By Kristi Rosa
When acquired in patients with cystic fibrosis, clinical outcomes are known to be even worse, affecting several organs—primarily the lungs—and resulting in an increased rate of declined respiratory function as well as infections that can have severe, and sometimes deadly, consequences.
Now, however, for the first time, investigators have found that telavancin—a drug that is currently used to treat skin infections and hospital-acquired pneumonia—has potent in vitro activity and low resistance development potential when used against S aureus isolates in patients with cystic fibrosis, making it a promising potential treatment option for this population.
“Telavancin (TLV) is a lipoglycopeptide antibiotic approved by the US Food and Drug Administration in 2009 for the treatment of complicated skin and skin structure infections and in 2013 for the treatment of cases of nosocomial pneumonia, however its application for the treatment of CF-MRSA pneumonia infections was not known, so our studies are contributing to extending the application of TLV for CF treatment,” Adriana E. Rosato, PhD, associate professor in the department of Pathology and Genomic Medicine at Houston Methodist Research Institute told Contagion®. “We were also inspired by the fact that CF patients have a short life time—until 40 to 50 [years]—so our priority is to contribute to better treatment in this patient population.”
Dr. Rosato and her team hypothesized that TLV might be a promising treatment option for CF-patient-derived MRSA and MSSA infections, as in vitro studies have shown that TLV has activity against MRSA.
To prove this, the investigators screened a total of 333 strains of CF patient-derived S aureus of the wild-type or small-colony-variant phenotype, collected from both adults and children at 3 different cystic fibrosis centers: Houston Methodist Research Institute, UW Health and the Center for Global Infectious Disease Research. TLV was found to display activity against all 333 strains collected.
When testing the activity of the drug against 23 MRSA strains, the investigators observed intermediate resistance to ceftaroline (CPT)—a new beta-lactam antibiotic that targets PBP 2a in MRSA—in 20 of the strains, and high-level resistance to CPT in 3 of the strains. The authors note that although high levels of resistance to CPT is rare, intermediate resistance is more common in patients who have chronic infections.
“Among all strains, the TLV MIC90 was 0.06 mg/liter, i.e. 8-fold lower than the daptomycin (DAP) and CPT MIC90 and 25-fold lower than the linezolid (LZD) and vancomycin (VAN) MIC90,” the authors write.
Using time-kill experiments, the investigators assessed the in vitro effectiveness of TLV compared with DAP, VAN, and CPT. They found that TLV showed activity against all tested strains and displayed rapid bactericidal activity as well. The activity profile for the drug at a free serum concentration of 8 mg/liter showed that TLV performed better than VAN (16 mg/liter), LZD (10.4 mg/liter), and CPT (16 mg/liter).
The investigators also set out to determine the fate of mutation selection that could be projected by the potential prolonged use of TLV in patients with cystic fibrosis. To do this they looked at 3 specific strains: AMT 0114-48, WIS 664, and TMH 5007. They found that due to the ease of mutation selection which had been noted in control strains, TLV mutant resistance is independent of the CF patient background of the strains.
“We demonstrated that TLV has bactericidal activity against the S aureus strains tested, including those against which CPT and LZD displayed reduced activity, which might provide TLV a significant advantage over the drugs currently used to eradicate those strains and prevent future exacerbations,” the study authors write.
A clinical trial is currently underway to assess the pharmacokinetic profile of TLV in patients with cystic fibrosis, who usually need dose adjustment because of an increase in the volume of distribution and clearance.
“[The next step for our research is] to perform in-vivo analyses studies that could lead to translational application/clinical trial,” Dr. Rosato added. “However, we are limited in research funds to continue our investigations.”