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Resistance to Antibiotics

There has been an increase in the resistance of various bacteria to antibiotics, and now it's even happening with viruses. The problem is going to continue to be a problem and the development of new drugs that are likely to replace the old drugs that we have relied on for a long time are really not performing the way one would expect. We are approaching an area where, over a period of years, unless something dramatic and new occurs, we are going to run out of drugs to treat some of the more serious infections.

We are focusing on out-patient medicine, but when you talk about bacteria, we see the same bacteria outside that we do inside, so there is not a lot of difference. Therefore, I am going to cover organisms which are problem organisms, relatively common causes of infection and which are evolving in terms of resistance. If I had been giving this talk 15 years ago, many of these organisms would not even have come up, such as the pneumococcus, the group A streptococcus and many of the others that I will be talking about.

The pneumococcus has become a problem organism and as time goes by will become more and more of a problem organism. We didn't even talk about pneumococcus in terms of sensitivities for many, many years because all of them were highly sensitive to penicillin, the cephalosporins and erythromycin, so we had lots and lots of choices.

Today, over forty-four percent have some level of resistance to penicillin that can result in problems in terms of treatment. By the way, when you want to predict what is going to happen in the United States, you look at what happens in Spain. Now, don't ask me why Spain, but virtually every resistant organism that we have seen in the last 10 to 15 years has appeared first in Spain, spread throughout Europe and then to the United States. Twenty years ago, it was Japan. Drugs are very, very freely used in Japan and in Spain. Patients can buy drugs at the pharmacy without prescriptions and can be exposed to multiple antibiotics. They are misused in great numbers.

In the United States, with the last survey, which was about a year ago, forty-four percent of pneumococci were relatively resistant to penicillin - either intermediate resistance, which means 0.1 to 1 mcg/ml of penicillin required for inhibition (the reason that number was picked is because going back about 10 years, every single pneumococcus was sensitive to 0.1 and as a matter of fact, sensitive to a lot less than 0.1), or high-level resistance, greater than 2 mcg/ml. These organisms are often resistant to other antibiotics, such as erythromycin, clindamycin, doxycycline or other tetracyclines and cephalosporins. Greater than 2 should be the definition if we are not dealing with meningitis. You can treat these intermediate-resistant organisms with penicillins.

Resistance of pneumococcus is not by production of penicillinase, but by changing of the penicillin-binding protein so that the penicillin attaches to it less well. Penicillin and cephalosporins work by virtue of binding to penicillin-binding proteins which are necessary for construction of the cell wall. When they bind to these proteins, they render them inactive so that they are not able to aid in the manufacture of the cell wall. When the penicillins or cephalosporins lose their affinity for the penicillin-binding protein, they become inactive. Meningitis caused by pneumococci must be treated with a third-generation cephalosporin.

With non-meningitis, if it is intermediate susceptibility, and fortunately that is most of the resistant ones, you can use penicillin or any of the cephalosporins, providing that you give dosages high enough to inhibit the organism and that is the case when you use recommended dosages. With high-level resistance, theoretically there may be failures and other agents should be used.

Many of these resistant pneumococci are still sensitive to doxycycline, chloramphenicol, which I don't think any of you would use, and levofloxacin. The pneumococci have becoming more and more resistant but haven't yet reached the point where they are resistant to levofloxacin, but that is coming in the future. The newer quinolones that I spoke about are more active than levofloxacin and they may give us some more time before the pneumococci continue in their march and reach levels where they will be resistant to the newer quinolones also.

There are screening methods that will screen significant isolates, but not the standard isolates. You isolate a pneumococcus from somebody with pneumonia or from a middle ear infection and unless asked, the laboratory may well not do any of the screening tests to see whether or not it is resistant. Clearly, with blood isolate or a spinal fluid isolate, they will do the sensitivities.

Now to switch to Haemophilus influenzae. This is an important organism in sinusitis and otitis media and amoxicillin resistance is now very common - over thirty-five percent of strains are resistant. Therefore, it is perfectly clear that amoxicillin is not a good drug in dealing with Haemophilus influenzae. On the other hand, amoxicillin clavulanic acid has excellent activity. Second-generation cephalosporins have very good activity, such as cefuroxime. The third-generation cephalosporins and

Gonococci have been becoming more and more resistant over many, many years. Penicillin and tetracycline resistance are now rampant. There is increasing resistance to ceftriaxone and other third-generation cephalosporins, but the degrees of resistance are still relatively low compared to the levels achieved, so that we have not changed the recommendations for treatment of gonococcal infection with cephalosporins.

The quinolones have all been extremely active against gonococci and multiple quinolones are approved for treatment of gonococcal infection. Strains resistant to the quinolones are very common in Asia, very uncommon in the U.S., but there have been a number of reported courses, predominantly from the Northwest part of the United States - Seattle and other areas on the West Coast, probably related to importation from the Far East, where resistance is very common.

The oral anaerobe organisms that we don't really think about very much are important in oral abscesses, in parapharyngeal infections, occasionally but not very often in sinusitis - it's usually chronic sinusitis, chronic putrid sinusitis - and in lung abscess. These oral anaerobes have been becoming more resistant to antibiotics over the years and penicillin resistance has become extremely common among the oral, what used to be called bacteroides and now called prevatella.

E. coli are the most common cause of urinary tract infection by far. What has happened over the years is that they have become more and more resistant to the drug that was most commonly used in treatment of urinary tract infection, which was amoxicillin. Today, over forty percent of community strains of E. coli - that means people who haven't been anywhere near a hospital.

These strains, for the most part, have remained sensitive to trimethoprim, trimethoprim sulfamethoxazole, amoxicillin clavulanic acid and the quinolones. The Infectious Diseases Society of America recently wrote their approach or standards for treatment of urinary tract infection and therein mentioned the fact that resistance has been increasing to trimethoprim and trimethoprim sulfa and is approaching twenty percent in some parts of the United States and when it hits twenty percent, in their judgment.

Nobody knows in which parts of the country - in your area, for example - whether ten percent are resistant, twelve percent are resistant, or eighteen percent are resistant - unless somebody there has done a study and collected all of the organisms and reported it. Remember, reports that appear in the literature usually appear about two or three years after the study.