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The Quinolones

Although there have been some new antibiotics over the last few years, the vast majority of the activity has been with the quinolones and continues to be with the quinolones. There is actually one quinolone that was just approved by the FDA within the last week or two and I'll mention that. Aside from that, there is only one other important drug that has been released in the last two or three years, and that was approved in the last month or two by the FDA - Synercid. We'll talk about Synercid later on, but it is not a quinolone. If you know the quinolones and were up to date on antibiotics one or two years ago, you are still up to date on antibiotics, with perhaps the exception of the quinolones and Synercid.

Quinolones are bactericidal agents. They are very, very important agents because they are an entirely different class. The quinolones we'll talk about today are fluoroquinolones and are very, very different in terms of their activity from what Nalidixic acid, or NegGram, was. These drugs have what is called a long post antibiotic effect. Post antibiotic effect means that after they no longer have inhibitory activity against the organism, they continue to exert an effect against that organism for a period of time before it can start growing again. This ranges as high as six hours with the quinolones, so that you don't necessarily need to have an active drug around 24 hours a day. With many of them, you can have active drug for 18 hours and then none for the next six hours and the organism still will not begin to grow. Resistance is actually unusual. It is not plasmid mediated. Remember, the plasmids are those little pieces of DNA that can be exchanged between gram-negative rods, so in one exchange, all of a sudden, a drug is no longer effective and E. Coli can give a plasmid to a klebsiella and now the klebsiella is totally resistant.

Trovafloxacin (Trovan) was a remarkable new drug and was marketed just about 1-1/2 years ago. It looked very safe and extremely effective. It was the first quinolone with very broad-spectrum activity, even against anaerobes. It seemed to be perfectly safe, very very non-toxic, until it got out into the population and there were millions and millions of doses given. With that, hepatotoxicity began to be seen and there were deaths and patients who required liver transplantation.

The trade names are as follows: Ciprofloxacin is Cipro; Lomefloxacin is Maxaquin; Enoxacin is Penetrex; Ofloxacin is Floxin; and Levofloxacin and Levaquin. Some of the newer quinolones - sparfloxacin, grepafloxacin, trovafloxacin - are Zagam, Raxar and Trovan. Now you can virtually forget about these three, because I have already told you about the experience with trovafloxacin, so that people really are pretty much afraid to use it. Grepafloxacin has been withdrawn from the United States.

Norfloxacin, or Noroxin, was approved for use in urinary tract infection and where high concentrations are developed locally - prostatic infection, infectious diarrhea, because you are taking it orally, it is poorly absorbed, blood levels are low and that is why it is not used for any other kind of systemic infection. So it works in the gut, it is concentrated in the prostate and it is concentrated in the urine, but it really is more of a historical drug than anything else, because of its very poor blood levels.

Ciprofloxacin, which was the second one released, is still an excellent drug. It has excellent activity against gram-negative bacilli, including pseudomonas. It is approved for urinary tract infection and pneumonia, but should not be used for pneumococcal pneumonia, even though it has been in the past, because the pneumococci are very borderline sensitive.

I would have no use for either lomefloxacin or enoxacin. These are ciprofloxacin-like drugs that are supposed to do the same thing as ciprofloxacin and they do have the same activity as ciprofloxacin with the exception of pseudomonas, where these are not active.

400 mg of lomefloxacin, whose claim to fame is that it has a longer half life, so you just give it once a day, and enoxacin, which is given in the same dose basically as ciprofloxacin, 400 mg twice a day. But there are more side effects with these drugs. Lomefloxacin is one of the worst in terms of photosensitivity. They both have the same GI and central nervous system side effects that ciprofloxacin does. So with the exception of the ability to give lomefloxacin once a day as opposed to giving ciprofloxacin twice a day, there are no advantages of these drugs, and there are disadvantages. For example, enoxacin is the one that has the most interaction with theophylline, raising theophylline blood levels, much more so than ciprofloxacin. In my personal opinion, I see no real advantage for these two drugs.

Then along came quinolones with more gram-positive activity. This was an important consideration because originally, ciprofloxacin was thought to be adequate therapy for pneumococcal and staphylococcal infection, but it became obvious that the sensitivities were borderline and then I told you about that slow, small step-type of resistance which occurs over time, and that happened with ciprofloxacin. Ciprofloxacin no longer should be used for gram-positive organism infection.

Ofloxacin, levofloxacin, sparfloxacin and grepafloxacin all had much better gram-positive organism activity, particularly against the pneumococcus. Of these, ofloxacin is the weakest and levofloxacin is the one that has been used the most.

Sparfloxacin and grepafloxacin looked even better - because they are more active against the gram-positive organisms, particularly pneumococci. The problem is that both of these drugs have the unfortunate side effect of prolonging the QT interval and that can result in lethal arrhythmias, especially in association with other drugs that prolong the QT interval.

Trovafloxacin looked like a superb drug. It had very, very little in the way of side effects - just some minor GI side effects, virtually no phototoxicity, no QT interval prolongation, the central nervous system side effects were not very marked, and it looked like an absolutely clean and safe drug. When it came along, I thought that this was going to be a world beater, because it was extremely active against the gram negatives - not pseudomonas, against the gram positives and against anaerobes.

There are many, many other quinolones which have numbers - they don't even have names - which virtually every pharmaceutical company is working on. This is very much like the situation was with the cephalosporins a number of years ago, where it was a cephalosporin of the week and now we're entering into that phase with the quinolones.

Of the agents that are available or were available until recently, I just drew up a chart here which will list all of the dosages in one place and show you that the serum levels are not very high for any of these. These all give relatively low serum levels and the half lives. Now when you think about a half life and you want to think in terms of one dose a day or two doses a day, the cut off usually with drugs that don't give very high levels, is usually somewhere around six hours.

What about renal failure? Half life increases with renal failure. Norfloxacin, which is not absorbed very much, does not have an increased half life. But it virtually does increase with all of the other drugs other than the two that are no longer available. You have to decrease the dose of the quinolone in people with renal insufficiency. Otherwise, you may get into difficulty, for example, with central nervous system toxicity.