By Robert J Gianotti, MD
Welcome to the first autumn installment of Primecuts. Here in upstate New York the leaves are already beginning to change as I drink a tasty mug of Oktoberfest. My day of football overindulgence is interrupted only by thoughts of Listeriosis and that tasty cantaloupe sitting uneaten on the counter. My heart goes out to the unfortunate farmers in Colorado as they suffer the aftermath of a rare but serious outbreak of Listeria infection in the heartland. I’m reminded that even in the age of food mass production and FDA regulation we continue to find ourselves at the mercy of the microscopic. This week’s literature was “ripe” for the picking, as I present to you…an ode to the microbe.
I will start on a positive note, as yet another win in the war against chronic hepatitis C infection was published in the September 15th edition of NEJM[1]. The ILLUMINATE Study Team has presented the results of a non-inferiority trial examining the virological response to two different treatment durations with peginterferon-ribavarin + telaprevir, an orally bioavailable inhibitor of the nonstructural 3/4A HCV protease. The side effects of this regimen are known to increase in frequency and severity with longer durations of treatment. Here it is clearly shown that 24 weeks of treatment is equally effective as 48 weeks of treatment when the first 12 weeks include telaprevir. It was shown previously in trials of telaprevir with peginterferon and ribavirin that a subset of patients have both rapid (undetectable HCV viral load at 4 weeks) as well as an extended rapid (undetectable HCV viral load at 12 weeks) virologic response. This data was used to design the current study where rapid responders were randomized after 12 weeks of telaprevir to continue either 24 or 48 weeks of combined peginterferon-ribavirin. The rates of sustained virologic response – defined as undetectable HCV virus at 24 weeks after completion of therapy- were equivalent in both groups (92% vs 88%). This 4% difference (95% CI, -2 to 11) excluded the non-inferiority margin of -10.5%, thus demonstrating that the shorter treatment duration in rapid responders was just as effective as the standard 48 weeks. The meaning of these results are exemplified by the discontinuation rates due to adverse events in the 24 week vs. the 48 weeks group (1% vs. 26%, p<.0001). Additionally, high rates of rapid virologic response were seen in groups with previously poor response such as those with high viral load, genotype 1a, and those with cirrhosis. The benefits of telaprevir continue to be supported in the literature and the results of this study bring good news to all those patients who may have previously been unable to tolerate extended treatment. Now, we will move to some more news from NEJM in the battle against another stubborn worldwide foe, malaria.
A safe and effective malaria vaccine would be sure to prevent thousands, if not millions of cases of deaths and disability on its way to winning a few awards. Theraet al2] in this week’s NEJM show some promising results of a blood stage vaccine against Falciparum malaria. The recombinant vaccine included apical membrane antigen 1 protein that has been previously shown to activate an immunological response and have a good safety profile. The study was a randomized, double blind trial of 400 children in Mali who received either the control rabies vaccination or the experimental AMA1 vaccine. The primary end point of clinical malaria was not found to be significantly different between groups (efficacy 17.4%, HR 0.83 with 95% CI 0.63-1.09). This finding was in spite of proven efficacy against specific P. falciparum strains with AMA1 homology with a specific efficacy of 64.3% (HR 0.36; 95% CI, 0.08 to 0.86; P=0.03). This specific effect is a step in the right direction toward creation of a vaccine with several stage and strain specific antigens that may produce a safe and robust prevention of clinical malaria. In thinking about intraerythrocytic parasites my mind wanders back across the Atlantic from Africa to Long Island, a breeding ground for tick borne illnesses.
The Annals of Internal Medicine has published an early online case series of 159 patients with transfusion related Babesia infection[3]. No longer a disease of domesticated farm animals, this tick born protozoan that mimics malaria infection does not currently have an FDA approved test in blood products. A history of Babesiosis is an exclusion criteria for donation, but many potential donors who otherwise appear healthy may be unknowing carriers with a low level parasitemia. The data suggests that the transfusion mode of Babesia transmission is more common in the endemic areas of the Northeastern United States and more common in summer months coinciding with the peak of tick borne infection. Index patients were found to have a 20% all-cause mortality rate and the percentage that was directly related to Babesia infection is unknown. As with many infectious diseases, elderly patients are at higher risk for more severe hemolytic disease. This article highlights the need for practitioners to constantly be aware of the changing tide of novel microbes that potentially can avoid detection even after rigorous screening of blood products. It wasn’t that long ago that hepatitis C virus was unknown and then known only as non-A non-B hepatitis with little insight into the future implications in liver disease. I for one will think twice before foraging in the long grass for golf balls prior to donating blood.
My ode now moves northward to Alaska where researchers fromMcMaster University have unveiled some interesting data regarding antibiotic resistance [4]. Investigating the origins of resistance they have revealed the presence of multiple antibiotic resistance genes found in DNA samples obtained from 30,000 year old permafrost sediments. Travelling to the Yukon Territory, the group has elegantly shown resistance genes with sequences derived from Actinobacteria 16S rRNA sequences. Analyzing permafrost DNA they located B-lactamase sequences, tetracycline resistance elements, and VanXvancomycin resistance elements. They were able to isolate the vancomycin resistance genes vanHAX and synthesize the protein product, a ligase specific for D-alanine-D-lactate that was homologous to the modern day vancomycin resistance element. As antibiotic resistance grows and we are challenged with the discovery of new compounds we will constantly be faced with the challenge of evolution. In light of this paper, it is clear the resistance genes are out there, hibernating in the sands of time, waiting for their chance to be selected. Fortunately, a group from China is one step ahead in their effort to elucidate new drug targets.
In the current edition of Science, Shi et al. demonstrate a novel mechanism for pyrazinamide (PZA), a staple antibiotic used as first line treatment for Mycobacterium tuberculosis.[5] Interestingly, it has been demonstrated in several in vitro models that PZA preferentially targets non-replicating bacterium and is thought to play a pivotal role in the eradication of low metabolism, low replicating organisms. They found that the intracellular derivative of PZA, pyrazinoic acid is active in inhibiting the process of trans-translation by binding to ribosomal protein S1. The authors suggest that this process of trans-translation, which helps to free stalled ribosomes under stress conditions such as hypoxia and low pH, may serve as a useful pathway in novel antibiotic development.
Medical science has made many advancements in the fight against infection, but we are constantly reminded on the wards, in our homes, and on MSNBC of the continued back and forth between the microscopic and the macroscopic world. I think my own grandmother offered the best advice to take into the ongoing battle. She said “Eat to live…don’t live to eat…and always wash your hands.” For now I will stick with just plain old soap and water. I don’t have the energy to engage in a Darwinian struggle by using the antibacterial kind.
Dr. Robert Gianotti is an Associate Editor, Clinical Correlations
References:
- Sherman et al. Response guided telaprevir combination treatment for hepatitis C virus infection. NEJM 2011;365:1014-1024. http://www.nejm.org/doi/full/10.1056/NEJMoa1014463
- Thera MA et al. A field trial to assess a blood-stage malaria vaccine. NEJM 2011;365:1004-1013. http://www.nejm.org/doi/full/10.1056/NEJMoa1008115
- Herwaldt BL et al. Transfusion-associated babesiosis in the United States: a description of case. Ann Intern Med 2011 Sept. 5. E-pub. http://www.annals.org/content/early/2011/09/02/0003-4819-155-8-201110180-00362.full
- D’Costa VM et al. Antibiotic resistance is ancient. Nature 2011 Aug. 31. E-pub. http://easweb.eas.ualberta.ca/download/file/papers/paper_108.pdf
- Shi W et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 2011;333:1630-1632. http://www.sciencemag.org/content/333/6049/1630.full