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Penicillin resistant Pneumococcus and other bacterial resistance have become a rapidly increasing problems. So we have to be careful with the way we use antibiotics as we do any other drug. Some resistant mechanisms work by competitive antagonism. The sulfas are folic acid synthesis inhibitors. Those bacteria that are obligate folate synthesizers are inhibited because there are non-utilizable forms of folate that are synthesized when the sulfas are present. Some others are cell wall inhibitors. For example, penicillins and cephalosporins will cause defects in the formation of the cell walls. Essentially it's like taking the cement out from between the bricks. The cell membrane may, too, be interfered with. The antifungals very often will align themselves between the lipid and protein complexes and interfere with the metabolic functions of the cell membrane in fungi. Some will inhibit protein synthesis. For example, erythromycin, tetracycline and chloramphenicol will basically stop protein synthesis.
Others will cause protein synthesis to be altered. For example, the aminoglycosides like tobramycin or gentamicin cause the formation of non-utilizable proteins. So the bacteria go on trying to grow and yet the proteins which are critical to their structural integrity – enzymes, etc – are no longer there. Lastly, nucleic acid interference includes drugs like ciprofloxacin, which is a DNA gyrase inhibitor.
Penicillins. That is typically where most antibiotic lectures start. A reminder that if someone is truly allergic to one penicillin, they should be considered allergic to all other penicillins. But penicillins in general are fairly low in toxicity other than allergic reactions. You can occasionally get into electrolyte overload with some of the parenteral forms. Most of them contain either potassium or sodium and if you have a patient who has
Penicillin G is the first drug that we will basically talk about. It is useful in a number of Gram positive infections. It is relatively nontoxic. It is cheap. If you give it IM, though, it is painful and you have to give it frequently. IV, if you order aqueous penicillin G or penicillin G K or crystalline penicillin, the pharmacy will send you the potassium salt. Now, that contains about 1.8 milliequivalents of potassium per million units and if you are giving large have to alternate the sodium and potassium every other dose.
Phenoxymethyl penicillin is oral penicillin. There is no longer oral penicillin G on the market. That has been taken off the market. Penicillin V would be used when oral penicillin is indicated. Procaine penicillin gets around the problem of pain on IM injection of aqueous penicillin by complexing it.
But you get even lower blood levels with benzathine penicillin. This is another IM suspension marketed as Bicillin L-A where the release is extremely slow. You get very low blood levels so we would use this for rheumatic fever prophylaxis or for treatment of very susceptible infections like susceptible Strep throats where we don't think compliance is going to be very good. The problem with this is that it hurts. Many patients will complain of pain for three days or so after they get a shot of benzathine penicillin.
There is also a Bicillin C-R on the market. That is Bicillin Controlled-Release, if you will. That is a 50/50 mixture of procaine and benzathine penicillin. The procaine gives a moderately high blood level for the first day. After that, the benzathine is there to help eradicate.
Ampicillin is a drug that has a fairly broad spectrum. We typically use this for infections where H. flu or E. coli are likely pathogens. Obviously beta-lactamase production is somewhat limiting the utility of this drug in those cases but it still is a useful drug in many cases of infections like that. The problems are diarrhea. When you give it orally, a fair proportion of the patients will develop this – 10 to 20%. Rash is two-fold.
Ticarcillin is also a penicillin derivative but its major activity, rather than being Gram positive, is Pseudomonas. That is the principal use of ticarcillin. We give it IV in large doses. It is impractical to give this product IM. It contains about 5 milliequivalents of sodium per gram and we give big doses.
Carbenicillin indanyl sodium used to be available parenterally. It is no longer available that way. It is only available in an oral tablet that can be useful in urinary tract infections and prostatitis. It is a big pill. It is very bitter. It is very hard to get some people to take it and please don't ask them to crush
Ticarcillin clavulanate is Timentin. This is a parenteral product that may be useful when Ticar effectiveness is being reduced by beta-lactamase production. However, there are other single entity antibiotics that are equally effective and possibly less expensive. So we haven't found a lot of use for this particular drug but it is certainly one that is out there that may occasionally be useful.
Piperacillin is sort of the top of the line of the anti-Pseudomonal penicillins. It is better than ticarcillin against Pseudomonas but it is significantly more expensive. It doesn't have the significant bleeding problems. It has less sodium although sometimes it can be enough to get you into trouble. It is also available as Zosyn as a parenteral product combined with Tazobactam. Again, the Tazobactam is useful in preventing beta-lactamase induced destruction. It probably should be restricted to resistant organisms or treatment failures. Please note that the dose of piperacillin contained in this, if you are dosing it properly, is considered inadequate to treat Pseudomonas. So this is not a supercharged anti-Pseudomonal med but rather using Zosyn may extend the spectrum against some other Gram negative organisms which may be beta-lactamase producers.
Azlocillin is like piperacillin in its spectrum and its uses. It basically is essentially as good as piperacillin and I would suggest that whichever one you use depends on which one your institution can get the least expensively. You do not need to have both azlocillin and piperacillin in a given hospital.
Penicillin H resistant penicillins are useful for Staph aureus infections. That is essentially the only reason that these should be used because they are significantly more expensive and more toxic for other uses. Therefore, they should be limited to treatment of suspected or proven Staph aureus. These should not be used for methicillin resistant Staph aureus and I might point out that methicillin resistant Staph aureus is a misnomer. These are not only methicillin resistant, they are also beta-lactam resistant, so they are unlikely to be susceptible to any of the penicillins or the cephalosporins.
One other thing that you need to consider when you are prescribing these products is that most of the oral liquids of these products are literally unpalatable. I don't know if you have ever tasted oxacillin or dicloxacillin liquid but in taste tests with children, we routinely find that these products
Cephalosporins. There are now four generations of cephalosporins. The third and fourth generation cephalosporin differences are fairly minor and we will treat those as a group. First generation cephalosporins and second generation cephalosporins do not cross the blood-brain barrier in adequate quantities to be able to use those for any CNS infections. So none of these would be recommended for treating a meningitis, for example. The first
The cephalosporins, as a group, may be useful in penicillin allergic patients but the general rule of thumb should be if they had an anaphylactoid reaction to penicillin, avoid cephalosporins if you can. If they have a rash with penicillin, there is probably about a 5% incidence of cross-reactivity.
A major use for the first and second generation agents is in surgical prophylaxis, particularly the first generation agents. Gram negative spectrum with the first generation agents is quite spotty. We do not suggest that they be used for Gram negative infections.
Cefazolin is Kefzol. You'll notice I don't have cephalothin or Keflin on this. Cephalothin had to be given every six hours. It caused a lot of IM pain. Cefazolin is given every eight hours. It causes less IM pain and really in most hospitals has replaced cephalothin and therefore that's the only one I have listed here. So this would be the parenteral drug that usually would be used. Cephapirin or Cefadyl is another drug that is very much like cefazolin and has similar uses.
For the oral cephalosporins, actually these drugs may be quite useful in Staph aureus infections particularly as the liquids. Liquid Keflex of cephalexin. One of the products is bubble gum flavored. It's quite well tolerated by children. It's not terribly expensive so this may be a preferred product.
Our experience here has been that cephalexin is the product we prefer in preadolescent children when we are trying to treat a Staph infection or we want to use an oral first generation cephalosporin. For adolescents and adults, we often would use cefadroxil.
Second generation cephalosporins increase Gram negative coverage at the expense of some Gram positive coverage. They are more expensive than the first generation and if you are after simply Strep and Staph, these probably should not be chosen.
Cefotetan or Cefotan is another product very similar to cefoxitin in its uses. It is used less often, once a day or twice a day, so this may be preferable in some circles if you want to use a cephalosporin for anaerobes.
Cefmetazole can cause some reactions. Bleeding, disulfiram or Antabuse-like reactions with alcohol. We really don't see a unique use for this product so we tend not to talk very much about it.
Similarly, cefonicid is marketed as Monocid. It has more activity against H. flu but it is less active against Gram positives.
Now, if I need to stick a stick in a hornet's nest and shake it up, this is the one drug that I will potentially create controversy with and that's cefaclor or Ceclor. This drug is way overused. It is a very palatable drug. Children will take it. But it is not that effective. It has been shown that tissue levels may be lower than with other oral cephalosporins. Serum sickness is possible with repeat use, much more so than with any of the other.
Cefprozil is Cefzil. This is a product that is given once or twice a day as an oral tablet or suspension. It can be used for otitis media and soft tissue infections although this is not a drug of first choice usually. It certainly is a reasonable alternative particularly in patients who have trouble tolerating.
Cefuroxime is marketed as a parenteral product – Zinacef – and also as an oral tablet or suspension as Ceftin. While it used to be used in meningitis, it is no longer recommended for use because it is not as effective as the third generation agents. It does have good activity.
The problem with cefuroxime is that it is very bitter. The suspension needs to be given with food. Regardless, it tastes bad.
Third generation cephalosporins generally have an increased Gram negative spectrum with decreased Gram positive activity generally.
Cefotaxime is Claforan. This is probably the most useful of the third generation cephalosporin parenteral products. It is given parenterally usually every six hours. It is a drug of choice for neonatal sepsis and meningitis and is a drug for meningitis in general in pediatrics. It is useful in gonorrhea.
Ceftizoxime is Ceftizox. This particular product is like Claforan or cefotaxime but it is given every eight hours. However, we don't have a great deal of experience with this in children and the literature generally has not adapted this instead of cefotaxime. Cefotaxime continues to be the preferred drug.
Ceftriaxone is Rocephin. This particular product is just as good as Claforan against meningitis. The advantage here is that it is given once a day. The problem here, though, is that this drug has a much greater effect on suppressing bowel flora than does cefotaxime..
Cefoperazone is a product that used to be used for Pseudomonas. It still is available but it causes bleeding and Antabuse-like reactions and so we prefer to use newer products such as ceftazidime.
Ceftazidime is a drug that while it has a very broad Gram negative spectrum, it is principally used in treating Pseudomonas. Remember when we are treating Pseudomonas we would use at least two different agents because Pseudomonas tends to become resistant to any single agent used alone. This says it's the best cephalosporin in treating Pseudomonas and I would say it is that currently but it is not the most effective.
Cefepime is probably the most effective cephalosporin. This is Maxipime. This was marketed about 18 months ago. It is given twice a day. They consider it fourth generation cephalosporin because it has greater Gram negative coverage. It is more effective against Pseudomonas than is ceftazidime. Yet we would prefer for initial therapy to use ceftazidime and then if they become resistant or fail ceftazidime, switch to cefepime.
Cefixime is Suprax. This is given orally as a tablet or suspension. It has increased Gram negative activity and may be useful in gonorrhea but be aware that this product has no coverage of anaerobes, Staph or Pseudomonas and doesn't have very good pneumococcal coverage either.
Ceftibuten is the next product we are going to talk about. This is Cedax. It is given once a day. It is good against H. flu and M. cat.
Cefpodoxime is Vantin. This particular product is just about as good as cefuroxime against common soft tissue infections.
Loracarbef is not truly a cephalosporin but it is darn close. Actually what it is is Ceclor that's had a sulfur taken out of the ring nucleus.
Imipenem cilastatin is the next product we will talk about. This is Primaxin. Hopefully you don't have to use this drug too often but when you do you may find it to be quite useful. Basically imipenem is metabolized by the kidney. Cilastatin cuts down on its metabolism. It's useful in Gram negative.
Meropenem is a newer product that is marketed as Merrem. It is like imipenem but it doesn't require the cilastatin.
I use the term monobactams here but there really is only one monobactam currently marketed. This is a single ring from the basic penicillin nucleus.
This is useful strictly in Gram negative aerobes. It has no effect against Gram positive or anaerobes. Aztreonam is the drug that is a monobactam. This may have some synergy with aminoglycosides versus Pseudomonas and may be useful in certain, for example, abdominal uses for prophylaxis or treatment. The problem here, though, is because it does not cover Gram positives, you may suppress the Gram negatives and get Gram positive super infection.
Switching away then from the beta-lactam drugs we now come to the macrolide antibiotics. Erythromycin is the one that we've had around forever.
More importantly these drugs can potentially cause hepatotoxicity. The drug that is most often associated with it is erythromycin estolate or Ilosone although erythromycin ethylsuccinate can sometimes cause it. Erythromycin ethylsuccinate is marketed as numerous products.
Erythromycin derivatives do also come IV but the IV is extremely irritating. It's almost impractical to use this drug parenterally. There is no IM erythromycin product available.
Dirithromycin was marketed a year or so ago as Dynabac. The advantage here is that it can be given once a day.
The other macrolide antibiotics include azithromycin or Zithromax and clarithromycin or Biaxin. We will first talk about azithromycin. This comes both orally and parenterally. It is used once a day. It does have greater Gram negative coverage than erythromycin. It can be useful especially in things like chlamydia and Mycoplasma where erythromycin can't be used. In many community acquired pneumonias and in weekly HIV MAC prophylaxis. Be aware that food does inhibit absorption of Zithromax and it probably should be prescribed between meals.
Clarithromycin or Biaxin probably got a jump on erythromycin in terms of its clinical acceptance. Compared with Zithromax or azithromycin, though, it's given twice a day versus once a day. It can be given with food, though, so you don't have that caution.
Tetracyclines similarly have been around forever. The uses are numerous. They can be useful in Gram negative bacillary infections, for Rickettsial infections. For Lyme disease, doxycycline is the drug of choice in that case for Gram positives resistant to penicillin and in acne.
Aminoglycoside antibiotics have several toxicities. Ototoxicity is related to high peak concentrations. We know that that is the case. Nephrotoxicity we think is probably related to high predose or trough concentrations although that has not been conclusively proven.
Gentamicin. Some hospitals have taken gentamicin all together off their formulary but it still is a good drug against Gram negative infections including Pseudomonas. It does have some Staph activity. In penicillin resistant Staph, sometimes you will see Infectious Disease recommending things like gentamicin be used.
Tobramycin is a little better than gentamicin but it is basically used for the same uses. In fact, its dosage and its blood levels are essentially the same as would be used for gentamicin. Both of these are cheap drugs. Gentamicin is less than $1 a vial. Tobramycin is usually several dollars for a vial so these are not expensive drugs to use. The cost with these drugs in the past has been the cost of drug therapy monitoring and also the cost of whatever toxicity ensues because of nephrotoxicity.
Netilmicin is used like gentamicin. It is better than tobramycin. Some hospitals use this. Others don't. We have not used netilmicin. Again, like mezlocillin we decided that there are only so many of these we want to have around.
Amikacin is the best anti-Pseudomonal aminoglycoside that we have. However, the dose is higher, the recommended blood levels are higher and we usually recommend restricting this to treatment failures with tobramycin or Pseudomonas that is resistant to tobramycin because this may very well cost $20-30 per gram. It is significantly more expensive than the others of this group.