If there’s one thing that all Sci Fi nerds should know, it’s the catchy catchphrase of the cybernetic hive mind of The Borg – “Resistance is Futile”. True aficionados will recall the battle for Earth after the defeat at Wolf 359, where Captain Picard, captured and now “Locutus of Borg” was used by the Federation to destroy the Borg cube and save the Earth, proving that resistance, after all, was not futile.
In the same vein, many people view treating bacteria resistant to antibiotics as a futile endeavor. But it’s not as simple as all that. In order to understand why, we have to break down what it really means when we label a bacterial isolate as “Sensitive”, “Resistant” or “Intermediate”.
The core principle of bacterial resistance is the MIC, or minimum inhibitory concentration. The MIC is the concentration of a drug that will inhibit growth of that bacteria in the lab, in the old days tested using doubling-dilutions of drug and seeing which test tube the bacteria first grew in. The MIC was the dilution above that level (so if bacteria grew at a dilution of 1:32 but not in 1:16, the MIC would be 1:16). You can then give that value in terms of milligrams of drug.
Now, here is the key point. When we state that a particular MIC corresponds to being “sensitive” we mean that for THAT BUG and THAT DRUG it will kill the organism in the BLOOD, assuming normal dosing.
MICs cannot be compared between bugs. And more importantly they can’t be compared between drugs! You should NOT pick your drug based purely on the MIC that the lab reports out. In fact, a good lab will not report out the MICs, but will instead simply interpret them for you to say sensitive, resistant or intermediate (a weird concept, where the MIC is neither high enough to be considered truly resistant, but not low enough to be truly sensitive either – a clue that it isn’t a black and white interpretation). Unless you’re an ID doc or a pharmacist and you know what you’re doing, you have no need to know the MIC at all. The choice of drug should be based usually on the class of drug, and the location and type of infection you’re dealing with. I’d rather use oxacillin to treat staph with an MIC of 2 than vancomycin for the same infection with an MIC of 1, and I’d certainly never use rifampin by itself despite a potential MIC of 0.03.
If the infection is in a different body location, especially somewhere like the spinal fluid or brain where the blood-brain barrier can prevent drugs from getting in, then the MIC doesn’t apply. If only 20% of your blood level of drug gets into the spinal fluid, knowing that your bacteria is “sensitive” to blood levels isn’t entirely reassuring. In fact, for some bacteria the lab will report out separate “meningitis” MIC levels to take this into account, and many drugs have “meningitic dosing” which is much higher that normal dosing (remember, sensitivity MIC refers to that bug, that drug, in the blood, using normal dosing). Some drugs don’t even get into the spinal fluid at all – you’d never use cefazolin to treat staph meningitis for example, although for almost every other type of infection it’s one of the best anti-staph drugs out there.
The opposite may be true for urinary infections, as many drugs are concentrated in the urine, so urine levels may be 10-100 times the blood level, and even “Resistant” organisms will be killed.
But when you’re faced with a nasty bloodstream infection, or a pneumonia, or cellulitis where the MIC is probably helpful enough, and it’s resistant, what can you do?
It can depend on the resistance mechanism. Streptococcus pneumoniae has an altered binding protein, so simply swamping the bug with excessive penicillins might be enough to work. Staphylococcus aureus has a beta-lactamase that will destroy basic penicillins, and adding a beta-lactamase inhibitor will defeat that mechanism, or moving to a higher class of drug like a cephalosporin (first generation, of course).
But what about tougher bugs with weird mutations, pumps that remove antibiotics from the bacteria or porin mutations that prevent the antibiotic from getting into the bug in the first place? Sometimes a higher dose by itself isn’t enough. With some of the beta-lactam drugs the important concept is “time above the MIC” rather than sheer dose of drug. If the MIC is 32 but you can get blood levels of 33 for 24 hours a day using a continuous infusion, that will be enough to kill the infection, even though using traditional dosing that would be considered resistant. Prolonged infusion is a halfway house to try to achieve the same end, and can also be used to extend the total exposure of the organism to the drug “area under the curve” of a graph of drug concentration over time. And you can also simply use higher doses, assuming the drug isn’t toxic enough to limit that approach.
Incidentally this is why vancomycin is a crappy drug – sure, it kills MRSA, but the limits between effective and toxic are quite narrow, and you can’t increase the dose much at all without dinging the kidneys.
Another approach is the use of multiple drugs at once, targeting different bacterial biologic mechanisms. Intuitively it makes sense – attack the cell wall AND protein synthesis, or DNA replication, and you ought to kill it off faster. Often this approach is not simply additive – there is synergy between the two drugs such that 1+1=4 when it comes to killing ability. Relatively inactive drugs like the aminoglycosides (gentamicin, tobramycin) or rifampin, can be very effective when paired with a beta-lactam or other cell-wall agent. I call them the SALT drugs. Synergistic Although Lousy Therapeutically. And you’d never eat salt by itself, always with something else….unless you’re a goat.
One very interesting report of lab work with an old drug called colistin and vancomycin showed that if you put the two together, vancomycin could be effective against bacteria that it would normally have no activity at all against. The colistin punched holes in the bacterial membrane that allowed the vancomycin in to act on the inner cell wall. (WARNING – lab report only, do not try with real patients….yet…).
So when we are faced with resistant organisms, it’s never truly a totally lost cause. There are always ways to try to optimize either the dose or the timing of doses to keep drug levels up, or combinations to try, or novel ideas. But there’s no guarantee of success, in the same way that even with sensitive bacteria there are still going to be treatment failures.
Ultimately we need new drugs, and new drug classes. If we have to go up the development chain to counter old resistance mechanisms, all we’re going to go is promote the evolution of new resistance mechanisms. Even the newest anti-MRSA 5th generation cephalosporins are modifications of penicillin, when all is said and done. We really haven’t come very far at all.