Drug-Resistant Superbugs Elude Eradication

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.

CHICAGO – By all measures, methicillin-resistant Staphylococcus aureus cases and related deaths are steadily increasing around the globe, according to Dr. Theodore Rosen.

But MRSA isn’t the only bug that’s ramping up its antibiotic smarts these days.

“We are being bombarded every year by increasingly resistant bacteria,” Dr. Rosen said in an interview. “Some of these are relatively trivial, some are really bad – like MRSA – and some are wreaking havoc. I’m talking about Klebsiella causing horrendous, frequently fatal drug-resistant pneumonia; multidrug resistant forms of the plague (the same plague that wiped out a third of Europe); and drug-resistant tuberculosis, a disease we thought we’d cornered years ago.”

The surge in resistance is a predictable evolutionary response to the widespread use – and overuse – of antibiotics, said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston. Unfortunately, science, industry, and federal administrators are not adapting to the new environment nearly as quickly as their microscopic enemies.

“The number of new antibiotics approved over the past few years has been steadily decreasing, and in the last 2 or 3 years, only one new antibiotic has been approved,” despite promising data, said Dr. Rosen.

Stung by recent problems with already approved drugs, the Food and Drug Administration has become increasingly stringent about the approval of new medications, including antibiotics, he noted.

Pharmaceutical companies also play a role. “You stand to make a lot more money developing a drug for a chronic disease than one only given for 14 days, like an antibiotic,” said Dr. Rosen.

He discussed several antibiotics that showed promise but never found their way to the federal finish line. Two – oritavancin and dalbavancin – are molecularly related to telavancin, which was approved in 2009. “Oritavancin was rejected [by the FDA] because it did not show noninferiority to vancomycin,” he said.

Dalbavancin did well in phase III trials for uncomplicated skin and soft tissue infections. “You can give it once a week, and it’s incredibly potent, doing better by far in vitro than anything else available,” Dr. Rosen said. The drug received an FDA approvable letter, but never went further. According to the FDA “the studies were not well done and questioned some of the methodology, so Pfizer sold the rights to the drug, fearing it would not be the blockbuster they had hoped,” he said. The drug is now in developmental limbo.

Iclaprim, a trimethoprim-related drug, is also languishing. “It’s a good drug, with a 99.9% kill rate in vitro. It works in trimethoprim resistance and can be given orally or intravenously. It looked great in its phase II and III trials,” said Dr. Rosen.

However, the FDA rejected the drug. Iclaprim met its initial requirement of no more than a 12.5% efficacy difference with its comparator, linezolid. However, the FDA upped the ante to no more than a 10% difference, at which time Roche sold the drug to another company, which merged with another and sold iclaprim again. “No one knows this drug’s future,” Dr. Rosen said.

Several linezolid-like drugs have completed phase II trials “and look good,” Dr. Rosen said. “They have greater potency, can be taken orally once daily, and have solved some of the problems associated with linezolid – no hypertension, better gastrointestinal absorption, and less risk of myelosuppression.”

Monoclonal antibodies that bind to the staphylococcal clumping factor are also in the works. “This is a very clever way of treating staph bacteria, by keeping them from grabbing hold of fibrinogen so they can’t get into tissue,” Dr. Rosen said. Early studies have shown that patients who received the antibody plus an antibiotic did better than those who only received the antibiotic, and that the combination was able to clear MRSA carriage.

“Unfortunately, the company developing this ran out of money, so this antibody is sitting on the shelf somewhere until the company finds a new financial partner,” he added.

FDA’s insistence on noninferiority trials for antibiotics hinders approval, Dr. Rosen opined. “It’s difficult to figure out how noninferior the new drug has to be. Several have shown noninferiority – there were failures, but the failure rate was relatively low. The FDA, however, has said the rate must be lower, because otherwise, a certain number of patients would have done better on the comparator drug, even though each drug has its own positive and negative attributes.”

Placebo-controlled studies “are unconscionable” in patients with infection, and the only other method to determine effectiveness is a superiority study, “which is not really feasible with antibiotics, because so many work so well,” Dr. Rosen said.

Both paths to approval have flaws. “The FDA has had conference after conference with infectious disease experts. We have made little progress in negotiation and have no new antibiotics at a time when resistance is rising, and it’s critical that we develop more,” he said.

Time may be running out. Before the advent of penicillin in 1928, infection was the leading cause of death worldwide; in 2000, it was still the fourth-leading cause of death. “If our antibiotics stop working, we will rapidly go back to those pre-World War II days when all we had to treat infections were arsenic and sulfa. Yes, that’s a doomsday scenario, but it’s not inconceivable that we could once again live in a time when infections reign supreme,” he concluded.

Dr. Rosen reported having no relevant financial disclosures.

Prepared Response From the FDA

The development of new antibacterial drugs is an important public health issue and one that the Food and Drug Administration is working with academia and industry to address. FDA plays an important role in providing recommendations to companies on the types of trial designs to use to study a new drug.

Antimicrobial resistance is a problem. We need new therapeutic options to treat resistant bacteria and we will continue to need new therapeutic options in the future to treat patients with infections.

There are scientific, economic, and regulatory challenges that affect the development of new antibacterial drugs. Based on our current understanding of a number of infectious diseases, antibacterial drug effects, and clinical trial design, it is clear that some clinical trial designs used in the past were not an informative means to evaluate drug effectiveness.

The FDA is working to update guidance and meets with companies developing antibacterial drugs in to provide advice on their development programs so that they will be designed to meet the efficacy standards established by law. As part of these efforts, the FDA recognizes the need for approval pathways which are feasible.

The challenges we are facing in antibacterial drug development are largely scientific, and the path forward must be supported by sound science. To that end, the FDA has engaged scientific experts, including members of the Infectious Disease Society of America, in a series of recent public workshops and advisory committee meetings.

Draft guidance documents have been issued for acute bacterial otitis media, acute bacterial exacerbations of chronic bronchitis, acute bacterial sinusitis, community-acquired bacterial pneumonia, noninferiority clinical trial design, and acute bacterial skin and skin structure infections. And a draft guidance document for hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia will be issued in the coming months.

In addition to publishing guidance documents, the FDA meets with companies developing new antibacterial drugs and provides advice throughout drug development. The Agency looks forward to continuing to work with scientific experts to address the challenges of new antibacterial drug development.