Bacterial Resistance and Infection Control – Stanford University CF Centre
by Richard Moss, M.D.
Many patients and families are concerned about infection control. First, it is essential to understand what we mean when we talk about resistance of bacteria to antibiotics. What does it really mean?
There are 4 categories of bacterial sensitivity to antibiotics:
First, pansensitive – this means the bug is sensitive to all the antibiotics usually tested for potential treatment.
Second, sensitive – the bug is sensitive to several potential antibiotics, but it may be resistant to others.
Third, multiresistant – this is more complicated. According to the current definition, this means the bug is resistant to all antibiotics in two or more classes of antibiotics. Currently 3 classes of antibiotics are considered appropriate for treatment of Pseudomonas: certain beta-lactams, such as ceftazidime (Fortaz®); certain quinolones, such as ciprofloxacin (Cipro®); and aminoglycosides, such as tobramycin (Nebcin®, Tobi®).
Fourth, panresistant – the bug is resistant to all tested antibiotics of all classes.
Here is an example of an antibiotic sensitivity report for fictional patient Jane Smith on a clinic visit expectorated sputum culture that grew three strains of Pseudomonas aeruginosa, one strain of Stenotrophomonas maltophilia, and Staphylococcus aureus. What is listed is the antibiotic sensitivity pattern for 1 of the 3 strains of Pseudomonas, i.e., just one of 5 lists of antibiotic sensitivities we would get from this single culture report on this patient on this day:
“3+ mucoid Pseudomonas aeruginosa
Method Kirby Bauer
Tobramycin E test (not yet FDA approved)
MIC 32 No interpretation”
What is your categorization of this bug, and how should Jane Smith be approached regarding infection control on a clinic visit? You wouldn’t be expected to know the answer without a lot more knowledge of how the tests are done and what they mean. Here are several points about this culture result:
This bug is multiresistant. This is because it is resistant to all tested antibiotics in 2 out of the three 3 represented.
The only quinolone tested (because it has the highest and only frequently present quinolone activity against Pseudomonas) is ciprofloxacin. Resistant.
The three aminoglycosides tested are gentamicin, tobramycin, and amikacin. Resistant to all three.
The rest of the drugs shown–total of 7–are beta-lactams. Of these 7 drugs, the bug is sensitive to just one, cefepime. This sensitivity keeps the bug from being called panresistant. But because it is multiresistant Jane will be asked to don a mask for her clinic visit, and if hospitalized she will have respiratory isolation procedures in place.
Because it is multiresistant does it mean Jane is untreatable? No! If she is sick we can start cefepime (an iv-only drug). We would probably combine that with iv tobramycin, because even though the report says she is resistant to tobramycin there is synergy between these two antibiotic classes in attacking Pseudomonas.
If Jane is a little sick, or her PFTs have dropped, we may put her on Tobi®. Why? Although the conventional test (Kirby Bauer disc diffusion) says her bug is resistant to tobramycin, the “E test” done at Stanford (not commonly done elsewhere) shows the bug can be killed by tobramycin if a concentration of 32 micrograms per milliliter [mcg/ml] can be achieved. It is difficult to do this by iv tobramycin without risking toxicity to kidneys or inner ear, but it is easy to do by having Jane inhale 300 milligrams of tobramcyin solution for inhalation-a Tobi® dose — twice daily. This will produce a sputum level in the neighborhood of 1,000 mcg/ml, far above that needed to kill the bug, even after allowing for the fact that tobramycin can lose up to 90% of its activity in CF sputum.
THE CONCEPT OF RESISTANCE – A RED HERRING IN CF?
We have problems even defining and understanding what resistance means in the world of CF. The word resistance refers to lab tests done in a liquid suspension with a conventional set “dose” of bacteria and cutoffs between “sensitive” and “resistant” refer to levels of that antibiotic traditionally associated with curing systemic (i.e, blood) infections.
We know in CF that the conventional term “resistance” is questionable clinically. For example, if your Pseudomonas is called “resistant” because tobramycin does not kill it at the conventional testing cutoff level of 8 mcg/ml, this is not very relevant in a disease where the bug is living in the mucus rather than tissue or blood, and we can deliver 1,000 mcg/ml Tobi® to the mucus by aerosol. Moreover, the way the bug lives in your lung is as a mucoid biofilm-a gigantic communal mass of bacteria (up to one billion bacteria in one gram of sputum!) stuck together by a slimy material called alginate or mucoid exopolysaccharide. This is much different than the way lab antibiotic testing is done with individual bugs swimming around freely in liquid suspension.
We rely on universal direct and indirect contact precautions for ALL patients to reduce transmission of bacteria. The simplest way to describe this is to imagine a three foot zone around your body that should ideally not be entered by another patient (unless you live with them), and no shared object use without proper cleaning in between. All contacts by caregivers should be preceded by handwashing and cleaning of multi-use instruments such as stethoscopes.
We are concerned about acquisition and spread of Pseudomonas, and the infection control measures are designed to reduce the chance of spread. For multiresistant and panresistant bugs, we add restrictions on the patient such as use of mask when coming to clinic, and isolation when hospitalized. This is done to reduce the chance of transmission, not because the patient is sicker! The mask is an additional level of precaution but contact precautions are the key element for ALL patients.
In the near future the CFF Consensus Conference report on Infection Control will be published and available for detailed reading.