Ceftolozane/Tazobactam for Pseudomonas aeruginosa Infections: Going Beyond the Package Insert

Shmuel Shoham, MD; Patricia J. Simner, PhD; Kathryn E. Dzintars, PharmD

Disclosures

February 09, 2016

In This Article

'These Lungs Need Something'

A 26-year-old woman has cystic fibrosis, which is progressing. Without a lung transplant, it is doubtful she will make it to age 30. Her respiratory sample culture results are all too familiar to those who work in modern hospitals: Her airway is colonized with Pseudomonas aeruginosa that is resistant to all antibiotics tested.

Right now, the patient is stable and does not have an active infection. However, she will probably develop a respiratory infection either before or after the transplant that will hopefully save her life, and she is going to need something to clear the Pseudomonas.

Could ceftolozane/tazobactam be that "something"? Will this combination work against the P aeruginosa isolate with which she is colonized? Is the US Food and Drug Administration (FDA)-approved dose adequate for a lung infection? How do we use this drug wisely?

Dealing with such an organism requires a team effort. We present our approach to this case, combining the viewpoints of an infectious diseases specialist, an infectious diseases pharmacist with expertise in antimicrobial stewardship, and a medical microbiologist.

What Is Ceftolozane/Tazobactam?

Ceftolozane/tazobactam (Zerbaxa™) is ceftolozane, a novel broad-spectrum cephalosporin, coformulated in a 2:1 ratio with a known beta-lactamase inhibitor, tazobactam. A 1.5-g dose of ceftolozane/tazobactam is composed of 1 g ceftolozane and 0.5 g of tazobactam. It is FDA-approved for the treatment of complicated urinary tract infections (UTIs) and complicated intra-abdominal infections (in combination with metronidazole). Ceftolozane/tazobactam is active against most gram-negative bacilli, including P aeruginosa and Enterobacteriaceae, but lacks activity against metallo–beta-lactamase and serine carbapenemase producers.

The chemical structure is similar to that of ceftazidime, with the exception of a larger and heavier side chain on the cephem nucleus that confers potent activity against P aeruginosa, including isolates with derepressed AmpC enzyme production.[1] The drug has the ability to evade a variety of bacterial resistance mechanisms, specifically those seen in Pseudomonas species, including efflux pumps, reduced uptake through porin channels, and modifications to penicillin-binding proteins. The addition of tazobactam increases the drug's activity against some beta-lactamase–producing Enterobacteriaceae that would otherwise be resistant to ceftolozane.

Surveillance data from 32 medical centers throughout the United States have shown that 96.1% of nearly 2000 P aeruginosa isolates were inhibited by ceftolozane/tazobactam at a minimum inhibitory concentration (MIC) ≤ 4 µg/mL, demonstrating greater activity than other tested cephalosporins as well as piperacillin/tazobactam and carbapenems.[2] Moreover, this enhanced activity was also maintained against multidrug-resistant (MDR) isolates (MIC50, 2 µg/mL; MIC90, 8 µg/mL) and extremely drug-resistant isolates (MIC50, 4 µg/mL; MIC90, 16 µg/mL).

These data, combined with the known favorable pharmacokinetic, pharmacodynamic, safety, and efficacy profiles of beta-lactam antibiotics, make ceftolozane/tazobactam an attractive treatment option for the management of gram-negative infections, especially when P aeruginosa is suspected.

As with other beta-lactam antibiotics, the key determinant of efficacy is the proportion of time that drug concentrations in plasma exceed the MIC needed to kill the organism (T > MIC). On the basis of a neutropenic animal model of infection, the T > MIC needed to achieve 90% killing is 35% for extended-spectrum beta-lactamase Enterobacteriaceae and 31.5%-39% for P aeruginosa.[3,4] A dosage of 1 g of ceftolozane every 8 hours is expected to attain this target in nearly all patients with normal renal function who have UTI or intra-abdominal infections caused by organisms whose MIC is ≤ 4 µg/mL. The susceptibility interpretative criteria from the FDA and the Clinical and Laboratory Standards Institute (CLSI) for ceftolozane/tazobactam are ≤ 2/4 µg/mL for Enterobacteriaceae and ≤ 4/4 µg/mL for P aeruginosa.[5,6]

The side-effect profile of ceftolozane/tazobactam is similar to that of other beta-lactam antibiotics. The most common adverse reactions noted in the clinical trials leading to FDA approval were gastrointestinal upset and headaches. As with other antibiotics, allergic reactions and alteration of gut flora leading to Clostridium difficile infection are major concerns.

Another concern is the possibility of underdosing patients with changing renal function. It is crucial to closely monitor renal function in such patients so that dose adjustments can be made.

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