Diseases information. Disorders. Treatment.

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.
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Neomycin is not given parenterally at all but it can sometimes be used topically. It’s an extremely nephro- and ototoxic drug. We do not suggest that high concentrations be used for extensive wound irrigation. I would add a caution here. Topical drugs are later and I don’t know that we will get a chance to talk about those. Neomycin is a fairly potent contact sensitizing agent. It’s commonly sold over the counter in antibiotic creams and ointments. Neosporin is a classic example. Neomycin polymyxin and, I believe, it’s bacitracin that’s contained in there. The bacitracin is like penicillin. It covers the Gram positives. Polymyxin and neomycin have essentially the same spectrum. There is no reason to need to use both of those drugs together. Neomycin increases the risk of contact allergic reactions.

The suggestion that I have is instead of recommending Neosporin, recommend the product that contains polymyxin and bacitracin which is Polysporin. It should be readily available. Unfortunately, it is a little more expensive than neosporin but it may save you some phone calls in the middle of the night or some hysterical people who have broken out in a rash.

Lastly, streptomycin is an aminoglycoside that may be used in combination therapy for tuberculosis occasionally and I’ve listed some information about the availability of that product.

Clindamycin is Cleocin. This is used primarily for anaerobic infections, principally of GI origin. It can also be used in the treatment of Staph. It’s used a lot in dental work, for example. Its problem is pseudomembranous colitis. This is C. difficile overgrowth. The treatment of choice here is either oral or IV metronidazole or Flagyl or oral vancomycin.

Now, in the past, the practice has been to use vancomycin first orally and then use metronidazole or Flagyl second. I would suggest the opposite. The current thinking is to use metronidazole or Flagyl as your drug of choice and go to vancomycin oral if you get a treatment failure. You probably will have a treatment failure about 10% of the time with either drug. However, a course of Flagyl is about $15 or $20. A course of vancomycin may very well be upwards to $200 or more and that’s the oral drug. It’s extremely expensive and it also tastes terrible.

Be aware too, and notice here, that IV Flagyl can be used for pseudomembranous colitis but IV vancomycin cannot. So if you have a patient that is NPO and develops pseudomembranous colitis, your drug of choice is IV Flagyl.

Vancomycin is a drug that we would use for methicillin resistant Staph aureus or for Staph epidermidis. It can be used orally but that is only for local effect on the gut. When it is used, it needs to be administered over at least an hour to cut down on the so-called “red neck” or “red man” syndrome. This is a syndrome of flushing and very often hypotension and dizziness that occurs when you run in vancomycin too quickly. You will find some people will not even tolerate an hour and you may have to go infuse it over two or three hours.

Used alone, this drug, frankly, is not particularly nephrotoxic although it got a wrap as being nephrotoxic when it was originally brought out some decades ago. However, when you start using other nephrotoxic drugs with it, watch out. If you are using vancomycin and you add gentamicin, watch out. Watch your renal function, watch your blood levels because you are probably going to have to change one or the other drug dosage to accommodate declining renal function. Usually it is reversible.
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Dirithromycin was marketed a year or so ago as Dynabac. The advantage here is that it can be given once a day. It has uses in adverse reactions like erythromycin but it is more expensive. So if once a day dosing is that advantageous, this product might be useful.

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. It may be useful in some skin and soft tissue infections and in some other infections like M. avium and for eradication of H. pylori combined with several other drugs.

Be aware, though, that the suspension of this product first of all should not be refrigerated. The common mental set that we have is that if you have a liquid antibiotic it should be kept in the refrigerator. There are two problems with that with Biaxin. It destabilizes the drug and it makes it taste worse. It tastes bad. It has a grainy consistency and despite attempts by the manufacturer, it still doesn’t taste very good. I would encourage you to get a sample of this stuff and taste it before you prescribe an awful lot of it.

Chloramphenicol is a drug that hopefully you don’t prescribe very much unless you’re practicing outside the United States. It is a drug that occasionally may be useful. For example, it’s an alternative drug for treating meningitis. In the rare case where you would have a cephalosporin treatment failure, it is a good drug in that even with oral dosage forms you can get fairly high levels in almost every tissue space. It does have a reasonably broad spectrum of activity and this is a drug that you might be able to use in situations where you don’t have venous access. For example, if you were doing missionary work or something like that in the back country and don’t have venous access readily available, here is one that you can give orally and get some pretty profound effects. Be aware though that it can cause an idiosyncratic aplastic anemia with the first dose. There is also dose related bone marrow suppression so it should not be used long term.

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. It is also used in combination treatment of ulcers and doxycycline can be an alternate choice for the treatment of syphilis. I would caution though that these drugs should be avoided in pregnancy or in children under eight years of age. There is a progressive accumulation in the teeth and discoloration of the teeth with repeated courses of this drug and it may cause growth inhibition.

Superinfection is a problem. Photosensitivity is a problem with some of these derivatives. Antacids and food may inhibit absorption although it is less of a problem with doxycycline or minocycline. Doxycycline is also the least nephrotoxic and has the fewest effects on teeth so probably it’s the product that would be most widely used. Certainly plain tetracycline is the cheapest of this group and I would comment that some of the brand name products may be significantly more expensive than the generics. While there is controversy in using generics in some areas, the controversy is minimal in using antibiotics because frankly most antibiotics are made by only one or two manufacturers in this country and are jobbed out to other places. So they are all coming from the same vats basically. There is not much concern in terms of generic inequivalence in terms of these products.

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. Neuromuscular blockade can occur, particularly when other neuromuscular blockers are on board, for example. In an immediate post op period you might want to be careful about giving gentamicin or tobramycin for fear that some of the neuromusculars that may still be around in the system may cause them to stop breathing. Similarly, in myasthenia this may cause increased weakening. They are all excreted unchanged in the urine. We would change the dose in renal impairment.

I want to comment here before I go on and talk about the specific drugs and about the use of these drugs once a day. This has become an increasing trend in the use of aminoglycosides. The reason that you can use aminoglycosides once a day is that these drugs are selectively taken up in white cells or leukocytes and are carried to the site of infection. So long after we have detectable blood levels of these drugs, the drugs are still active at the site of infection. This is a so-called postantibiotic effect. This is not true of the penicillins or the cephalosporins. Once it’s out of the bloodstream, you can assume that it’s largely been removed from the site of infection as well. But that is why we see somewhat larger doses being given once a day with these products.

Now, the thought here is, “Well, if we’re giving such a large dose, don’t we get a peak that exceeds the recommended peaks for ototoxicity?” The answer is yes, we probably do. However, our experience has shown that the ototoxicity problem is no greater with once a day than it was with carefully monitored multiple dose therapy during the day and, on the other hand, the incidence of nephrotoxicity is much less. You probably recognize that the major problem that you have if you have an adverse effect from most of the aminoglycosides is deteriorating kidney function, particularly in older patients.

So this may be a major advantage in the future in treating, particularly our older patients, with aminoglycosides. It also reduces the need to monitor blood levels as closely and, in fact, it may totally circumvent the need to do it or limit it to one or two levels.

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.

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 bacilli, anaerobes and Staph resistant to other antibiotics. Seizures can be a problem with this product and it is very expensive. It can induce resistance to all other penicillins and cephalosporins so if you’ve made a choice to put your patient on imipenem cilastatin or Primaxin, you DC any cephalosporins and any penicillins thereon because the patient will become resistant to them.
Meropenem is a newer product that is marketed as Merrem. It is like imipenem but it doesn’t require the cilastatin and it does have an increased incidence of seizure problems. It is used essentially the same as would be imipenem and it is a very expensive product. But in certain circumstances like severe resistant Gram negative infections, you may be backed into a corner and end up having to use something like this.
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. Rather than having two rings it has only one of them so there is some risk for cross allergenicity with penicillins and cephalosporins but it is reasonably low. Again, probably be cautious if they have a rash history and use it with extreme caution if there is an anaphylactoid history of penicillin or cephalosporin allergy.
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. It can be used as a substitute for penicillin. However, pneumococcal and streptococcal resistance is a growing problem with this particular drug. You no doubt are aware that it can be used for lots of other things like Campylobacter and mycoplasma. It is a drug that can be used for impetigo although about one-third of patients will get pretty severe GI upset when you are giving oral erythromycin. Many clinicians have switched to using Keflex or cephalexin for systemic treatment of widespread impetigo and that appears from the literature to be equally effective with erythromycin and probably a lot better tolerated. So for widespread impetigo that might be a reasonable choice.
Toxicities with erythromycin. GI upset is a major one. Remember it does stimulate motilin activity in the gut. It causes GI hypermotility. We use erythromycin in some patients to stimulate GI motility but it is that same stimulation that causes a lot of the GI upset. So giving it with food (some people will try it to cut down the GI upset) often does not have much of an effect because you get the same release of motilin. 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 but it probably is less likely to cause it and many clinicians suggest that you try E.E.S. If they get significant GI upset and you still want to stay with an erythromycin then try erythromycin estolate or Ilosone. Others will say, “Well, we’re going to use erythromycin estolate first in children because it is the best absorbed and best tolerated but will avoid using it in adults.” That’s probably a wise suggestion. The use of Ilosone should probably be avoid in adults because the risk of hepatotoxicity tends to increase with age.
Erythromycin derivatives do also come IV but the IV is extremely irritating. It’s almost impractical to use this drugarenterally. There is no IM erythromycin product available.

I would point out to you that the Physician’s Desk Reference does explain how to mix this product with a local anesthetic for injection to cut down on the IM pain. So if you have patients who are going to be doing this or if you are administering this in your office, you may want to refer to that if pain has been a problem with the product and it very often is. Be aware that some of the cephalosporins do have those instructions in the PDR now.

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. We’re using a fair amount of cefepime now in some of our older patients who have cystic fibrosis who have become resistant to ceftazidime. Its expense is similar to the IV third generation cephalosporins so it is no more expensive but they all are reasonably expensive.

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. Diarrhea is common with this product – about 1 in 3 patients will develop loose stools, very often at about the second day. Usually that will spontaneously subside by the fourth day. Dividing it into two doses a day may reduce the GI upset or the diarrhea which suggests that this is more chemical irritation than it is actually an overgrowth. Like all of the third generation agents it is somewhat expensive.

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 but it has poor pneumococcal coverage. So if you were considering using this for many common pediatric soft tissue infections, for otitis media, it may not be the best choice.

Cefpodoxime is Vantin. This particular product is just about as good as cefuroxime against common soft tissue infections. It is considered one of the cephalosporins of choice for treating acute otitis media. Again, like cefuroxime, it has a bitter aftertaste and may be problematic in kids over three. But under three, many kids will take this without any objections. Most otitis is seen in kids under three so it may very well be a reasonable drug to try if you want to use a cephalosporin for acute otitis.

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 and substituted with a carbon. It’s called a carbacephem but for all intensive purposes it behaves like a cephalosporin. In doing that, it’s gotten around the high incidence of serum sickness that we see with cefaclor and it may be a reasonable alternative drug to consider if you want to treat soft tissue infections with a cephalosporin type drug.
Antibiotics

I have included in your syllabus a list of syndromes that have renal disease in them and I’m going to highlight some of them here, not all of them, but highlight a few of them and show you some pictures. One or two of them you may see in the photo-quiz outside. I wonder how they got there? So we’ll just go through a few syndromes that will both help you clinically and might help you on the Boards.

Syndrome number one, which I don’t have a picture of, is branchio-otorenal syndrome, BOR syndrome. You get dysplasia; unilateral renal agenesis is the renal anomalies, and other findings are branchial fistulas and in particular, preauricular pits and hearing losses. Those are underlined because those are the associations that you want to make. If you see somebody with a little pit in front of their ear and hearing loss, look for renal problems. Potter’s syndrome: renal failure, oligohydramnios. Remember that oligohydramnios tends to be associated with pulmonary hypoplasia. Because there’s not enough amniotic fluid to expand the lungs. You also get small posterior-set ears, micrognathia, beaked nose, wide set eyes. Here is a picture of Potter’s facies. These babies are usually stillborn. Micrognathia, look at the ears. Look how low set they are. This is what the kidneys look like; cystic dysplasia. Another picture of Potter’s facies. Ears are low set, not so low set, beaked nose, micrognathia. Pulmonary hypoplasia is the association.

Prune-belly syndrome; the renal abnormalities, dilated urinary tract, dysplastic, aplastic, multicystic and hydronephrotic kidneys. Underline absence of abdominal musculature, cryptorchidism. That’s called the triad because there are three of them. Cryptorchidism, absence of abdominal musculature, renal abnormalities. The triad.

Alport’s syndrome has glomerular lesions, hematuria and decreased GFR. Underline anterior lenticonus, cataracts, sensorineural deafness. First, lets look at prune-belly syndrome. Here is the prune-belly. Lacks abdominal musculature. Testes are not palpable. Renal abnormalities. Prune-belly syndrome. By the way, what do you notice? Is this a boy or a girl? Boy. Prune-belly syndromes are almost always in boys. And we can talk at some point about why that is, but it’s almost always in boys. Write it down. There are only about five reported cases in girls. And if they ask you that, tell them you want your money back. Prune-belly syndrome, boy, cryptorchidism, absence of abdominal musculature, renal problems. Hearing. Sensorineural high tone hearing loss. Cataract. This is the only condition, the only condition, that gives you anterior lenticonus. Everything else is posterior lenticonus in ophthalmology. This plus the characteristic glomerular lesion is Alport’s syndrome. I’ll go back and remind you, Alport’s syndrome; anterior lenticonus, cataracts, glomerular lesions, hematuria, decreased GFR.

Okay, we have a few more to go. This is a sort of characteristic … you see this little bulls-eye when you do your funduscopic? This is pretty characteristic. This is the lenticonus because what’s happening is you are looking in and the conical-shaped lens is like this, so you are going in and making your cuts in and I’ve never seen it described anywhere, but I’ve seen it a zillion times. And this is what it looks like. It almost looks circumferential. Bulls-eye in nature.
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Tuberous sclerosis; you’ve heard about tuberous sclerosis. The renal abnormalities, renal angiomyolipoma, cystic kidneys and renal cell carcinoma. An important clinical link and association. Other features, underline adenoma sebaceae, underline CNS tubers, retinal phacoma and of course some of the skin, the shagreen patches, the White Mountain ash spots. We’ll talk about Drash syndrome, which is diffuse mesangial sclerosis, nephrotic syndrome in end-stage renal disease. The association here is Wilms tumor and male pseudohermaphroditism. So let’s first … looks like I have Drash syndrome up here first. Here’s mesangial sclerosis, diffuse mesangial sclerosis and ambiguous genitalia. If you get a patient, a case, with nephrotic syndrome and ambiguous genitalia like this, what study do you want to do? A renal ultrasound because you want to look for Wilms tumor. And that’s the link and association, a very important link and association here. This is named after Alan Drash, the first person. It’s also called Denny’s Drash syndrome, nephrotic syndrome in childhood, diffuse mesangial sclerosis, Wilms tumor, male pseudohermaphroditism. So these are males that have ambiguous genitalia. The females do not.

Finally, what is this? Recognizable? Anaphylactoid purpura, right. Remember, it is usually classically over the lower limbs and buttocks. It is alliterative, palpable purpura. Write down, as a link and association, palpable purpura. Because you can feel it. Little lumps. Palpable purpura on the lower extremities, crampy abdominal pain, arthralgia, peak at 4-5 years of age. It’s mediated by IgA immune complexes. Histology in the kidney, mesangial proliferation and/or epithelial crescents. The worse the biopsy the worse the prognosis. If you have nephrotic syndrome and nephritis, that is the worst outcome. We biopsy them and if we see crescents, that’s the issue.

Type II RTA is different than type I RTA. It’s not that you can’t excrete hydrogen ions. It’s that the kidneys leak bicarbonate. There is a low threshold in the blood for spilling bicarbonate in the urine. Normally you and I start to spill about 22 … or kids, actually, start to spill 22-24. In type II RTA they start to spill at 15-16, so they begin to lose their bicarbonate with relatively low serum bicarbonates. The clinical findings, again, hyperchloremia. I can’t stress enough, hyperchloremia - metabolic acidosis. With what in the potassium? Low potassiums, low or normal. That’s the way to recognize this. High chlorides, low or low normal potassium with an acidosis. The urine pH is greater than 5.5 when the bicarbonates, or the serum bicarbonates or the CO2 is normal. But it can decrease to less than 5.5 when you get very acidotic. Because then you get underneath the threshold and the body is able to reabsorb all the bicarbonate, and in this situation the distal tubule is working fine. It’s only the proximal tubule that is messed up and spilling all the bicarbonate. The K can be low or normal. Never high. This is seen usually with Fanconi’s syndrome, but it may be isolated.

So what is the Fanconi’s syndrome? The Fanconi’s syndrome is a disease of the proximal tubule, that has all of the listed criteria, or many of the listed criteria; proximal RTA, they have amino aciduria, glucosuria, phosphaturia and hypophosphatemia and hypokalemia. They have uricosuria. They spill uric acid and decreased plasma uric acid. They have rickets, growth retardation, polyuria, dehydration, and sometimes low molecular weight globulin proteinuria.

What are examples? This is the one they will ask you. Number one, cystinosis. Most frequent cause. Galactosemia, Wilson’s disease are others. Glycogen storage disease, Wilson’s disease, galactosemia, but cystinosis, nephropathic cystinosis, is the archetypal one. Here are some other selected causes. The full group is in your syllabus; heavy metal poisoning, cisplatin, biphosphamide, and then some other nephrologic ones, and glue-sniffing. Now if you have an isolate, those with Fanconi’s syndrome, I’ve listed some causes of isolated proximal RTA that are shown here. It is highly unlikely they will ask you any of these. And they are listed here: sporadic, genetic, carbonic anhydrase inhibition.

How do you evaluate type II RTA? Again, hyperchloremia, metabolic acidosis. But the anion gap is negative. Remember I told you that for distal RTA the anion gap was positive. This one is not a problem with making ammonia. This is a problem just with leaking lots of bicarb. So the anion gap is negative. The urine pH is greater than 5.5 when the plasma bicarb is what is normal to you and me, but when the plasma bicarb falls below the threshold, the urine pH is low.

I am going to … this is another way to evaluate it. Again, this is something that pediatric nephrologists do. It’s a fractional excretion but instead of a fractional excretion of sodium, it’s a fractional excretion of bicarbonate. And we can do this, and this allows us to do that. Again, they will not be asking you that.

A quick word about type IV RTA. There is no type III. There was a mistake. Somebody made a mistake and so they called… we called just type IV. Type IV is so-called low-renin hypo-renin hypoaldosteronism. This again is a non-anion gap acidosis but it has hyperkalemia. Urine pH can look like type II RTA with a pH less than 5.5. Highly unlikely that they will ask you about this. Very unusual. It’s caused by true aldosterone deficiency, conditions which decrease renin secretion and conditions where the kidney cannot respond to mineralocorticoids. This is a reiteration; the diagnostic workup of suspected RTA. We look first for he serum anion gap. We see whether it is elevated. The metabolic acidosis is elevated. If it is you work up for a gap acidosis. If there is a normal gap, you want to evaluate for RTA. Then I put in how you go with RTA’s, either type II or type I and type IV. I’m going to skip over this, and I’m going to skip over metabolic alkalosis except to remind you that the laboratory studies for metabolic alkalosis will show you that besides a blood pH that is high, there is a low chloride, a low potassium, increased bicarbonate or CO2 in the blood. The few physical signs; tetany. Underline tetany and convulsions. This is one of the things that can give you tetany and convulsions, metabolic alkalosis.