Algeferin Conquers Antibiotic Resistant Bacteria: Too Good to be True?

An intriguing report from Science News touts the discovery of algeferin, a chemical from sponges. Algerferin said to be able to reprogram antibiotic resistant bacteria to make them susceptible to antibiotics again. Preliminary tests against "superbugs" (such as MRSA) and biofilms are said to be very promising.

The potential for treating biofilms, clusters of bacteria that cause serious nosocomial (hospital acquired) infections by adhering to foreign devices, such as IV catheters, is quite intriguing, as such infections are particularly difficult to treat. Especially notable was the statement that biofilms "dissolved when treated with fragments of the algeferin molecule. And new biofilms did not form."

Thus far, algeferin has been tested against a variety of resistant organisms, including MRSA and Pseudomonas. That the chemical can restore bacterial susceptibility to antibiotics would be terrific, if it holds up. We are running out of effective antibiotics, which are often irresponsibly squandered (from bacterial resistance partly due to inappropriate use of these drugs for viral illness and in “animal growth” feed, for example). Resistant bacteria are also spread throughout hospitals and nursing homes by ineffective or sometimes irrational infection control policies, as well as by carelessness and increasingly harried staff.

The promise of algeferin is quite exciting...but based on the history of antibiotic development, misuse, and resistance, I have little doubt the bacteria will outsmart algeferin--or its prescribers-- too.

New NIAID Grants for Studying CA-MRSA

Recognizing the urgent need to develop antibiotics to address the explosion in community acquired MRSA (CA-MRSA) skin and soft tissue infections, NIAID announced two new grants to study the efficacy of older, off-patent agents in treating these infections. If inexpensive drugs such as Trimethoprim-Sulfamethoxazole or tetracyclines can be used, perhaps it will slow the use of expensive new drugs such as linezolid.

These older antibiotics are often used now by Infectious Diseases specialists, in an attempt to reserve new agents until absolutely necessary. Unfortunately, this trend goes against human nature. Many primary care physicians as well as some other specialists are anxious to use the new-fangled drugs. Some seem to need to boast that they are up to date by their use of the newest agents and scoff that use of inexpensive, older agents is behind the times.

The two new trials will be led by University of California, Los Angeles and the University of California, San Francisco. Each of the trials is designed to enroll up to 1,200 people. The associated contracts will total up to $19 million over five years.

While I am delighted to see the additional funding for this rapidly growing problem, the results of these studies will likely not be available for several years. In the interim, the excessive use of the new agents will continue, leading to further resistance. I sometimes wonder whether an urgent intervention, such as restricting the use of certain new drugs to specialists in the field, wouldn't be more rational, especially since there are almost no new antibiotics in the pipeline. I know this is heresy, but too much is at stake to squander our few resources in this battle. Perhaps we should be "unAmerican" and not allow business interests and free enterprise to win this battle but lose the global war.

Court Limits Access to Experimental Drugs for Terminally Ill

In a rather bizarre twist, a federal court has just ruled that there is no constitutional right to experimental drugs for those who are terminally ill and have no other options. "Terminally ill patients desperately need curative treatments," Judge Thomas B. Griffith wrote for the majority. But "their deaths can certainly be hastened by the use of a potentially toxic drug with no proven therapeutic benefit." [...] While I understand the conclusion that was reached, the rationale, if one can even call it that, is paternalistic, at best, and downright irrational on its face.

On the one hand, I can understand the demand for access to a novel compound when there is otherwise no hope. On the other, remember the House of God adage, “They can always hurt you more?” While drugs might prolong a person’s life, they might also make it far more miserable than it would have otherwise been. I have seen that far too many times.

There are also problems from the pharmaceutical’s perspective in allowing such expanded access, beyond the obvious liability issues. For example, it may drain very limited supplies of the investigational drug. Also, particularly for very small biotech companies, staffing is often quite limited. There are heavy regulatory submission requirements when an investigational agent is used outside of a protocol; the limited staff might not be able to meet these requirements as well as their other obligations to the drug development or ongoing clinical trials.

What happened to the concept of an individual’s autonomy? For example, I support Oregon’s right to die, or Death with Dignity Act. If there were unlimited supplies of these drugs, I would leave it to the individual, after presentation of an “informed consent,” to reach his or her decision regarding the desirability of taking an investigational medication. But there aren’t unlimited resources. Thus, ideally, perhaps this decision should be left to the patients and the individual sponsors to negotiate based on the availability of different resources.

What do you think?

For other reading, try:

The Right to a Trial by Jerome Groopman, one of my favorite authors! [New Yorker]

Court Rules Out Terminally Ill for Tests [Associated Press]

Should Dying Patients Have A Right To Use Experimental Drugs? [Justice Talking]

Death in Gene Therapy Trial

"Death Points to Risks in Research" touts the Washington Post story.

I would like to comment on Rick Weiss’ article, from the perspective of a clinical researcher. The death of Mrs. Mohr, subsequent to her participation in the Targeted Genetics gene therapy trial, is a tragedy, and worse, was perhaps an avoidable tragedy. There does appear to be a need to re-evaluate the safety mechanisms that are employed to protect patients who are candidates for trial participation, and to re-examine the propriety of the exclusion of public participation in the trial review and approval process that was initiated in 2000.

From the description, it appears that there were serious lapses in Mrs. Mohr’s care. However, there are also several errors in this report which do a disservice to the public, who need to be educated about trials and how to assess whether to participate, rather than be needlessly scared away by inaccurate reports.

For example, a “serious adverse event” requires prompt reporting to the FDA, whether or not it is felt to be related to the drug. The definition of a serious adverse event is one that causes death or is life-threatening, is permanently disabling, results in a congenital anomaly/birth defect, or one that results in new or prolonged hospitalization. Most sponsors require reporting from the investigator within 24 hours. The FDA should have been notified within days after Mrs. Mohr’s admission to the hospital (CFR 312.32).

There are two significant factual errors in the claim that “Two fundamental rules of clinical research were violated that day.” First, there is no FDA requirement that a patient take a consent form home and review it. That is also an impossibility on many trials dealing with acutely ill patients, for example. Nor is there any requirement that the investigator not present the consent form to the volunteer. In fact, some times there is no one else capable of explaining the trial in detail and answering the volunteers questions. To avoid this type of question regarding the adequacy of consent, I try to have family members present when I review the consent, so I can address their concerns as well, and also try to include an impartial witness.

It sounds as though the consent form for this trial was inappropriately technical. Consents are generally pitched at an 8^th grade level. Obviously, this is harder to do with a sophisticated gene therapy trial, but should be the goal.

It is disturbing and unusual to have an early phase trial include patients who are on multiple medications likely to cause serious side effects. The decision to allow this is now shielded from public review; there must be transparency, public review and accountability of the approval process.

I hope that there will be a thorough, thoughtful and very public review of this and other gene therapy trials, in particular.

However, articles in the popular press, such as the one in the Washington Post, often seem to dwell on the costs of clinical trials, and to ignore the benefits those trials have brought. Before the development of antibiotics, for example, an infection was often a death sentence, most cancers were considered incurable, and there was no way to control the disastrous effects of diabetes, heart arrhythmias, and many other common illnesses. While clinical trials are not perfect, and do sometimes injure those they are supposed to help, we have come a long way in the past 50 years, in terms of our abilities to develop useful interventions while providing reasonable protection to study participants. Every medicine goes through this sort of trial process. We need new medicines for serious diseases, such as infections, urgently.

Protections need to be in place, but they should not incapacitate research nor scare volunteers unnecessarily. Since many of the issues here revolve around potential conflicts of interest, the first step would be greater transparency, public discussion, and debate.

Bacteria Talk. . .to Dr. Bonnie Bassler

I had the pleasure of watching the Nova segment last night about
Dr. Bonnie Bassler's work on communication between bacteria.
While I was somewhat familiar with this work, known as quorum
sensing, I was unaware of how it might be used to combat
infections by disrupting the communication between the bacteria.
The program also showed a fascinating glimpse of a brilliant
woman scientist. It was inspiring to hear of her background and
evolution. Being all too attuned to the particular difficulties women
have in the sciences, I was especially impressed by her achievements.
I would encourage anyone interested in biology or medicine to watch this clip
on bacterial communication, which is available on-line. I hope
that young women, especially, will learn of Dr. Bassler's story
and important research.