SAN DIEGO – Antimicrobial resistance continues to be a significant problem, but a few new agents have shown promise against certain pathogens.
Dr. April D. Miller
"As clinicians, we need to look forward to new drug discovery and development, and keep an eye on the current pipeline," April D. Miller, Pharm. D., said at the annual congress of the Society of Critical Care Medicine. "We also need to think of and study new and unique strategies to preserve the agents that we currently have available."
The problem of antimicrobial resistance "lies in the bugs themselves," said Dr. Miller of the South Carolina College of Pharmacy at the University of South Carolina, Columbia. Among gram-positive organisms, she said, there are rising rates of community- and hospital-acquired methicillin-resistant Staphylococcus aureus and rising minimum inhibitory concentrations to vancomycin. There are also increasing rates of vancomycin-resistant Enterococci, and reports about the possibility of linezolid-resistant Enterococci. In addition, she said, "increases in the rate of Streptococcus pneumoniae resistance can impact ICU clinicians as patients come in from the community with resistant organisms because of inadequately treated infections."
Among gram-negative organisms, increases in Acinetobacter baumannii, Enterobacteriaceae-producing carbapenemases, and Escherichia coli–producing extended-spectrum beta-lactamases have been reported. "Along with the bugs themselves, we also have new mechanisms of resistance," she continued. "The bugs are getting smarter. These include emergence of aminoglycoside 16S ribosomal RNA methylation and New Delhi metallo-beta-lactamase."
In the perfect world, Dr. Miller said, "we could match up all of these bugs with new agents. It doesn’t work that way, unfortunately. We’re all aware of the issue of the lack of available agents on the market or in the pipeline to be developed."
This prompted the Infectious Diseases Society of America to launch an initiative in 2010 calling for the development of 10 new antibiotics by the year 2020. One of those new agents is telavancin, a lipoglycopeptide from Theravance that was approved in September 2009 for complicated skin and skin-structure infections and is currently marketed under the brand name Vibativ. Two other lipoglycopeptides, dalbavancin and oritavancin, are not currently available and continue to be studied.
Newer lipoglycopeptides influence cell membrane potential in addition to inhibiting cell wall synthesis by preventing polymerization and cross-linking of the cell wall, Dr. Miller said. They also feature increased protein binding. "While there are not a lot of data on what this means clinically, they do have the ability to affect their penetration into various body sites," she explained. "These new mechanisms and new binding sites afford us additional and expanded spectrums of activity."
Lipoglycopeptides also have unique pharmacokinetics compared with currently available agents. For example, the half-life of vancomycin is 6-12 hours, while that of telavancin is 7.5 hours. Both oritavancin and dalbavancin have a half-life of about 195 hours. "In clinical studies, the manufacturers are exploring once-weekly or twice-weekly dosing [of oritavancin and dalbavancin], which would be of tremendous benefit for outpatients," Dr. Miller commented. "But for ICU patients we think about the possibility of adverse reactions or dosing issues as renal function changes. That could be a real problem because of the prolonged elimination."
The phase III trial of telavancin for complicated skin and skin-structure infections found that a dose of 10 mg/kg IV daily was as effective as vancomycin 1 g IV every 12 hours (Clin. Infect. Dis. 2008;46:1683-93).
Two phase II trials of telavancin for hospital-acquired pneumonia found that a dose of 10 mg/kg IV daily was not inferior to vancomycin 1,000 mg daily. The unpublished studies involved 1,503 patients and "were good enough for FDA approval, but leave us with some lingering questions about how telavancin compares to vancomycin for hospital-acquired pneumonia," Dr. Miller said.
Among all three telavancin studies combined, a higher proportion of patients in the telavancin group experienced a 1.5-fold increase of serum creatinine from baseline, compared with their counterparts in the vancomycin group (15% vs. 7%, respectively). The proportion of adverse renal events was also higher in the telavancin group (3.1% vs. 1.1%).
Dr. Miller next discussed ceftaroline, a fourth-generation cephalosporin approved in October 2010 for acute skin and skin-structure infections as well as for community-acquired bacterial pneumonia. The drug is expected to be on the market soon under the brand name Teflaro (Forest Laboratories).
"Its spectrum of activity is quite different from that of the other cephalosporins, such that it retains activity against methicillin-susceptible Staphylococcus aureus isolates as well as isolates that are resistant to vancomycin," Dr. Miller said. "It has very good activity against Streptococcus pneumoniae, and like other cephalosporins it has minimal activity against Enterococci. It retains activity against Moraxella catarrhalis and Haemophilus influenzae, which we think about as common pathogens in community-acquired pneumonia. It has some activity against Klebsiella species, but unfortunately it doesn’t have any activity against extended-spectrum beta-lactamase producers or Pseudomonas species. So when we think about empiric coverage, there are definitely some holes with ceftaroline."