Maas spectrometry exerts a peculiar hold over the minds of its advocates. They tend to be passionately committed to it, like no other technology I've seen.
MS is indeed a powerful technology. A sample is ionized so that it has a net electrical charge, and the time that it takes to fly toward a cathode is used to calculate its mass (more time = more mass). The identity of compounds in a sample can be deduced from matching expected with observed molecular weights. Under ideal conditions, only a few femtograms of material are needed. Good stuff indeed.
When complex samples, such as tissues, cells or fluids are analyzed, a complex pattern of peaks is observed. These patterns are very data-rich, and can be mined to produce a signature, and the signatures can be used for clinical tasks such as predicting therapeutic response to cancer drugs - or identifying bacteria.
The allure of this technology to a micro lab manager is obvious - a universal platform for identifying bacteria. A loopful of bacteria from a colony are smeared on a plate, overlaid with an acidic solution, zapped by a laser, and out comes a readout that IDs the sample.
When it works (and it works most of the time) it is beautiful and very rewarding. But it doesn't work all of the time - some species are just not distinctive enough in their signature to give a good result. More importantly, MS is very sensitive to the sample matrix, meaning that it doesn't work nearly so well on direct specimens. As a result reliable ID will still take at least a day, in order for purified cultures to be prepared.
I think this very good but not perfect success rate is the key to the enthusiasm (if not obsession) that many mass spec'ers exhibit. When you train a dog, you do not always give the treat - the uncertainty in the dog's mind as to whether she will be rewarded causes her to pay much closer attention to her master. Casinos operate on the same principle - provide just enough reward to create hope and anxiety, and the reward becomes much more gratifying and addictive. The occasional failure serves to redouble the true believers determination to succeed.
I was glad to see that the recent paper by Donna Wolk and colleagues takes a level-headed approach to the strengths and weaknesses of mass spec, despite its title. And it is likely true that mass spec will instigate a "fundamental shift in the routine practice of clinical microbiology". I just don't think patients will see much benefit.
Although all clinical microbiologists are trained to focus on organism ID, this parameter is decreasingly important in an age of widespread antibiotic resistance. An instrument that can ID hundreds of potential pathogens is nice for lab workflow but consider: just 4 organisms account for 80% of positive blood cultures (counting Coagulase-negative Staph as one organism); 6 account for 90%; and 7 for 95%. The ability to ID a Citrobacter or Proteus will help very few patients. Knowing whether a septic patients' Gram-negative rod is susceptible to cephalosporins or carbapenems has much more therapeutic utility, regardless of whether it is an E. coli or a Klebsiella.
There have been some initial efforts to determine susceptibility and resistance using MS - looking for specific enzymes, or antibiotic degradation products, or even cellular response to antibiotic exposure. I think all of these will ultimately fail because of the vast heterogeneity of resistance mechanisms and differences in strain responses to antibiotic challenge. Even with copious data storage and analysis capabilities, the signature of each strain of each species to each antibiotic over a range of physiological conditions will have to be validated, and have to be constantly updated as new strains and resistance mechanisms emerge. This is implausible.
What would really benefit patients (as opposed to lab managers) is a same-day test that would return ID results for the top 4-6 pathogens, with susceptibility results for 2-3 frontline antibiotics each. Such a test would ensure that 90% of critically ill patients receive appropriate antibiotics, instead of the 50% that now do.
But that brings us back to the question of the economics of test development. We were working on a panel test at MicroPhage. But with microbiology labs unwilling to pay $50 for our test that returned same-day results for MRSA/MSSA, how much would they have been willing to pay for a small panel? Potential partners and investors surmised that the answer was "not enough", and the project never really got traction. So long as antibiotics and susceptibility testing are undervalued, the prospects for developing a test that will get patients the right antibiotic right away are not good. Instead what we will have are $150,000 instruments like mass spectrometers that improve workflow and reduce staffing costs.
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