In a previous post I discussed some of the hurdles - mainly economic - to developing rapid diagnostics for bacterial infectious disease. Despite these problems, several new technologies have been developed and are finding their way, however slowly, into clinical microbiology labs.
The problem with all of them is that they are great at identifying bacteria, but are limited in their abilities to determine resistance and susceptibility. In a low-resistance environment, this is not a significant limitation. Historically, doctors would consult a reference that matches clinical presentation and bacterial species with preferred antibiotics, and prescribe accordingly. They might also consult their hospitals' antibiogram, a tally of observed antibiotic susceptibilities at their hospital.
But what do you do when the antibiogram looks like the one below (which is very typical)?
Your rapid test may have identified the infecting bug as Acinetobacter, but then what? None of the antibiotics on the list are highly likely to be effective for any particular strain, but there is a pretty good chance that one or two might be. You just don't know without a susceptibility report on the bug that has been isolated from the patient - and that still takes 2-3 days. The rapid ID test has told you what the patient is infected with, but not what treatments are likely to work.
This limitation is true whether the rapid-test technology is PCR, PNA-FISH, or the new favorite of many, mass spectrometry. It's true that PCR tests can detect the presence of some resistance genes. But the prevalence of these genes (e.g., mecA in S. aureus, vanA in E. faecium) is so high that doctors usually assume resistance and treat accordingly regardless of the test result. A negative result for a resistance gene does not necessarily mean that the strain is susceptible, as there can be new variants and new pathways for resistance that gene tests may not detect. Accordingly, no gene tests have been cleared by the FDA for determination of antibiotic susceptibility. The distinction between negative and susceptible is not always obvious to doctors, and the FDA has required the Cepheid MRSA PCR test to carry a label to that effect.
The basic problem is that antibiotic susceptibility and resistance are complex phenotypes that can't be reduced to a problem of detecting a few molecules or gene sequences. Resistance can occur through thickening or modification of the cell wall, chemical modification or mutation of ribosomes, or production of degradative enzymes and efflux pumps. Each of these mechanisms can have many variants and pathways, and new ones are always evolving. Even if (actually, when) it becomes possible to get an entire genome sequenced within a few hours, it will not be possible to read out a susceptible phenotype with high confidence. There are just too many possible genetic variants that would have to be validated first.
So for now and the indefinite future, ID-only rapid tests will continue to have limited clinical impact, and susceptibility testing will have to proceed by traditional methods: expose a bacterial strain to the antibiotics of interest, and observe the response. This process typically takes 2-3 days at present. Some methods to reduce this time are being developed, and I will write about them in a later post.
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