Continuing the Fight Against Gram-Negative Infections: The New Agents—Part 1

Keith A. Rodvold, PharmD

Antimicrobial-resistant (AMR) organisms, particularly Gram-negative bacteria, present a critical threat and a substantial burden. In the United States alone, these organisms account for more than 2 million infections, 23,000 deaths, and $2 billion in excess medical spending per year.¹ In February of this year, the World Health Organization (WHO) updated its list of Priority 1, critical organisms to include carbapenem-resistant and extended-spectrum beta-lactamases (ESBLs), carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Other Gram-negative bacteria, including bacteria that produce Klebsiella pneumoniae carbapenemase (KPC), bacteria with plasmid-mediated resistance to carbapenems, and bacteria with plasmid-mediated resistance to colistin, pose increasing threats. It is not surprising, then, that AMR Gram-negative infections, and antimicrobial agents that target them, received a large amount of attention the 2017 ASM Microbe conference in New Orleans, Louisiana.

How Our Newest Antimicrobial Agents Are Faring

The combination products of a cephalosporin and beta-lactamase inhibitor ceftolozane-tazobactam (Zerbaxa) and ceftazidime-avibactam (Avycaz), which were approved by the FDA approximately 2 years ago, are our newest weapons in the battle against AMR Gram-negative bacteria. Several surveillance studies demonstrating the sustained in vitro activity of these agents were presented at the meeting.

Contagion^® Editorial Advisory Board member, Jason Pogue, PharmD, BCPS-ID, reported that ceftolozane-tazobactam was the most potent of several agents tested against 454 clinical Pseudomonas aeruginosa isolates from hospitalized patients across the United States.² Most of these isolates (77.3%) were multidrug resistant (MDR). Susceptibility rates for ceftolozane-tazobactam were 81.5% overall and 80.1% against MDR isolates, compared with 33.9% and 22.2% for piperacillin-tazobactam, 20.3% and 8.0% for extended-spectrum cephalosporins, and 12.3% and 6.1% for imipenem or meropenem.

Kellie Goodlet, PharmD, BCPS, also reported good in vitro activity based on a surveillance study of 1257 Pseudomonas aeruginosa isolates collected from adult inpatients at US hospitals. The overall susceptibility rate was 97% for ceftolozane-tazobactam, compared with 72% to 76% for cefepime, ceftazidime, piperacillin-tazobactam, and meropenem.³ Among the isolates that were non-susceptible to all 4 beta-lactam comparators, 80% remained susceptible to ceftolozane-tazobactam.

Dee Shortridge, PhD presented US surveillance studies of 2,956 Gram-negative isolates collected from intensive care unit (ICU) patients⁴ and 2,656 Pseudomonas aeruginosa isolates collected from hospitalized patients,⁵ as well as a global surveillance study of more than 51,000 isolates collected from North and Latin America, Europe, and Asia Pacific.⁶ All 3 studies reported good activity overall for ceftolozane-tazobactam against Pseudomonas aeruginosa isolates, with susceptibility rates of approximately 92% to 97% and lowest concentration of antibiotic at which 90% of isolates were inhibited (MIC₉₀) of .5 μg/mL.⁴ Ceftolozane-tazobactam was also potent against MDR isolates (89.2%) and extensively drug-resistant (XDR) isolates (79.8%),⁵ as well as Enterobacteriaceae isolates (90% to 92.4%) and ESBL-producing Enterobacteriaceae strains (77.8% to 86.8%).⁴ MIC₉₀s for ceftolozane-tazobactam were 2 μg/mL for all Enterobacteriaceae and 8 μg/mL for ESBL-producing strains.

Ceftazidime-avibactam also continues to be active against Gram-negative pathogens. Philippe Lagacé-Wiens, MD, reported a ceftazidime-avibactam susceptibility rate of 94.6% and an MIC₉₀ of 8 μg/mL against all Pseudomonas aeruginosa isolates in a study of more than 13,000 Gram-negative bacterial isolates collected from Canadian hospitals.⁷ Ceftazidime-avibactam was also susceptible to 99.9% of Klebsiella pneumoniae isolates overall (MIC₉₀ .5 μg/mL) and ESBL-producing Klebsiella pneumoniae isolates (MIC₉₀ 2 μg/mL), 99.7% of all Enterobacter cloacae isolates (MIC₉₀ 1 μg/mL), and 92.0% of ertapenem-resistant Enterobacter cloacae isolates (MIC₉₀ 8 μg/mL).

Krystyna Kazmierczak, PhD, also reported strong ceftazidime-avibactam activity against 11,810 Enterobacteriaceae isolates collected as part of the INFORM surveillance program. Susceptibility rates in this study were 99.1% overall and 94.2% against MDR isolates. Reduced activity (78.5%) was observed against meropenem non-susceptible isolates (MIC₉₀ >128 μg/mL) due to Class B enzymes and was improved against meropenem non-susceptible, metallo-beta-lactamase (MBL)-negative isolates (99.4%; MIC₉₀ 4 μg/mL) and colistin-resistant isolates (96.4%).⁸

It should be noted, however, that background resistance is changing susceptibility patterns for these agents. Dr. Shortridge’s global surveillance study found ceftolozane-tazobactam susceptibility rates as low as 55.3% for ceftazidime-non-susceptible Pseudomonas aeruginosa isolates and 64.6% for meropenem-non-susceptible isolates.⁶ Erik Skoglund, PharmD, reported ceftolozane-tazobactam susceptibility rates of 75% against Pseudomonas aeruginosa isolates overall, 67% against MDR isolates, and 50% against XDR isolates in a small study of meropenem-non-susceptible isolates collected from bloodstream infections.⁹ These findings are consistent with recently published studies reporting ceftolozane-tazobactam susceptibility rates of 84.9% for MDR and 76.9% for XDR Pseudomonas aeruginosa isolates.¹⁰

Several recent publications have reported the clinical use of ceftolozane-tazobactam for the treatment of infections caused by MDR Pseudomonas aeruginosa.^11,12,13 A small study of 15 patients reported a 67% clinical cure rate for ceftolozane-tazobactam and 27% all-cause mortality rate in patients with XDR Pseudomonas infections.¹¹ A multicenter, retrospective study of 35 patients reported clinical treatment success in 74% and treatment failures in 9 cases of carbapenem-resistant Pseudomonas aeruginosa with MICs of 8 μg/mL or higher.¹² Finally, in a small salvage study of 12 patients, late recurrence occurred in one patient after microbiological eradication, with MDR Pseudomonas aeruginosa infections that was now resistant to ceftolozane-tazobactam.¹³

Likewise, the study presented by Dr. Lagacé-Wiens demonstrated less potency for ceftazidime-avibactam against AMR Pseudomonas aeruginosa (susceptibility rate 66.7% to 75.3%).⁷ Although surveillance studies document a low frequency of ceftazidime-avibactam resistance among Enterobacteriaceae carrying the bla_KPC gene,¹⁴ other studies report the development of bla_KPC-3 mutations conferring resistance in Klebsiella pneumoniae within 10 to 19 days of exposure to ceftazidime-avibactam exposure.¹⁵

Continuing the Fight Against Gram-Negative Infections: Help for Existing Carbapenems—Part 2

DISCLOSURES

Keith A. Rodvold, PharmD has relevant financial relationships with the following commercial interests:

• Advisory Board: Achaogen, Bayer, The Medicines Company, Motif, Nabriva, Paratek, Shionogi, Theravance, Melinta, GlaxoSmithKline, Spero Therapeutics
• Research Support: Allergan, Theravance
• Speakers Bureau: Merck & Co., Inc. and The Medicines Company

Dr. Keith A. Rodvold received his BS and PharmD degrees from the University of Minnesota. He completed his research fellowship in clinical pharmacokinetics and pharmacology at St. Paul-Ramsey Medical Center and the University of Minnesota and was a Clinical Pharmacy Specialist at St. Joseph’s Hospital in Marshfield, Wisconsin. He is also a Professor of Pharmacy in Medicine in the College of Medicine at the University of Illinois at Chicago. Dr. Rodvold is currently conducting research in the area of clinical pharmacokinetics and pharmacodynamics of anti-infective agents. Dr. Rodvold has authored more than 145 original research and review publications, 40 book chapters, and is co-editor of the textbook, Drug Interactions in Infectious Diseases. The American College of Clinical Pharmacy presented Dr. Rodvold with the 2003 Russell R. Miller Award in recognition of his sustained and outstanding contributions to the literature of clinical pharmacy. Dr. Rodvold is a former member of the Anti-Infective Drug Advisory Committee and Pediatric Drug Advisory Subcommittee for the Food and Drug Administration. He is an active member of numerous professional societies and has been elected Fellow of the Infectious Diseases Society of America, American College of Clinical Pharmacology, and American College of Clinical Pharmacy.