Ceftolozane/Tazobactam: A New Option in the Treatment of Complicated Gram-Negative Infections

TLDR: Ceftolozane/tazobactam: a new option in the treatment of complicated gram-negative infections and its potential to improve the quality of life for patients with recurrent infections.

Abstract: One of the major causes of antimicrobial resistance is the overutilization of antimicrobial therapy. Annually, two million people in the United States present with infections resistant to at least one antimicrobial agent of choice typically used to treat that type of infection.1 In treating antimicrobial-resistant infections compared with non–antimicrobial-resistant infections, it is expected that the hospital stay will be extended by 6.4 to 12.7 days,2 mortality will increase twofold,3 and costs will rise by at least $18,588 per occurrence (results reported from a Chicago hospital in 2008).2 This equates to approximately $20 billion per year in direct health care costs alone.3 Gram-negative organisms commonly harboring antimicrobial resistance include the ESKAPE pathogens (Table 1).4 These organisms are responsible for numerous infections, including bacterial meningitis, central venous catheter infections, pneumonia, urinary tract infections (UTIs), and complicated intra-abdominal infections (cIAIs).4,5 The associated mechanisms leading to resistance (Table 1) include production of extended-spectrum β-lactamases (ESBLs) and Klebsiella pneumoniae carbapenamases, decreases in influx porin activity/expression, increases in efflux pumps, and altered penicillin binding proteins (PBPs).6 To combat some of these mechanisms of resistance, Cubist Pharmaceuticals developed a novel investigational antimicrobial agent—an antipseudomonal cephalosporin with a β-lactamase inhibitor, ceftolozane/tazobactam (CXA-201). Due to the increasing number of gram-negative–resistant infections, this entity targets resistant PBP- and ESBL-producing organisms.7,8 One phase 2 and four phase 3 clinical trials of ceftolozane/tazobactam have been completed.9,10 Table 1 “ESKAPE” Pathogens4 CLINICAL MICROBIOLOGY Tests of the spectrum of activity against gram-positive aerobic bacteria found that ceftolozane by itself showed activity against Streptococcus species; however, this activity was limited. The addition of tazobactam to ceftolozane led to slight improvements against these gram-positive bacteria. Studies of the ceftolozane/tazobactam combination against gram-positive anaerobic bacteria, specifically Clostridium species, also demonstrated limited activity. On the other hand, ceftolozane’s spectrum of activity against gram-negative aerobic bacteria remained consistent or improved upon the addition of the β-lactamase inhibitor. The spectrum of activity against ceftazidime-resistant and ESBL-harboring Enterobacteriaceae was also significantly improved. In fact, with the addition of tazobactam, lower minimal inhibitory concentrations (MICs) were required to inhibit 90% of isolates (MIC90) in most gram-negative anaerobes. The greatest reductions were observed in Bacteroides and Prevotella species. When tested against ceftazidime-resistant Enterobacteriaceae, ceftolozane/tazobactam was shown to have a twofold more potent effect compared with cefepime and an eightfold more potent effect compared with piperacillin-tazobactam. Moreover, carbapenems such as imipenem/cilastatin and meropenem remained the most active, with 80.4% and 91.6% susceptibility, respectively.8 Ceftolozane/tazobactam also demonstrated superior in vitro activity against ceftazidime-resistant Escherichia coli and K. pneumoniae when compared with ceftriaxone, cefepime, and piperacillin/tazobactam. While the carbapenems retained good activity against this bacterium, the KPC-producing strains of K. pneumoniae remained highly resistant to β-lactam antimicrobials.11 Ceftolozane/tazobactam was shown to be more active than piperacillin/tazobactam, ceftriaxone, and ceftazidime when tested against ceftazidime-resistant strains of Enterobacter and Citrobacter species; however, less activity was noted when compared with cefepime and carbapenems. Activity against ESBL-producing Proteus mirabilis strains was similar to that of piperacillin-tazobactam. The addition of tazobactam did not alter the activity of ceftolozane appreciably in vitro against P. aeruginosa strains; however, an eightfold increase was observed in the activity of ceftolozane over ceftazidime. In P. aeruginosa strains that were susceptible to ceftazidime and imipenem, ceftolozane/tazobactam was superior to piperacillin/tazobactam and imipenem, and comparable to doripenem. In ceftazidime-resistant P. aeruginosa strains, ceftolozane/tazobactam retained its overall activity. For P. aeruginosa strains with documented resistance to both ceftazidime and imipenem, ceftolozane/tazobactam was shown to have the most activity, followed by doripenem. Based on the available data, the combination of ceftolozane/tazobactam appears to be extremely valuable in the treatment of various resistant bacterial infections, which to date remains a clinical practice dilemma.