coverage for gram-positive and anaerobic pathogens. It does have some coverage of Streptococcus and anaerobes including Bacteroides fragilis, Fusobacterium and Prevotella, but the clinical efficacy of ceftolozane/tazobactam for these pathogens has not been well established. The manufacturer does recommend that metronidazole be added to ceftolozane/tazobactam for the treatment of cIAI. In all clinical scenarios, it is prudent to verify susceptibilities with the clinical microbiology laboratory when initiating treatment.

The 10 x ’20 initiative has been committed to adding 10 new antibacterial drugs by 2020. Momentum has been forward-moving since 2009, and IDSA’s endorsement for the progress of R&D has been promising. Ceftolozane/tazobactam can be considered for treatment with some scrutiny, including understanding that its treatment based on the spectrum of coverage of ESBL gram-negatives may be limited due to the mechanism of resistance, lack of K. pneumoniae carbapenemase or MBL coverage, and a mixed gram-positive/gram-negative infection. Additionally, there are limited published data for its treatment of other disease states caused by MDR pathogens. It will be cost-prohibitive compared with other available agents on the market, but this should be balanced with the cost associated with treating a significant infection. Clinical use and ongoing research of ceftolozane/tazobactam will help define its final place in therapy.

References:

FDA Medwatch. Zerbaxa (ceftolozane and tazobactam): Drug Safety Communication – FDA Cautions about Dose Confusion and Medication Errors. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm447629.htm. Accessed May 27, 2015.
Infectious Diseases Society of America. Clin Infect Dis. 2013;doi:10.1086/652237.
ZERBAXA package insert. Cubist Pharmaceuticals. www.zerbaxa.com/pdf/PrescribingInformation.pdf. Accessed May 27, 2015.
Zhanel GG, et al. Drugs. 2014;doi:10.1007/s40265-013-0168-2.

For more information:

Kimberly D. Boeser, PharmD, BCPS AQ-ID, is an infectious diseases clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center. She can be reached at kvarejc1@fairview.org.

Disclosure: Boeser reports no relevant financial disclosures.