Superheroes of Gram-Negative Bacteria

The FDA recently approved 2 new antibiotic combinations targeting resistant Gram-negative organisms. The approval of ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz) marks the first time a cephalosporin has been paired with a beta-lactamase inhibitor, and both are welcome additions to the Gram-negative armamentarium.

Zerbaxa

Ceftolozane is a novel cephalosporin combined with an existing beta-lactamase inhibitor, tazobactam. Tazobactam is also available co-formulated with piperacillin as the brand-name product, Zosyn.

Ceftolozane/tazobactam was approved on December 19, 2014, for the indications of complicated intra-abdominal infections (cIAI) in combination with metronidazole, and complicated urinary tract infections (cUTI), including pyelonephritis.¹

Ceftolozane/tazobactam is active against many Gram-negative organisms, including Enterobacteriaceae and Pseudomonas aeruginosa. While touted for its Gram-negative activity, ceftolozane/tazobactam is has some activity against anaerobes (Bacteroides fragilis) and some Gram-positive organisms (Streptococcus anginosis, S. constellatus, and S. salivarius). Notably missing from its spectrum of activity is reliable staphylococcal activity.

Ceftolozane/tazobactam was developed to target resistant Gram-negative organisms. One advantage of ceftolozane/tazobactam over currently available cephalosporins is its activity against select extended-spectrum beta-lactamases (ESBLs).

Ceftolozane/tazobactam has in vitro activity against the Class A (TEM, SHV, CTX-M), some Class C (AmpC), and some Class D (OXA) beta-lactamases. However, It has no activity against the metallo-beta-lactamases (NDM-1, IMP, VIM), nor against carbapenemases (KPC).²

A large phase 3 trial compared ceftolozane/tazobactam plus metronidazole with meropenem for 4 to 14 days in 979 patients with cIAI. The majority of patients were white, male, and aged in their mid-50s. The appendix was the primary source of infection in almost half of the patients, followed by cholecystitis. The primary endpoint was clinical cure at 24 to 32 days after the start of therapy. Overall, ceftolozane/tazobactam + metronidazole was deemed non-inferior to meropenem therapy (83.0% vs. 87.3%, respectively, 95% confidence interval (CI) -8.91 to 0.54). Adverse reactions were similar in both groups.³

Another large phase 3 trial evaluated ceftolozane/tazobactam against levofloxacin for 7 days in 1068 patients with cUTI. The majority of patients were white, female, and <65 years. Most (82%) had pyelonephritis. The primary endpoint was clinical cure and microbiological eradication at 5 to 9 days after the last drug dose. Overall, ceftolozane/tazobactam was found to be non-inferior to levofloxacin therapy (76.9% vs. 68.4% respectively, 95% CI 2.3 to 14.6). Adverse reactions were similar in both groups.²

Ceftolozane/tazobactam is currently being studied in a phase 3 ventilator and nosocomial pneumonia trial against meropenem, and in a phase 1 dose-finding study in pediatric patients for the treatment of Gram-negative infections.^4,5

Avycaz

Ceftazidime is a third-generation cephalosporin originally approved in 1985. It is co-formulated with a new beta-lactamase inhibitor avibactam and was approved on February 25, 2015, for the indications of cIAI in combination with metronidazole and cUTI, including pyelonephritis.

Since ceftazidime has been used clinically for many years, the approval process for ceftazidime/avibactam relied on ceftazidime historical data plus phase 1 and 2 data only. As a result, there is limited safety data available, and the FDA labeling carries a statement to reserve ceftazidime/avibactam for patients with little or no other treatment options.⁶

Ceftazidime/avibactam has broad Gram-negative activity including Enterobacteriaceae and P. aeruginosa. It encompasses the entire spectrum of ceftazidime, but the addition of avibactam allows it to maintain activity in the presence of certain resistance mechanisms. It has minimal activity against anaerobic and Gram-positive organisms.

Avibactam can inhibit a broader class of ESBLs; thus, ceftazidime/avibactam is active against Class A (TEM, SHV, CTX-M), some Class C (AmpC), and some Class D (OXA) beta-lactamases. Although it is not active against the metallo-beta-lactamses (NDM-1, IMP, VIM), it is the first cephalosporin and beta-lactam to be active against carbapenemases (KPC).⁷

A phase 2 trial compared ceftazidime/avibactam plus metronidazole against meropenem for 5 to 14 days in 203 patients with cIAI. The majority of patients were white, male, and in their mid-40s. The appendix, followed by the stomach/duodenum, were the most common origins of infection. The primary endpoint was clinical cure 2 weeks after the last drug dose. Cure rates were similar between the 2 groups: 91.2% for ceftazidime/avibactam plus metronidazole versus 93.4% for meropenem (95% CI -20.4% to 12.2%). The incidence of adverse effects was also similar between groups.⁸

A second phase 2 trial compared ceftazidime/avibactam with imipenem/cilastatin for 7 to 14 days in 135 patients with cUTI. Most of the patients were white, female, and in their mid-40s, and approximately two-thirds had pyelonephritis. The primary endpoint was clinical cure at 5 to 9 days after the last drug dose. Cure rates were similar between the 2 groups: 70.4% for ceftazidime/avibactam versus 71.4% for imipenem/cilastatin (95% CI -27.2% to 25.0%). The incidence of adverse effects was similar between groups.²

Additional phase 3 trials have been completed in adults with cUTI and cIAI. Ceftazidime/avibactam is also being studied in a phase 3 trial of ventilator and nosocomial pneumonia.¹⁰

Table 1: Comparison Between Ceftolozane/Tazobactam and Ceftazidime/Avibactam

Generic Name

Ceftolozane/Tazobactam

Ceftazidime/Avibactam

Brand Name

Zerbaxa

Avycaz

FDA Indications

cIAI (with metronidazole), cUTI (including pyelonephritis)

cIAI (with metronidazole), cUTI (including pyelonephritis)

Usual Dose

1.5 g IV q8h

2.5 g IV q8h

Infusion Time

1 hour

2 hours

Ratio of Cephalosporin to Beta-Lactamase Inhibitor

2:1 ceftolozane:tazobactam

4:1 ceftazidime:avibactam

Cost¹

$99.60 per 1.5 g vial

Not yet available

Pregnancy Category

B

B

Renal Dosage Adjustment

Yes, for CrCl < 50 mL/min

Yes, for CrCl < 50 mL.min

Hepatic Dosage Adjustment

No

No

Drug Interactions

No clinically significant CYP450 interactions.

No other enzymatic interactions anticipated.

No clinically significant CYP450 interactions.

Avibactam is a substrate of OAT1 and OAT3.

While not studied, avoid Probenecid.

Adverse Reactions >5% As Seen in Clinical Trials

Diarrhea, headache, nausea, pyrexia

Abdominal pain, anxiety, constipation, dizziness, increased Alk Phos, increased ALT, nausea, vomiting

In vivo² Gram-negative Activity

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumonia

Proteus mirabilis

Pseudomonas aeruginosa

Citrobacter freundii

Citrobacter koseri

Enterobacter aerogenes

Enterobacter cloacae

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumonia

Proteus mirabilis

Pseudomonas aeruginosa

In vivo² Gram-positive Activity

Streptococcus anginosus

Streptococcus constellatus

Streptococcus salivarius

N/A

In vivo² Anaerobic Activity

Bacteroides fragilis

N/A

ESBL Activity

Class A (TEM, SHV, CTX-M)

Class C (AmpC)

Class D (OXA)

Class A (TEM, SHV, CTX-M)

Class C (AmpC)

Class D (OXA)

Carbapenemases (KPC)

_{¹ Cost information from www.UpToDate.com Accessed March 5, 2015² In vivo activity refers to organisms isolated during clinical trials. Medications may have greater in vitro activity beyond what is reported here.cIAI: complicated intra-abdominal infections; cUTI: complicated urinary tract infections; IV: intravenous; Alk Phos: alkaline phosphatase; ALT: alkaline aminotransferase; N/A: not available; ESBL: extended-spectrum beta-lactamase}

No new compounds active against Gram-negative organisms have been approved in several years. Therefore, these 2 antibiotic combinations are welcome additions in the fight against resistant Gram-negatives, with 1 possessing activity against carbapenemases.

The cephalosporin class has a long-standing safety history, and clinicians are familiar with their use. The thrice-daily dosing is a slight drawback. Concomitant antimicrobials must be added if coverage against anaerobes or Gram-positive organisms is desired.

While only the cost for ceftolozane/tazobactam is currently available, at approximately $300 per day for patients with normal renal function, this price point is comparable to newer agents against resistant Gram-positive organisms (tedizolid, linezolid, daptomycin). However, this is a significant price increase over other Gram-negative agents (piperacillin/tazobactam, meropenem, cefepime)—many of which have generic formulations available.

Considering all of this information, it can be assumed that these 2 antibiotics will be reserved for patients with resistant Gram-negative infections, rather than being used as first-line agents.

References:

1. Zerbaxa prescribing information. Cubist Pharmaceuticals, Inc. Lexington, MA 2014.

2. Zerbaxa (ceftolozane/tazobactam) FDA Summary Review. Accessed: March 5, 2015.

3. Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, 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 Feb 10. pii: civ097. [Epub ahead of print]

4. NCT02070757. Safety and efficacy of ceftolozane/tazobactam to treat ventilated nosocomial pneumonia (ASPECT-NP). Accessed March 5, 2015.

5. NCT02266706. Pharmacokinetic and safety study of ceftolozane/tazobactam in pediatric subjects receiving antibiotic therapy for proven or suspected Gram-negative infection or for peri-operative prophylaxis. Accessed: March 5, 2015.

6. Avycaz Prescribing Information. Forest Pharmaceuticals, Inc. Cincinnati, OH 2015.

7. Avycaz (ceftazidime/avibactam) FDA Summary Review. Accessed: March 5, 2015.

8. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infections in hospitalized adults: results of a randomized, double-blind, Phase II trial. J Antimicrob Chemother. 2013;68:1183-92.

9. Vazquez JA, Gonzalez Patzan LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime/avibactam versus imipenem/cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin 2012;28:1921-31.

10. NCT01808092. A study comparing ceftazidime/avibactam versus meropenem in hospitalized adults with nosocomial pneumonia. Accessed: March 5, 2015.