New antibiotics: Prevention is important, too!

Losee Ling et al recently described a new antibiotic compound, called teixobactin, that kills pathogens without detectable resistance. The abstract of their study notes that

. . . We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

It's a beautiful study, and obviously everybody hopes these implications are realized, and soon; new drugs are very badly needed. Eli Perencevich, writing in the blog Controversies in Hospital Infection Prevention, summarizes some of the important results from the study and also offers an important perspective,

I agree with Dr. William Schaffner's comments in the NY Times as he called the study/method “ingenious” yet also cautioned that "it’s at the test-tube and the mouse level, and mice are not men or women, and so moving beyond that is a large step, and many compounds have failed.” I would add one additional caveat  -- teixobactin had little activity against most Gram-negative bacteria including E. coli, Klebsiella and Pseudomonas. . . . Since the real resistance crisis is in multi drug-resistant Gram-negatives (think CRE, NDM-1), we better get back to digging in the dirt.

Certainly, these and other Gram negatives are important. As I've mused before, it's critically important to research infection prevention approaches in addition to investing in new drug development. We must understand how to prevent infections from occurring and spreading in healthcare (and other) settings before new drugs are introduced. It is clear that we do not possess this understanding, at least on any significant scale or in any sustainable way, at present.

(image source: CDC)

Travel and infection: The global mixing bowl

"Healthy travellers to countries where carbapenemases-producing Enterobacteriaceae (CPE) are endemic might be at risk for their acquisition, even without contact with the local healthcare system." So begins a recent Eurosurveillance report by Ruppé and coworkers describing acquisition of CPE by healthy travelers to India. The study describes data from the VOYAG-R project, which has many objectives, including measuring the rate of acquisition of multidrug-resistant Enterobacteriaceae (MRE) in people returning from travel Latin America, Sub-Saharan Africa, and Asia and the length of MRE carriage after trips. 

CRE was the topic of a previous blog post; such pathogens are associated with significant morbidity and mortality (especially in transplant patients and those with hematological malignancies) and are increasing in incidence globally. They are difficult to detect and treat, and are important in hospital infection prevention. The Ruppé et al study reports the acquisition of CPE in three healthy French travelers returning from India. The travelers reported no contact with hospitals or healthcare centers while traveling, leading the authors to conclude that the findings are "worrisome as they attest to the development of a community reservoir for CPE, at least in India."

The study illustrates many important issues, including that those traveling to high prevalence regions are at risk for becoming colonized with CPE. Once colonized, they can carry CPE back to their origination. One can think of such regions has having a high epidemiologic weight for the global propagation of CPE. Such movement of CPE and related pathogens has been described previously. In one example, importation of MRE strains producing NDM-1, OXA-48, and ESBL into the Netherlands after a patient received healthcare in Egypt was observed. In other cases, the acquisition of CPE cannot necessarily be attributed to travel or other risk factors, but what is clear is that such pathogens have spread over large distances and are now regularly observed in many areas. 

Other pathogens are known to exhibit transient colonization, though data are frequently rare and highly variable. The picture of latent introduction of CPE is probably also relevant for other bacteria of interest in hospital epidemiology. Such a picture highlights the need for surveillance, yes, but also for effective hospital infection prevention and control. As has been pointed out, this can be difficult, especially for CRE. We need a better understanding of the mechanical pathways of infection in order to design and implement better prevention practices. 

(image source: Wikipedia)

CRE outbreaks: What should we learn?

Infections with Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria are associated with significant morbidity and mortality and are increasing in incidence globally. KPC- and New Delhi Metallo-beta-lactamase (NDM)- producing bacteria collectively are referred to as carbapenem-resistant Enterobacteriaceae (CRE). They are difficult to detect and treat, and thus are an important issue in hospital infection prevention.

Studies emphasize the importance of early intensification of infection control to interrupt the transmission of KPC-producing Klebsiella pneumoniae, but it is clear that infection control efforts aren't always effective at blocking transmission of the pathogen. A dramatic demonstration of this occurred in 2011 in an outbreak at the US National Institutes of Health Clinical Center. A paper by Snitkin and co-workers describes the process that unfolded in the NIH outbreak and the role that whole-genome sequencing (WGS) of isolates played in understanding how the outbreak progressed despite early implementation of infection control procedures. The study illustrates how WGS can provide evidence for unexpected transmission routes, and concludes that "integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission."

I think there are additional lessons from this and similar outbreaks, including that it is less than clear how, mechanistically, infection travels from host to host. The NIH staff took every intervention that could be expected to stop the spread, but those failed to break the chain of transmission. There is very limited science behind most infection prevention interventions. We don't understand in a detailed way the trips taken by pathogens as they sojourn from one host to the next, the relative probabilities of survival along the pathways, and other important facets of the contagion process.

These gaps need significant attention -- and funding for both research and education -- if we are to identify the most effective and efficient methods for control and prevention.

(image source: CDC)

A voice from the past: I told you so

This picture circulated on Twitter recently. To many it may seem amusing, even quaint at this point nearly 70 years after the shot was taken, but it is also sobering.

The CDC's recent report on  Antibiotic resistance threats in the United States, 2013 lists drug resistant Neisseria gonorrhoeae as one of the three most "urgent" threats in terms of antibiotic resistance today (the other two being CRE and C diff), along with 12 other "serious" threats (including ESBLs, VRE, MRSA, and DR-TB) and 3 more merely "concerning" threats. The issue of drug resistance will only get worse unless something is done to counter it; unfortunately, it's a very complex problem at this point.

Curiously, and prophetically, Alexander Fleming, at the end of his Nobel lecture in 1945, warned that resistance would be a problem if administration wasn't managed carefully:

But I would like to sound one note of warning. Penicillin is to all intents and purposes non-poisonous so there is no need to worry about giving an overdose and poisoning the patient. There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body.

He continued with a vignette:

The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. Here is a hypothetical illustration. Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies. Who is primarily responsible for Mrs. X’s death? Why Mr. X whose negligent use of penicillin changed the nature of the microbe. Moral: If you use penicillin, use enough.

It seems he had remarkable clairvoyance. Although antibiotics can't be "bought by anyone in the shops" unless they have prescriptions, they are low cost and sometimes even free. They probably are very over-prescribed.

Just to bring things full circle, the annual CDC survey on STDs depicts increases between 2011 and 2012, with a large number of infections due to gonorrhea. The report notes that

With increased resistance to the fluoroquinolones and the declining susceptibility to cefixime, dual therapy with ceftriaxone and either azithromycin or doxycycline is now the only CDC recommended treatment for gonorrhea. (Emphasis added.)

(image source: Wikipedia)