New Drugs and Ancient Enemies: Bacteria have Time on Their Side

April 20th, 2015

A much-needed new antibiotic to fight the scourge of drug-resistant gram negative pathogens that have arisen in recent years has been approved by the Food and Drug Administration. Drinks on the house. Tomorrow in the sober light of day we can ask the question that has accompanied every new antibiotic debut for the last few decades: How long before drug resistance appears?

First the good news, which starts with the Food and Drug Administration’s readiness to fast-track new antibiotics that demonstrate safety and efficacy. That was the case with the recent approval of Ceftazidime-avibactam (marketed as AVYCAZ™ by Actavis plc in Dublin, Ireland), which has been approved to treat adult patients with complicated intra-abdominal infections and complicated urinary tract infections. The new antibiotic combines ceftazidime, a cephalosporin with in vitro activity against certain gram-negative and gram-positive bacteria, and avibactam, a non-beta-lactam beta-lactamase inhibitor that inactivates certain key beta-lactamases and protects ceftazidime from degradation. The addition of avibactam to ceftazidime protects ceftazidime from breakdown by Extended Spectrum Beta-Lactamases (ESBL), Klebsiella pneumoniae carbapenemase (KPC) and AmpC producing pathogens, Actavis reports.

“The FDA is really starting to fast track some of these antimicrobial agents,” says Trevor Van Schooneveld, MD, a member of the Society for Healthcare Epidemiology of America (SHEA) and medical director of the antimicrobial stewardship program at the University of Nebraska Medical Center in Lincoln. “This new drug was approved on Phase II data only – not Phase III. There is a real push in the FDA to really drive these drugs and get them to market sooner. The advantage of the ceftazidime-avibactam is that it is going to be active against some of our very resistant gram negatives like the ESBL producers and even some of the carpenamase producers. Because the new beta-lactamase that it has actually inhibits those enzymes.”

The modern antibiotic era began a mere 75 years ago with the use of penicillin in WWII, ending a long reign of pestilence and cheating death of millions of patient lives. But the bugs never sleep, and the arrival of bacteria resistant to this new antibiotic is inevitable. How is this possible and so predictable? The confounding truth is that antibiotic resistance already exists for this drug and -- remarkably – drugs that have not yet been invented. We know that antibiotic use and misuse by humans creates selective pressure and drives drug resistance. The less discussed corollary to that fact is that the resistance genetic traits and enzymes to defeat antibiotics have been in bacteria for millennia.

To test this hypothesis researchers descended into the depths of Lechuguilla Cave in Carlsbad, NM, one the deepest and most remote cave systems in the world. Access is restricted to those with a permit and there are areas in the cave depths were few if any humans have ever trod. That was the idea. Researchers wanted to culture bacteria that could not have possibly been exposed to man-made antibiotics.

In this “remarkable ecosystem that has been isolated for millions of years, well before the clinical and agricultural use of antibiotics [we found the] presence of multidrug resistant organisms,” the authors note. Resistance spanned most of the major drug families in both gram positive and gram negative strains, they found. On average, 70% of the gram-positive strains were resistant to three to four different antibiotic classes. Three strains were resistant to 14 antibiotics. Gram negative bacteria are highly efficient at developing resistance, so only antibiotics currently known to have activity against gram negatives were used on the cave strains. Approximately 65% of the gram-negative strains showed resistance to three to four antibiotic classes.

The researchers speculated that these colonies of bacteria evolved such defenses due to the competition for resources in a stark environment with no water and light. In any case, the findings suggest that antibiotic resistance mechanisms are hard-wired into bacteria, so drugs killing off susceptible strains clear the path for the resistant ones to appear. Add their known ability to transfer resistance traits between species on genetic plasmids, and it’s only a matter of time before they crack the code and defeat the drug.