Mechanisms of Resistance

ZERBAXA Demonstrated In Vitro Activity in the Presence of Certain Mechanisms of Resistance

ZERBAXA demonstrated in vitro activity against Enterobacteriaceae in the presence of some ESBLs and other beta-lactamases and against P. aeruginosa isolates with certain mechanisms of resistance1
  • The clinical significance of in vitro data is unknown
ZERBAXA® (ceftolozane and tazobactam) Demonstrated in Vitro Activity Against Enterobacteriaceae

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  • In clinical trials, some but not all isolates of E. coli and K. pneumoniae producing beta-lactamases were susceptible to ZERBAXA (MIC ≤2 mcg/mL)
  • ZERBAXA is not active against bacteria that produce serine carbapenemases (K. pneumoniae carbapenemase [KPC]) and metallo-beta-lactamases
As shown in separate, surveillance studies
  • CTX-M is the most prevalent ESBL group, representing more than 80% of US-based E. coli ESBLs2,c
  • The 3 most prevalent P. aeruginosa mechanisms of resistance are chromosomal AmpC, loss of outer membrane porin, and upregulation of efflux pumps1,d

cThis study documented the in vitro activity of several recommended antimicrobials against 3449 Gram-negative bacilli isolated in 30 and 25 participating sites in North America in 2010–2011, respectively, and characterized the ESBL identified in ESBL-positive and ertapenem-non-susceptible isolates of Enterobacteriaceae. E. coli, K. pneumoniae, Enterobacter cloacae, P. mirabilis, K. oxytoca, Citrobacter freundii, Enterobacter aerogenes, Serratia marcescens, and Morganella morganii were the most common species isolated. 2

dA total of 998 P. aeruginosa clinical isolates were collected during 2012 in 27 US hospitals and tested against ceftolozane and tazobactam and comparator antimicrobial agents as part of a surveillance initiative. The surveillance study included one isolate per patient per episode that was deemed by the participant investigator to be the cause of infection.1

ESBL=extended-spectrum beta-lactamase; MIC=minimum inhibitory concentration.

Important Safety Information for ZERBAXA® (ceftolozane and tazobactam)
  • Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min. In a clinical trial, patients with cIAIs with CrCl >50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA plus metronidazole vs 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to ≤50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
  • Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
  • Clostridium difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
  • Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
  • Adverse reactions: The most common adverse reactions occurring in ≥5% of patients were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.
Before prescribing ZERBAXA, please read the accompanying Prescribing Information.

References: 1.Castanheira M, Mills JC, Farrell DJ, et al. Mutation-driven ß-lactam resistance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomonas aeruginosa isolates from U.S. hospitals. Antimicrob Agents Chemother. 2014;58(11):6844-6850. 2. Hoban DJ, Badal R, Bouchillon S, et al. In vitro susceptibility and distribution of beta-lactamases in Enterobacteriaceae causing intra-abdominal infections in North America 2010-2011. Diag Microbiol Infect Dis. 2014;79(3):367-372.

RESP-1076949-0006 04/15

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Indications and Usage

ZERBAXA® (ceftolozane and tazobactam) is indicated in adult patients for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

ZERBAXA used in combination with metronidazole is indicated in adult patients for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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Important Safety Information for ZERBAXA® (ceftolozane and tazobactam)
  • Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline creatinine clearance (CrCl) of 30 to ≤50 mL/min. In a clinical trial, patients with cIAIs with CrCl >50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA plus metronidazole vs 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to ≤50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
  • Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to ceftolozane/tazobactam, piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
  • Clostridium difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
  • Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
  • Adverse reactions: The most common adverse reactions occurring in ≥5% of patients were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.
Before prescribing ZERBAXA, please read the accompanying Prescribing Information.