Saturday, September 26, 2015

ICAAC Nostalgia

Like many other antibiotic researchers, I was absent from ICAAC this year.  Of course, in my case, I have a good excuse – I’m retired and don’t really go to meetings anymore unless someone is paying my way. But I admit that I miss ICAAC with a nostalgia that is difficult to describe. I feel a great sadness when I think of all those colleagues who are no longer with us. I miss my colleagues and I miss discussing the latest developments in antibiotic discovery and development. I especially miss the posters where I used to wander, read, absorb and discuss and question to my heart’s content. Those interactions with young (and sometimes not so young) investigators were so stimulating.

Looking back on all those years of ICAACs, though, I remember the increasing drought of the most recent meetings.  In the beginning of my years at ICAAC – dating back to the early 1980s – I focused tightly on the science of antibiotic resistance and the epidemiology of resistance.  ICAAC back then was so busy and complicated (it used to be combined with IDSA meetings) that if you didn’t focus, you were confused and lost for a week.  Later, as my career evolved (or devolved) to antibiotic discovery and development, I focused on new molecules in addition to trying to keep abreast of key, relevant developments on the resistance front. My favorite session became the Saturday morning review of new antimicrobial agents.  I would look forward to discovering which posters the organizers had identified as being the most interesting new discoveries being presented at ICAAC.  For many years, I was not disappointed.  There were always at least a few posters that peaked my interest and curiosity and that promised a future of new therapies.

Over the years between say 2005 and 2013 (my last ICAAC), though, the Saturday morning poster review had become depressing rather than invigorating.  The organizers were obviously struggling more and more to come up with interesting new agents to highlight. The lack of new agents in the pipeline was never more apparent than at those ICAAC meetings. By 2013, knowing that I would retire in a few months, I even felt a sense of relief that I would not have to relive the Saturday morning disappointment again. I had become a little lost in the great halls of the meeting.  Even the exhibitions were faltering.  There were so few pharmaceutical companies trying to sell so few new products that even the pens and candies being provided seemed somehow sad and worn. If it weren’t for the occasional poster, I probably would have packed my bags and left on the Saturday before the meeting even really had gotten started.

This year, I looked over the abstracts and presentations.  There were a few promising, potentially exciting new developments on the B-lactamase inhibitor front, but that seemed to be about it for small molecules.  Eravacycline was the subject of a great number of abstracts demonstrating its potent activity against large global collections of resistant pathogens, but these findings were overwhelmed by the news that it failed to achieve its primary endpoint in a clinical trial of complicated urinary tract infection. I was, of course, thrilled with the findings on the clinical trials of the Merck antibody against C. difficile toxin B.

So while I look back on ICAAC meetings of the past with yearning and nostalgia, I’m afraid that 2015 would have been another disappointing year for the antibiotic pipeline.

Tuesday, September 15, 2015

Rapid Diagnostics - Today and Tomorrow by Fred Tenover


The announcement by the US Department of Health and Human Services of a $20 million prize for innovative point-of-care rapid diagnostics has overshadowed the fact that there are already over 100 FDA-cleared molecular diagnostic tests available in the United States. Many of these tests are characterized as “moderately complex”, which means that they can be performed, not just by medical technologists, but by laboratory technicians, STAT laboratory personnel, and even nurses who have received appropriate training and competency testing. A few for influenza testing are CLIA waived. It now is possible to identify 17 viruses and three bacterial species directly in respiratory samples in approximately 1 hour, detect five species of Candida directly from a blood sample without prior culture, or identify Mycobacterium tuberculosis and simultaneously determine if the strain is rifampin-resistant directly from sputum samples in less than 2 hours. Molecular diagnostics are widely used to differentiate methicillin-susceptible from methicillin-resistant Staphylococcus aureus strains directly from blood culture vials in approximately 1 hour.  Molecular assays can also determine if a woman in labor is colonized with Group B streptococci in approximately 45 minutes directly from a vaginal/rectal swab to guide decisions on prophylaxis to prevent neonatal sepsis.  In Europe, a novel assay can detect 91 different carbapenem-resistance genes representing five families of beta-lactamases (KPC, VIM, NDM, OXA-48, and IMP-1) directly from a rectal swab sample in 48 minutes to aid infection control decisions. 
The question of how to justify the increased cost of rapid diagnostic tests compared to traditional culture methods often arises. In response, health econometric studies have been undertaken and show that rapid detection of MRSA from blood cultures, Clostridium difficile from stool samples, and M. tuberculosis from sputum samples are all highly cost-effective even in low prevalence settings.  Perhaps one of the greatest examples of how rapid diagnostics can be cost effective and have a positive impact on antimicrobial usage is from a sexual transmitted infection clinic in London that welcomes both male and female patients but is heavily frequented by men who have sex with men. The clinic offers molecular testing for Chlamydia trachomatis and Neisseria gonorrhoeae using a PCR-based method that detects the organism in urine, throat, and rectal samples from men; and urine, throat, rectal, and vaginal swabs from women.  All the specimens are self-collected and processed on site, with results often available within 2 hours from time of collection.  Instructions for collecting specimens are provided via short videos in specimen collection rooms.  Patients enter their health information via iPads, are instructed on which types of specimens to collect, are screened for HIV, and receive a text message on their phone when their results are ready. Testing volumes over the last 2 years have soared from 10,000 specimens per annum to over 100,000, and it is estimated that they have reduced unnecessary prescriptions for antibiotics by almost 100,000 doses, while effective therapy has likely reduced transmission in this community.
Rapid molecular tests are also being used in several clinical trials of novel antimicrobial agents to aid enrollment of subjects by rapidly identifying patients with MRSA/MSSA infections, C. difficile infections, or in the near future, patients infected with carbapenem-resistant Enterobacteriaceae through testing of respiratory and urine samples.  In each case, the test results are available in approximately one hour and the goal is to identify and enroll a patient in a trial before they receive the second dose of a non-protocol antimicrobial agent.
One challenge that remains in many medical centers is to insure that results generated rapidly are communicated and acted upon with equal speed by physicians.  This has been a larger problem than one would imagine.  If a result is entered into the patient’s medical record after the physician has seen the patient that day, he or she may not look for the result until later in the day or maybe not until the following day before rounding.  To optimize the use of rapid blood culture results, many hospitals rely on their antibiotic stewardship program, infectious disease-trained pharmacists, or infectious disease fellows to make sure that the result obtained influences therapy quickly, This may mean changing vancomycin to a semisynthetic penicillin for staphylococcal infections shown to be MSSA, or discontinuing antibiotics for viral respiratory infections.
Given the breadth of molecular testing options available, why is uptake of the new technologies rather slow? Many laboratories issue newsletters letting physicians know that new rapid technologies are being brought on line, but more than a few physicians are reluctant to trust the new results, preferring instead to wait for traditional test results.  Ironically, the “gold standard” susceptibility testing methods being replaced, besides being 24-48 hours slower, are often less sensitive due to outdated breakpoints.  As the Infectious Diseases Society of America indicated in its paper “Better tests, better care”, there is a considerable educational process that is still required to bring physicians on board with the new reality of rapid results.  The positive impact on patient management and improved outcomes of molecular results are just beginning to be realized. 

 Fred C. Tenover, Ph.D. D(ABMM)
Vice President, Cepheid
904 Caribbean Drive
Sunnyvale, CA 94040

Thursday, September 10, 2015

Tetraphase Update

I am saddened to report that Tetraphase failed to achieve their primary endpoint in their pivotal phase III study of eravacycline in the treatment of complicated urinary tract infection (the IGNITE 2 trial).  This is  a very puzzling result to me. Their trial in intraabdominal infection succeeded even with highly resistant pathogens. (Coming clean - I helped design their trials).

I know that Tetraphase did a great deal to assure themselves and everyone else that the UTI trial would succeed and that eravacycline would be an effective new antibiotic for UTI caused by resistant strains of Gram negative pathogens. They studied levels of eravacycline excreted in urine and antibacterial titers in urine of normal volunteers treated with various doses. They carried out a preliminary analysis of the first 143 patients of their phase III trial in order to choose an oral dose of eravacycline (200 vs 250 mg) with which to continue the study.  In the lead-in portion, all eravacycline groups appeared to be superior to levofloxacin. Based on these data and safety data, a 200 mg oral dosage was chosen. I was very excited about eravacycline since it was the only orally available antibiotic in late stage trials with activity against resistant Gram negatives. 

The primary endpoint of the study was clinical and microbiological cure at the test of cure – about one week following end of therapy. The non-inferiority margin was set at 10%.  908 patients were enrolled in the trial. Apparently, this was not achieved.  In their press release and in the investors’ call, Tetraphase did not provide further details such as how wide the margin was. Other details such as an analysis by pathogen was also not available.

Even though eravacycline did not achieve its primary endpoint, it was superior to levofloxacin among those patients whose infecting organisms had elevated MICs of levo. This suggests to me that eravacycline does, indeed, have a reasonable antibacterial effect in the urine.

The announcement of these results prompted me to recall the days when Tetraphase was trying to find partners for their program before they went to the public markets. I was an enthusiastic supporter of this effort and I participated in a number of these meetings. I was surprised and disappointed at the time when none of the companies to whom they were speaking were willing to invest in Tetraphase and eravacycline.  It is true that there were some problems in the preclinical data set for eravacycline, but none were anything more than I had seen previously for successful products. I considered that the overall data package as a strong one.  Apparently the regulatory authorities agreed with me as Tetraphase progressed through phase II and phase III studies. At the time, and now in retrospect, I thought that this was another indication that the naysayers never take risk.  It is only those rare product champions that take the risk. 

In the case of Tetraphase, it still remains to be seen whether the naysayers will win the day or not.