Antibiotic Toxicities

Antibiotic Toxicities by Janet Wong, M.D.

Aminoglycosides

..Agents include amikacin, gentamicin, kanamycin, tobramycin, streptomycin

. Adverse Effects: Ototoxicity and nephrotoxicity

. Ototoxicity is caused by destruction of cochlear hair cells in the organ of

Corti, resulting in high-frequency, irreversible hearing loss (amikacin)

. Vestibular dysfunction results from damage to vestibular hair cells

(gentamicin)

. Ototoxicity can occur early in treatment or after cessation of antibiotic

Aminoglycosides. These are used for gram-negative infections.

Most of them have some gram-positive activity, but you would never

use it for a gram-positive infection unless you're using it with other

drugs. The most common that we still use in kids is gentamicin,

also tobramycin, not much with kanamycin, even less with streptomycin.

Pulmonologist are using inhaled tobra for some CS patients.

The main type of toxicities that we see from aminoglycosides are

ototoxicity and nephrotoxicity.

There are two kinds of toxicity to the ear. The direct ototoxicity is

actually destruction of the cochlear hair cells and it produces a

high-frequency, irreversible hearing loss. This can occur early. It

can occur late. It can occur after you've gone through you're

therapy. It's most commonly seen with amikacin and kanamycin.

The vestibular dysfunction, which causes damage to the vestibular

hair cells is most commonly seen with gentamicin and streptomycin.

These can occur at any time during therapy.



Risk Factors for Ototoxicity

. Excessive dose

. Preexisting renal disease

. Excessive peak serum concentrations

. Concurrent use of loop diuretics or vancomycin

. Prior exposure to aminoglycosides or loud noise

. Old age

. Hereditary tendency for auditory or vestibular problems

Risk factors. The very young and the very old. Those may be some

people to worry about. Ototoxicity is usually directly related to the

peak level that you get. So, if you give 10 x the dose of

aminoglycoside, that's the kind of patient that I would worry about

their ears. If something could happen to their ears. Pre-existing

renal disease, obviously if you are not getting rid of it and you're

having high peaks for whatever reason you're not following them

and you don't check peaks and troughs, there is a data suggesting

that maybe we don't need to do that all the time anymore and

maybe it doesn't really suggest efficiency of therapy. Let's say your

patient had renal disease that you didn't pay attention, so you're

getting too much of it producing high peaks. If you use other agents

which also have Ototoxic potential in combination vancomycin and

other loop diuretics. Prior exposure to aminoglycosides or loud

sound. Again, the very young, the very old. If you have a hereditary

tendency for any ear problems you need to be concerned with

aminoglycosides and the exact amount of ototoxicity we always

think is rare in infants but they're hard to evaluate, especially the

premature infants. All premature infants should get their hearing

screened usually before they leave the premature nursery and I talk

about the micro-preemies. The 500 to 1000 gm infants, but if they

have hearing loss was it to the multiple courses of aminoglycosides

they got or the fact that they had intraventricular hemorrhage or a

brain abscess or was it the fact that they were exposed to multiple

loud noises. So the exact mechanism is not well known.



Nephrotoxicity

. Characterized by gradual onset of partial to complete, reversible, non-oliguric

renal failure

. Elevations of BUN and creatinine, hypertension, excessive urine protein

. Risk Factors for Nephrotoxicity

$$High dose

$ Prolonged course of therapy

$ Liver disease

$ Concurrent use of other nephrotoxic medications

$ Salt and water depletion

Nephrotoxicity, I think of the patients who had high troughs. They're

not clearing their aminoglycoside. They really need to be on it twice

a day which is clearly just enough to get their peaks down but still

maintains a very high level which is hurting their kidneys as time

goes by. What we see is a gradual onset which could complete the

kidney shut down. Usually we'll see elevations of BUN or creatine

or hypertension and excessive urine protein.

Risk for nephrotoxicity. Again, high doses or prolonged courses of

therapy, especially for hemoglobin. Liver disease, concurrent use

of other nephrotoxic medications, again, vancomycin, salt and

water deprivation.



Aminoglycoside Drug Interactions

$ Nephrotoxicity is associated with co-administration of cephalothin,

cyclosporine, amphotericin B, furosemide, ethacrynic acid, methoxyflurane,

indomethacin

$ Aminoglycosides potentiate the respiratory suppression of nondepolarizing

neuromuscular agents

$ Oral kanamycin and methotrexate increase methotrexate toxicity

With each kind of drug we are going to talk about adverse effects

and drug interactions. The interactions, mostly we worry about

increased nephrotoxicity. Again, increased nephrotoxicity when you

use aminoglycosides in combination with all other potential

nephrotoxicity drugs. Cyclosporine, amphotericin B, some of the

loop diuretics, indomethacin, most people don't realize that

cephalothin is one of those. One of the interesting things

aminoglycosides do or potentially potentiate is the respiratory

suppression of nondepolarizing neuromuscular agents, but if you

think about it too, in the old days before the cephalosporins when

we used ampicillin and gentamicin exclusively when the newborn

babies came in or you had the baby that presented with a little

constipation, some cranial nerve findings, just kind of being floppy,

you put him on amp and gent and all of a sudden boom they got a

lot worse, so it potentiates that neuromuscular blockade. I don't

think anybody's going to use a lot of oral kanamycin, but oral

kanamycin and methotrexate can increase methotrexate toxicity.



Tetracyclines

$ Short acting: Oxytetracycline, tetracycline

$ Intermediate acting: Demeclocycline

$ Long acting: Doxycycline, minocycline

The tetracyclines. There are short acting, intermediate acting, and

long acting. Tetracycline hydrochloride has such a bad reputation

with teeth staining and other side effects. Very short acting along

with Oxytetracycline, the long acting Doxycycline, actually it has the

best CNS penetration of any of the tetracyclines. This is really the

tetracycline of choice. Minocycline which dermatologists use for

bad acne.



Tetracyclines

$ Nausea and vomiting are$

Photosensitivity

most common $ Decreased prothrombin activity

$ Hepatotoxicity occurs following$ Overgrowth

of resistant

high doses, intravenous bacterial organisms

usage, or in pregnancy $ Esophageal ulcers

$ Nephrotoxicity in pre-$ Intravenous

administration: pain,

existing renal disease phlebitis, tissue injury if

$$Tetracycline-calciumextravasation

occurs

orthophosphate complex

inhibits bone growth

in neonates and produces

teeth staining

Nausea and vomiting are a very common scenario in almost any of

the oral antibiotics that we use. We can see in hepatotoxicity,

usually following high doses or especially in pregnant individuals

who have been prescribed. Nephrotoxicity in pre-existing renal

disease. What we all worry about is the tetracycline-calcium

orthophosphate complex that inhibits bone growth and produces

teeth staining. It is clear to us now that this was a big problem with

tetracycline hydrochloride, and Oxytetracycline is the least offensive

in this group. Doxycycline is next. It is quite clear that it's probably

the number of times that you got tetracycline and for the duration

that you got it also. Probably right around five or six times puts you

at risk for teeth staining. Doxycycline given for a short course, one

time or two times before you're eight or nine years of age, you're

probably not going to see this. Dentists can fix staining cosmetically.

Oversensitivity, a question of whether to give your patients who

are on long term prophylaxis sun block or not. I think most dermatologists

probably do when they use Minocycline because most

dermatologists use sun block. I tell my patients who are going to

Africa that use Doxycycline for malaria prophylaxis that they need

to be concerned about that and consider that. The esophageal

ulcers are also associated.



Tetracyclines Drug Interactions

$ Aluminum, calcium, magnesium, and iron can impair absorption

$ Effectiveness of oral contraceptives are reduced by tetracyclines

$ Enhanced renal toxicity with methoxyflurane or loop diuretics

$ Enhance anticoagulant effect with warfarin

$ Can cause digoxin toxicity

$ Reduced concentrations of tetracyclines with rifampin or anticonvulsants

Drug interactions, if you're on any of the aluminums, calcium, or

magnesium containing things to settle your stomach and you're

getting oral tetracyclines, that can interfere with your prescription.

There has been some data suggesting that the effectiveness of oral

contraceptives can be reduced by tetracyclines and that should

make you worry when you are given ten days of tetracycline for your

fifteen-year-old with PID, but it doesn't really make us change what

we do, just maybe counsel them that that is a possibility and they

need to be aware of that. There can be some increased renal

toxicity with loop diuretics. A lot of the drugs we're going to talk

about interfere with warfarin or Coumadin levels one way or the

other and this is not different. The reason why tetracyclines cause

digoxin toxicity is probably an interference with metabolism of the

digoxin when it is absorbed by the bacterial overgrowth caused by

tetracycline. Again, with rifampin or anticonvulsants you get some

reduced concentrations with tetracycline.



Chloramphenicol

..Bone marrow suppression

$ Dose, duration related and reversible (>7days). Associated with an

elevated serum iron, low reticulocyte count, and low hemoglobin

$ Severe, irreversible, idiosyncratic aplastic anemia (occurs anytime during

therapy or weeks after)

$ Mechanism: direct toxicity of nitroso-chloramphenicol on DNA

Chloramphenicol, not many of us are still using chloramphenicol,

probably because in most every instance there are alternative

drugs which are just as good or better. I think chloramphenicol is

still a very, very good drug. It's still going to have it's place. I still

think it's a very great anaerobic drug. It still has a role potentially in

brain abscesses. The most common kind that we see, when you're

on chloramphenicol for longer than about seven days, you start

developing some of these kind of symptoms. Classically you see

elevated serum iron, low reticulocyte count, and low hemoglobin.

Once you stop your chloramphenicol these correct by themselves,

pretty rapidly. So you can kind of watch them drift down.



Rare Adverse Effects-chloramphenicol

$ Hepatitis

$ Pseudomembranous colitis

$ Encephalopathy

$ Hemolytic anemia in patients with G6PD deficiency

$ Ototoxicity from topical preparations

The severe, irreversible, idiosyncratic aplastic anemia can occur

anytime you start chloramphenicol. It's classically described and

seen mostly with oral chloramphenicol, but it could be seen with IV

chloramphenicol as well. Again, the mechanism is thought to be

the direct toxicity of the nitrosochloramphenicol on the DNA. The

amount that we saw here is anywhere from 1 in 40,000 to 1 in

100,000 courses of chloramphenicol. So it's a very uncommon side

effect, but it can occur anytime and this is a life-threatening

complication. Other kinds of less common adverse effects that you

might see or things you should probably think about, the liver,

pseudomembranous colitis, encephalopathy, hemolytic anemia in

patients with G6PD, and ototoxicity which is classically described

with topical preparations. Not much with IV or p.o. preparations.



Chloramphenicol Drug Interactions

$ Phenytoin, cyclophosphamide, and warfarin can have elevated levels

because of inhibition of hepatic microsomal enzymes by chloramphenicol

$ Phenobarbital and rifampin can both induce hepatic microsomal enzymes,

reducing chloramphenicol levels

$ Co-administration of chloramphenicol and cimetidine may increase potential

for aplastic anemia

$ Concurrent use of acetaminophen may increase chloramphenicol metabolism

Drug interactions, again commonly given with phenytoin,

cyclophosphamide, or warfarin. If you have elevated levels of these

because of chloramphenicol with an inhibition to microsomal

hepatic enzymes. Phenobarbital and rifampin, would stimulate the

liver so you clear the chloramphenicol a lot faster. You could also

have increased levels of chloramphenicol in the face of liver failure

or shock. Most of the bad things, or life-threatening things that we

see with chloramphenicol are associated with peak levels above

twenty-five, usually greater than thirty, some with thirty to forty,

that's where we got into trouble with that. There have been some

problems at least with co-administration of chloramphenicol and

cimetidine and increased risk for aplastic anemia. Concurrent use

of acetaminophen has been reported to increase chloramphenicol

metabolism.



Chloramphenicol Toxicity

$ Can cause direct myocardial metabolic derangement (grey baby syndrome),

with diminished tissue oxygenation and shock

$ Abdominal distention, emesis, respiratory failure, cyanosis, hypotension or

shock; metabolic acidosis can occur beyond the neonatal period

$ Usually associated with levels >30-40 mg/L

The mechanisms of toxicity that we saw for grey baby syndrome

was a direct myocardial metabolic derangement at the tissue level

with decreased tissue oxygenation and shock. Other things that you

can see are abdominal distention, emesis, respiratory failure,

hypotension, metabolic acidosis, which can occur at any time, even

beyond the neonatal period. Again, usually associated with high

levels.



Rifamycins

$ Rifampin, rifabutin

$ Contraindicated in pregnancy

$ Causes orange discoloration of urine, tears and all biologic secretions in 80%

of patients

$ Rapid and potent inducers of CYP3A4, the most abundant human

cytochrome P450, found predominately in the liver and small intestine

Rifamycins. The main ones that we have now which are available

for us are rifampin and rifabutin. Most of the rifabutin is used for

MAI or MIC prophylaxis in pediatric HIV patients. Rifampin we're

still using for prophylaxis for meningococcal. We use it on occasion

in combination with some of our Staphylococcal medications and

of course in tuberculosis. It is contraindicated in pregnancy, not in

breast-feeding. There are four absolute contraindications to breast-

feeding antibiotics as you can get. The complete absolute contraindications

to breast-feeding among antibiotics some are

metronidazole, sulfonamides, and chloramphenicol. The others you

can work around or they say are not absolute contraindications.

However, in pregnancy it is contraindicated. Rifampin causes red

colored urine. It will stain and can destroy your contact lenses as

well. Rapid and potent inducers of CYP3A4, the most abundant

human cytochrome P450 are found predominately in the liver and

small intestine.

The adverse reactions you can see with rifampin really are multiple

shock-like syndrome, acute hemolytic anemia, especially in postpartum

women, African-American women, Hispanic women, and

teenagers etc. Hepatic toxicity is enhanced by chronic liver disease

or concurrent administration of isoniazid or pyrazinamide. Most

individuals say if you're using it in combination with these you stay

with 10 mg per kg per day. You can see liver dysfunction as well.



Reduced Serum Concentrations

$ Oral anticoagulants $ Glucocorticoids

(warfarin) (prednisone)

$ Benzodiazepines $ Azole antifungals

(diazepam) (fluconazole)

$$Cardioactive drugs $$Immunosuppressives

(digoxin) (cyclosporine)

$ Contraceptive steroids $ Anticonvulsants

(norethindrone) (phenytoin)

$ Hypoglycemic agents $ Antimycobacterials

Rifabutin, basically can cause the same thing as rifampin. Anemia,

leukopenia, thrombocytopenia, arthralgia, myalgia, fever have all

been reported.

Drug interactions. With erythromycins, what they do is they will

reduce the serum concentration, increase the plasma clearance,

and decrease the elimination half-life of a bunch of drugs so you

end up with low serum concentration. You have a lot of drug-drug

interactions that you need to worry about if you are using erythromycins.

Mostly what you are going to do is lower the serum

concentrations of all these.



Metronidazole

$ Neurotoxicity (seizures, headaches, encephalopathy) may be caused by

large doses

$ Peripheral neuropathy may result from large doses or prolonged courses

$ Gastrointestinal upset is most common

$ Metallic taste (oral or parenteral administration)

$ Rare adverse reactions: Maculopapular rash, chest pain, palpitations,

discoloration of the urine, gynecomastia, acute pancreatitis

Metronidazole, I think we are using it more and more now. If you

look at aerobic susceptibilities now, in most studies clindamycin is

not really the gold-standard drug anymore that we thought it was.

About 25% of Bacteroides fragilis or fragilis group is resistant to

clindamycin now. I think metronidazole has really stepped out as

the drug of choice when you have a patient who has had an intra-

abdominal catastrophe. So we're using it a little more in the

pediatric patients. Only about 2 to 3% of Bacteroides fragilis are

resistant to that particular drug. It can however, give you

neurotoxicity with seizures, headaches, encephalopathy, most of

these are in patients with chronic neurological problems. Now, we

certainly use it in brain abscesses as one of our gold-standard

drugs for brain abscesses. We don't really see an increased

amount of seizure discharges that we think, at least are from

metronidazole. But in most cases it's going to be the chronic

neurological disorders. It can cause a peripheral neuropathy,

usually if you've been on it for a few months or you're using very

high doses. Especially a lot in the young, gastrointestinal upset.

This is a very common scenario. It does leave a metallic taste in

your mouth or can. You have some rare adverse side effects,

rashes, pain, discoloration of the urine. It can also cause acute

pancreatitis and gynecomastia. This is a common form of what you

will see with gastrointestinal upset too, acute pancreatitis. In a

child, regardless of his age, if he has an abdominal catastrophe,

I'm going to use metronidazole. There are some carcinogenic

effects in lab animals but we've never seen that in people and

mutagenic effects in utero also.



Metronidazole Drug Interactions

$ Reduce plasma clearance of warfarin

$ Phenobarbital and corticosteroids can reduce serum concentrations of

metronidazole

$ Cimetidine can inhibit hepatic metabolism and increase serum concentrations

of metronidazole

$ Disulfiram-like reaction may occur with alcohol

$ Impaired hepatic clearance of phenytoin, resulting in increase serum levels

A lot of things are going to refer to warfarin whether it increases it's

effect or decreases it's effect. This is one that will reduce the

plasma clearance or some people will get an increased effect of

that. Phenobarbital and corticosteroids will reduce the serum

concentrations of metronidazole. Cimetidine may inhibit hepatic

metabolism and increase serum concentrations of metronidazole.

Remember if you have a patient taking Flagyl you may not want

them to drink, because they may end up vomiting and their

stomach may not like that too much and it's a real recognized kind

of side effect. Metronidazole is contraindicated in pregnancy or in

breast-feeding. For infants, if you have a patient with Trichomonas

you may get a 2 gm dose of metronidazole. All you need to do is

take it for a couple of days and then it's okay to take it. It's really the

patient who is taking metronidazole chronically everyday that you

need to worry about.



Sulfonamides and Trimethoprim

. Sulfonamides include sulfadiazine, sulfamethoxazole, sulfasalazine,

sulfisoxazole

. Erythema multiforme major (Stevens-Johnson syndrome) and toxic

epidermal necrolysis are the most severe hypersensitivity reactions

. Severe cytotoxic reactions may have an immuno-metabolic basis

. Patients with HIV have a two- to seven fold greater incidence of hypersensitivity

Most of what we talked about with trimethoprim from sulfa is

related to the sulfa content. The sulfa components that we use

most commonly are sulfadiazine, sulfamethoxazole, sulfasalazine,

and sulfisoxazole. Again, skin manifestations are the most common

side effects that you will see with sulfonamides. Erythema multiform

major, which we call Stevens-Johnson syndrome, and toxic

epidermal necrolysis are the most severe hypersensitivity reactions.

Patients with HIV have a two to seven fold increase of

hypersensitivity to the sulfonamides or to a sulfonamide combined

with trimethoprim. So again, these patients have a lot of problems

with these agents. The older you are the worse you do.



Sulfonamides

. Rashes are the most common problem

. Acute IgE-mediated hypersensitivity reactions and drug-induced lupus

erythematosus reactions

. Self-resolving granulocytopenia, megaloblastic anemia, thrombocytopenia

have been described

. Renal failure with crystalluria and reversible hepatocellular dysfunction and

jaundice have been described with sulfamethoxazole

. Aseptic meningitis

Rashes are very common. You can get an acute IgE-mediated

hypersensitivity, a serum-like sickness syndrome. You can also get

a drug-induced lupus erythematosus reaction. You can get

granulocytopenia. We've had a couple of patients on chronic

trimethoprim sulfate who have developed granulocytopenia and

that's self limited. If you stop that it doesn't come back and it's

usually the sulfa compound there that we see. Renal failure with

crystalluria and reversible hepatocellular dysfunction with jaundice

has been described with sulfamethoxazole. Mostly in combination

with trimethoprim. There are a few patients who have gotten

aseptic meningitis.



Sulfonamide Drug Interactions

. Inhibits metabolism of warfarin, phenytoin, methotrexate, oral hypoglycemic

agents leading to toxicity of these agents by competing for albumin binding

sites

. Associated with increased nephrotoxicity of cyclosporine despite reduction

in cyclosporine levels

Warfarin inhibits the metabolism of warfarin, phenytoin,

methotrexate, oral hypoglycemic agents. You get increased

anticoagulant effect. You can get depression because your Dilantin

levels go way high and you may get hypoglycemic because your

oral hypoglycemic agents work a little bit better. So you need to be

concerned about that. They do that by competing for binding sites

on human albumin. Potentially you will also see elevation of free

bilirubin in these patients as well. There is an associated risk that

has been described as an increased nephrotoxicity of cyclosporine

in combination with cephalomide. So that would be something to

be concerned about in a transplant patient potentially.



Trimethoprim

. Trimethoprim-sulfamethoxazole

. Gastrointestinal upset and sensitivity skin reactions occur in 3.5% of patients

. Fatal hypersensitivity reactions of the skin (eg, erythema multiforme major)

may occur

. Contraindicated in pregnancy because of possible teratogenic effects

Trimethoprim by itself we don't really use very much. Most all we're

going to see is in combination with sulfamethoxazole, so in a lot of

the problems we see with this it's hard to break off whether it's the

trimethoprim that does it or the sulfamethoxazole that does it.

Gastrointestinal upset and again, skin rashes occur in about 3 to

5% of the patients. It's the most common thing that we see. The

fatal hypersensitivity reactions like the skin rashes can certainly

occur, but again it's hard to differentiate which component you see

here. It's contraindicated in pregnancy due to possible teratogenic

effects.



Quinolones

. Non-fluorinated agents: nalidixic acid

. Fluorinated: ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, ofloxacin,

levofloxacin, sparfloxacin

. Diarrhea and skin rashes occur in 4-8% of patients

. Neurologic effects: headaches, dizziness, tremors, seizures, confusion can

be enhanced by non-steroidal anti-inflammatory drugs

The quinolones are not used much for kids, especially kids that

have problems with puberty. The FDA says we can't use them in

kids less than eighteen. I personally use them sometimes if the

kids have gone through their growth spurt. The reason for that is

because of the studies with beagle puppies who got the quinolones

whose bones didn't seem to grow very well and the cartilage didn't

seem to develop. It's pretty much species specific as far as we

know. There is very good data in cystic patients and patients

outside the United States that show that with these quinolones

human patients do just fine. Obviously, if you have a four-year-old

whose quadriplegic with microcephaly and a G-tube and has

chronic UTIs and you keep them in the hospital forever and you

sent him home on Cipro, their parents probably don't really care if

there's a theoretical risk they may not grow two inches taller. So I

would use it in certain situations. They are actually very well

absorbed and very well tolerated. My cut off is if they've gone

through puberty or seem to have gone through puberty. These

drugs will probably never be first line drugs for kids, simply

because at least most of these have very poor pneumococcal

activities. So some of the newer ones are getting better with

pneumococcus, but pneumococcus is such a big deal for us that

it will probably never be a first line for a lot of things we see. They

are very well tolerated; diarrhea and skin rashes are sometimes

seen. You can have neurologic effects; very bad headaches, so you

certainly can see neurologic manifestations in rare occasions.



Quinolones

$ Rare adverse reactions: arthralgia, crystalluria, acute renal failure, antibiotic

associated colitis, serum sickness-like reactions, eosinophilia, leukopenia,

thrombocytopenia

$ Not approved for children <18 years of age

$ Interference with cartilage growth in beagle puppies

$ Human studies in cystic fibrosis patients and other infants have failed to

show these problems

Rare adverse reactions, arthralgia, crystalluria, acute renal failure,

serum sickness like syndromes, eosinophilia. Eosinophilia will be

kind of common on anybody that is having drug reactions. Again

human studies in the United States and across the world really

haven't shown this to be a real problem in kids at this time.



Quinolone Drug Interactions

. Decreased quinolone availability (eg, azlocillin, cimetidine, di- and trivalent

cations [magnesium, aluminum], ranitidine, sucralfate)

. Reduction of metabolism of other medications by inhibiting cytochrome

P450, leading to toxic levels (eg, diazepam, phenytoin, cyclosporine,

warfarin, metoprolol)

Decreased quinoline availability if you take some of these other

drugs with them and you get reduction of metabolism of other

medications by inhibiting the cytochrome P450, taking toxic levels

of a lot of drugs.



Penicillins

. Natural penicillins: penicillin G, procaine penicillin G, penicillin V, benzathine

penicillin

. Penicillinase-resistant penicillins: cloxacillin, dicloxacillin, methicillin, nafcillin,

oxacillin

. Aminopenicillins: amoxicillin, amoxicillin-clavulanate, ampicillin, ampicillinsulbactam

. Extended spectrum penicillins: carbenicillin, ticarcillin, ticarcillin-clavulanate,

mezlocillin, piperacillin, piperacillin-tazobactam

Penicillins. If you have meningococcal meningitis or

meningococcemia, if you give their entire course with a third

generation cephalosporin you don't need to give them rifampin

prophylaxis. Still in this country penicillin is the drug of choice. A lot

of the penicillin side effects and adverse effects that we see are

going to be consistent. Natural penicillins are penicillin G, procaine

penicillin, benzathine penicillin. Penicillinase-resistant penicillins;

those things that are fairly specific for Staph and Strep, not much

activity against anything else. Aminopenicillins; amoxicillin,

ampicillin, ampicillin-sulbactam, which you use for otitis etc.

Extended spectrum penicillins, extended to include difficult to treat

gram-negatives, to include Pseudomonas and their combinations

of Timentin, which is ticarcillin and clavulanate, and Zosyn, which

is piperacillin and tazobactam. Remember that the Beta-lactamase

inhibitors here actually might have some antibacterial activity but

it's best to think of them as having none. They just really inhibit the

Beta-lactamase production, which then takes those things that are

resistant based upon Beta-lactamase and makes them susceptible

again. The majority of Pseudomonas resistance is not based upon

Beta-lactamase.



Natural Penicillins

. Nonfatal anaphylaxis in (1/1000 adult exposures)

. Fatal anaphylaxis is rare

. Other hypersensitivity reactions include serum sickness, cutaneous rashes,

contact dermatitis

. Allergic reactions are the prominent with procaine penicillin

. Other reactions: hemolytic anemia, interstitial nephritis, seizures;

hyperkalemia is associated with high doses or prolonged exposure

Natural penicillins; the nonfatal anaphylaxis supposedly happens

one in every thousand exposures. Fatal anaphylaxis is rare. Other

hypersensitivity reactions are serum-like sickness, cutaneous

rashes, and contact dermatitis. With natural penicillin a lot of the

allergic problems we see tend to be with procaine penicillin

specifically and 80 to 90% of those are specific to procaine

penicillin. What about the procaine? It's really unclear what makes

you more susceptible to that. Other less common reactions are

hemolytic anemia; interstitial nephritis; seizures; this really has to

be with high dose penicillin, if you are approaching 15 to

20,000,000 units a day, yes you may have seizures or if you are

using 10,000,000 units a day of penicillin and 500,000,000 mg per

kilo per day of third generation cephalosporin, you may have

enough Beta-lactamase there to cause you a seizure. Overall

penicillin is fairly safe. Penicillin is pretty specific for Staph and

Strep. If you have patients that you treat as outpatients we usually

file weekly CBCs, watching their neutrophils, because we know that

we can watch them break down and this is pretty much true for any

Beta-lactam antibiotic. Remember there are some other antibiotics

that should have Beta-lactam ring. Cephalosporins do.



Penicillinase-resistant Penicillins

..Dose and duration related neutropenia, especially with nafcillin

. Interstitial nephritis is most commonly associated with methicillin

. Dicloxacillin and nafcillin can increase metabolism of warfarin

A lot of these like to go through the liver and you can see some

problems with the liver, especially cloxacillin. The kind of classic

form in adults is why methicillin is not used much in adults is

interstitial nephritis. Nafcillin competes with your bilirubin binding

or will do that in the face of a immature liver. So the first month of

life of the newborn or a sick neonate you maybe want to use

something that goes through the kidney. We didn't see any

problems with interstitial nephritis with nafcillin, but the older you

get the more problems you have nafcillin. Methicillin likes the

kidney, the other kinds like the liver.



Aminopenicillins

. Hypersensitivity reactions are similar to those occurring with natural

penicillins

. Amoxicillin and ampicillin are associated with a maculopapular rash that is

lymphocyte mediated and which more frequently with intercurrent vital illness

(eg, EBV)

. High incidence of diarrhea (5-8%)

. C. difficile associated diarrhea occurs at rates of less than with clindamycin

. Seizures with high dose ampicillin

. Similar problems occur with combination drugs

. Gastrointestinal effects of amoxicillin-clavulanate correlate with the dose of

clavulanate (new bid preparation causes less diarrhea)

Aminopenicillins; hypersensitivity just like other penicillins. The

most common thing we see is rash. So is it a drug rash? Is it a

hypersensitivity to penicillin? Or is it the fact that really he didn't

have otitis media and he may have Epstein-Barr virus and you just

potentiated this rash and that's what makes it so difficult to call a

true hypersensitivity reaction or allergic reaction to some of these

penicillins just based upon a rash. I usually ask for other things,

wheezing, hives, family history, etc. You do get a high incidence of

diarrhea, especially with the old preparation of amoxicillinclavulanate,

since they've lowered the amount of clavulanate, this

has certainly gone away or at least it has in the patients I've seen.

That seems to be the most common reason for patients having so

much diarrhea. If you look at cases of antibiotic associated colitis,

you will see more attributable now to ampicillin and the

cephalosporins than you will the clindamycin, but you have to look

at their case rates, because we are using more ampicillin and

cephalosporins now than we are clindamycin. If you do it,

clindamycin is still more common.



Extended-spectrum Penicillins

. Anaphylaxis and hypersensitivity reactions are similar to other penicillins

. Thrombophlebitis may occur, especially with mezlocillin and piperacillin

. Congestive heart failure may be precipitated by carbenicillin because of high

sodium content

. Adverse effects also include hypokalemia, eosinophilia, neutropenia,

elevated serum transaminases, platelet dysfunction, prolonged bleeding

times

. Pseudomembranous colitis

Extended-spectrum penicillins; anaphylaxis and hypersensitivity

reactions just like the other penicillins. Thrombophlebitis, especially

with piperacillin, I don't use any mezlocillin, so especially

piperacillin. I don't use much carbenicillin. It's still the one of these

that you can actually still give orally. If they can take a big horse-pill

you can still give them carbenicillin. Congestive heart failure

precipitated by carbenicillin due to a high sodium content,

piperacillin and ticarcillin will give you platelet dysfunction. If you

have a patient who already has thrombocytopenia, you may want to

stay away from some of these extended-spectrum penicillins

because if you have small numbers already and you make them

slick they may not work as well. So you may have some bleeding

problems. There is a risk for pseudomembranous colitis just like all

the others.



Extended-spectrum Penicillins-drug Interactions

..Decrease anticoagulant effect of warfarin

. Piperacillin can potentiate the action of nondepolarizing neuromuscular

blocking agents

. Carbenicillin, ticarcillin, mezlocillin, can inactivate aminoglycosides if used at

high doses for prolonged periods

. Azlocillin and mezlocillin can increase cefotaxime toxicity in patients with

renal impairment secondary to decreased drug excretion

Drug interactions. Makes warfarin not work so well. Piperacillin

along with aminoglycosides can potentiate that neuromuscular

blockade. In a few patients it's been described. Theoretically, there

is some data suggesting ticarcillin in combination with

aminoglycosides may inactivate that aminoglycoside if you use high

doses of ticarcillin for prolonged periods. So keep that in mind if

you are using piperacillin or ticarcillin in combination with

gentamicin and tobramycin and your patient is kind of doing well

and then stops doing well for some reason, if you're using that

combination. Cefotaxime is a pretty safe drug as far as antibiotics

go. Azlocillin and mezlocillin can increase cefotaxime toxicity in

patients with renal impairment secondary to decrease drug

excretion. You're not going to use much azlocillin and mezlocillin

in combination with cefotaxime.



Cephalosporins and Related Drugs

Cephalosporins

. Anaphylaxis

. Hypersensitivity reactions may be compound specific (eg, cefaclor)

. Hypersensitivity reactions include interstitial nephritis, autoimmune

thrombocytopenia, pulmonary eosinophilia, serum sickness-like reaction, drug

fever

. Seizures and nephrotoxicity are associated with high doses and poor renal

function

. Gastrointestinal upset is most common with oral agents

. Ceftriaxone has been associated with reversible biliary pseudolithiasis and

rapidly fatal immune-mediated hemocytic anemia

Cephalosporins. First generations have very good gram-positive

coverage, not much gram-negative coverage. Some, but not a lot.

E. coli, fairly good in some instances. Think of it as a gram-

positive, Staph, Strep coverage. Cephalosporins do not kill

enterococcus. Good gram-positive, except for enterococcus.

Second generation; gram-positive coverage, a little bit less than the

first generation, but still fairly good and better gram-negative

coverage. Third generation; less gram-positive coverage, still for

the most part covers pneumococcus very, very well. Not much

Staph aureus but Pseudomonas coverage in some instances. The

new fourth generation cephalosporins. Cefepime or Maxipime is

the one that's coming out that we are using some in kids now. It

supposedly has the coverage of the first generation as far as Staph

and Strep goes and a gram-negative coverage of a third generation

to include Pseudomonas. So fourth generation cephalosporin. CSF

penetration is good. I have not seen off the top of my head meningitis

at this time, but that doesn't mean it's not out there, I just can't

recall it at this time. The second generation cephalosporin, some

of these at the bottom, Cefoxitin, Cefotetan, Loracarbef, actually are

not technically cephalosporins.



Cephalosporin Drug Interactions

..Those containing the tetrazolethiomethyl side chain (cefamandole,

cefmetazole, cefoperazone, cefotetan, moxalactam) have warfarin-like

activity, antiplatelet effect, and cause disulfiram-like reactions

. Risk of nephrotoxicity is increased with agents such as aminoglycosides,

colistin, polymyxin B, vancomycin

. Cefpodoxime-proxetil absorption is reduced by H2 antagonist, famotidine

Side effects. The rate of true anaphylaxis if you are penicillin

allergic is probably somewhere around 10 to 20% would be true of

cephalosporin allergic. Some hypersensitivity reactions are

compound specific. For instance with Cefaclor. We've noticed for

a long time that with Cefaclor that we've seen an increase of serum

like sickness syndromes or Stevens-Johnson syndrome with

Cefaclor. We weren't sure if it was because of the amount of

Cefaclor we were using or it really wasn't linked to Cefaclor itself.

There are some studies out there indicating that actually it may be

a genetic predisposition. Some people may be more predisposed

to have problems with this class of drug of second generation

cephalosporin than the other classes. So if you see a hypersensitive

reaction it may actually be compound specific. Just because

you get Stevens-Johnson with Cefaclor doesn't mean you can't use

Keflex. Now be very careful, but there is some data suggesting that

Cefprozil, also second generation cephalosporin, we are starting

to see some cases that is the same kind of thing. So it may be

class specific to this second generation cephalosporin class.

Anything the penicillins can do, the cephalosporins can do, with

interstitial nephritis etc. Seizures and nephrotoxicity with high

doses. Gastrointestinal upset. Ceftriaxone, we'll start with

ceftriaxone for a minute. Two things with Ceftriaxone; remember for

newborns ampicillin-gentamicin or ampicillin-cefotaxime are

acceptable combinations in the first three months of life. You don't

really want to use ampicillin-ceftriaxone in the first weeks of life.

Really because it competes with bilirubin binding sites and you may

see some problems with hyperbilirubinemia at that time. You can

still use ceftriaxone for infants. If your baby is born to a mother that

has GC that has not been treated give the baby one dose of

ceftriaxone and you're not going to interfere with anything based

upon one dose. But for prolonged therapy in the newborn age

group, cefotaxime is a better choice than ceftriaxone. In most

patients who receive ceftriaxone for any amount of time you will see

a reversible biliary pseudolithiasis or you get sludge in the gallbladder.

Most all patients are asymptomatic with this. The only way it's

really been found is by doing studies with ultrasound. Looking at

patients on ceftriaxone. For the most part it's clinically not a big

problem and that will go away on it's own. More importantly

however, there have been three or four cases now reported of

rapidly fatal immune-mediated hemolytic anemia with ceftriaxone.

These are patients who hemolyze and die within twenty minutes of

receiving ceftriaxone. These have been patients who have received

ceftriaxone in the past...they got it IV. These are all patients who

have seen ceftriaxone before and at least one of them, I believe,

has had antibodies to ceftriaxone that were measurable. So this is

a real potential risk. It probably is going to occur very uncommonly,

but it's something that you need to be a little bit aware about. It's

kids who have seen ceftriaxone before.

I mentioned to you that Cefotetan, cefoxitin, or meropenem really

are not cephalosporins, they actually are cephamycins. We kind of

lump them together with second generation cephalosporins. That’s



Cephamycins

. Cefmetazole, cefotetan, cefoxitin

. Anaphylaxis and hypersensitivity reactions: skin rashes, fever, urticaria,

angioedema

. Laboratory abnormalities: eosinophilia, leukopenia, thrombocytopenia,

increased prothrombin time, positive Coombs test, elevated serum

transaminases and alkaline phosphatase

. Disulfiram-like reactions with alcohol

why these drugs actually work for anaerobes where the others

really don’t. Anything that cephalosporins can do, these can do. If

you have a cephalosporin problem, you can have a problem with

these as well. This does, however, give you a metronidazole-like

reaction with alcohol.

Loracarbef is actually a carbacephem. It is a version of cefaclor.

They’ve taken it and modulated it and made it a little bit different

compound with is. It really has fewer side effects than cefaclor and

we haven’t seen acute hypersensitivity reaction with this that we’ve

seen with cefaclor. It is the best-tasting drugs in all those kind of

comparisons. Loracarbef is number one, cefaclor is number two.

It is expensive. Again, same kind of drug reactions that we see with

the other cephalosporins.



Carbacephems

. Loracarbef

. Fewer side effects than parent compound (cefaclor)

. No cross over with serum sickness like reactions with cefaclor

. Adverse effects and drug interactions are the same as for cephalosporin class

. Potential cross sensitivity to Ig-E mediated anaphylaxis with penicillins and

cephalosporins

Carbapenems: imipenem-cilastatin, trimaxim or meropenem,

which is Merum. Meropenem has come out in the last six months

and really does have indications for meningitis. There is a lot of

good data in kids using this. Either a dose of 20 mg per kg or a

dose every day for non-CNS disease or 40 mg per kg for CNS

disease. We had some problems with patients having seizures,

especially if they had a seizurogenic-type illnesses like meningitis,

and it seemed to be potentiated by the use of this compound.

Meropenem certainly has less seizures than Primaxin does. They’ll

usually say we don’t see seizures like this does, and that’s why you

should use it in meningitis. Actually they do see seizures with it, but

it’s no greater rate than you see seizures with cefotaxime or

anything else. I really think that this class of drugs has excellent

anaerobic coverage. I think you have very good activity, anaerobic

activity with this class of drugs.



Carbapenems

. Carbapenems include imipenem-cilastatin, meropenem

. Neurologic reactions (seizures) are related to high dose, CNS disease, poor

renal function, and co-administration of cyclosporin and theophylline

. Diarrhea occurs in 3% of patients

. Hypersensitivity reactions and nausea are common and can be reduced with

longer infusion times

. All adverse effects are less common with meropenem

. Potential cross-sensitivity with Ig-E medicated anaphylaxis with penicillins or

cephalosporins

Diarrhea in 3% of the patients. GI upset again, seen pretty heavily

with Primaxin when you use the bigger doses. You can get

hypersensitivity reactions and nausea again, which can be reduced

with longer infusion times. Remember you still have the betalactamase

ring here, so anything that you can see with the others

you can see with these. All the bad adverse side effects that we

saw with the first carbapenem, this one, or to a lesser degree with

meropenem. Again there is this potential cross-sensitivity based on

IgE medicated and mediated anaphylaxis with penicillin, based on

the sharing of the ring.



Monobactams

$ Monobactams: aztreonam

$ Elevated serum transaminases, eosinophilia, thrombocytosis, prolonged

prothrombin time, neutropenia

$ Rash, phlebitis, diarrhea, alteration in taste, abdominal pain, increased tearing

$ Potential cross-sensitivity with Ig-E medicated anaphylaxis with penicillins or

cephalosporins

Monobactams: monobactams again still has part of that betalactamase

so you can still see some cross-sensitivity and IgE

mediated anaphylaxis that we talked about. The one drug here is

aztreonam. Think of aztreonam as an aminoglycoside without the

necessity for levels. Mostly gram negative coverage, Pseudomonas

etc. You can see some liver toxicity or some eosinophilia with this.

Long bleeding times. Rash, phlebitis, diarrhea, alterations in taste,

all kind of common things.



Glycopeptides

$ Glycopeptide: vancomycin

$ Ototoxicity (high frequency hearing loss) occurs more frequently in patients

with decreased renal function and co-administration of aminoglycosides

(levels > 40 mg/dl)

$ Red neck syndrome is related to histamine release with rapid infusion ( <3045

minutes)

$ Hypotension can be related to histamine release, direct myocardial depression,

and peripheral vasodilation

$ Can potentiate non-depolarizing neuromuscular agents with high dose or renal

compromise

The glycopeptides: remember, vancomycin and teicoplanin.

Teicoplanin is not available, but it does have some activity,

obviously, with vancomycin and pneumococcus. The only

glycopeptide we have in this country is vancomycin. Ototoxicity with

vancomycin is well described. Again, in patients with decreased

renal function or co-administration of other nephrotoxic or other

toxic drugs, like the aminoglycosides. Toxic levels greater that 40.

When you really look at the data, it’s peak levels really greater than

80. Approaching 80 or above that we see that. Red man syndrome

now it’s called red neck syndrome. Mostly due to the histamine

release and you can decrease that by increasing the amount of

infusion time. I certainly try to get an antihistamine sometimes to

see if it decreases. It’s not really an indication to stop the administration

of this drug, especially if you need it. You just continue

through it. Piperacillin aminoglycosides can potentiate some of this

neuromuscular blockade.



Macrolides

$ Macrolides: erythromycin, clarithromycin, azithromycin, roxithromycin,

dirithromycin

$ Gastrointestinal discomfort and nausea are common

$ Reversible cholestatic jaundice can occur 10-14 days after initiation of therapy

$ Generalized pruritus, maculopapular rash, serum sickness like reactions,

erythema multiforme major associated with large doses or in patients with

renal failure

$ Intravenous administration has been associated with cardiac toxicity

(prolonged QT interval, ventricular tachycardia, premature ventricular

contractions, nodal bradycardia, sinus arrest), hepatotoxicity, and venous

irritation (rate associated)

Macrolides: common ones are erythromycin, clarithromycin,

azithromycin, troleandomycin. By far one of the most common

complications is gastrointestinal discomfort and nausea and gas.

You can get reversible cholestatic jaundice. Some other kinds of

side effects are itching, rashes, serum sickness-like syndromes,

erythema multiforme. Also seen with large doses in patients usually

with renal complications. In patients that we might use intravenous

erythromycin products, or macrolides on: for instance Legionella,

or if you are in an NICU that you are worried about urea plasma

urealyticum. There have been associated cardiac toxicities with

this; prolonged QT interval, ventricular tachycardia, etc.,

hepatotoxicity and it is very irritating to the veins. Much like

doxycycline is.



Clarithromycin and Azithromycin

$ Nausea, diarrhea, dyspepsia are less frequent than with erythromycin

$ Headache, reversible neurologic change, glossitis, stomatitis, taste perversion,

elevated transaminases have been rarely reported

Clarithromycin and azithromycin. GI upsets are less than with plain

erythromycin but that they still occur but to a much lesser degree.

Headache, reversible neurologic changes can be seen. Taste

perversion is common, such as metallic taste. Azithromycin. All

the suspensions are the same price. Once a day for five days,

makes it very appealing for families. And I think it does have its

role. Probably otitis media as a secondary agent or tertiary agent.

I think it does have a role in adolescents that have pneumonias,

etc. that you worry about microplasia and Chlamydia. I think that

the one good thing that azithromycin has done, besides being

antibiotic one time a day, is really show efficacy for many things at

five days of therapy instead of ten days of therapy. And hopefully

we’ll start backing down everything else to about five days of

therapy for otitis and uncomplicated pneumonias. We treat most

things ten days because prevention of rheumatic fever with

penicillin is based on ten days, so everything else is ten days.



Macrolides-drug Interactions

$ Increase plasma concentration via inhibition of CYP34A activity (warfarin,

carbamazepine, cyclosporine, digoxin, theophylline, benzodiazepines, ergot

alkaloids, valproic acid)

$ Severe myopathy and rhabdomyolysis with lovastatin co-administration

These macrolides compete with many, many, many different things

and you’ll see some very bad things, potentially go on. The main

thing, the main complications that have occurred recently that

we’ve taken great notice with is with terfenadine and astemizole, or

Seldane and its new components, where patients receiving

erythromycin were actually - some of the oral azoles - them got into

problems with ventricular tachycardia, cardiac arrest and death. A

variant, of ventricular tachycardia, (torsade de pontes): this is a

variant form of ventricular tachycardia.

The newer macrolides are safer but we haven’t used them long

enough to see if this is really going to be a problem.



Lincosamides

. Lincosamide: clindamycin

. Pseudomembranous colitis is more common after oral use

. Less common: cardiac arrest, elevated serum transaminases, skin rash,

erythema multiforme major, eosinophilia, serum sickness like reactions

. Potentiates the effects of non-depolarizing neuromuscular blocking agents

Lincosamides: clindamycin, out of this group, pseudomembranous

colitis is the classic one that you think about, especially after oral

use. I still use a lot of clindamycin for staph aureus, osteomyelitis;

either IV or p.o., a lot of home IV therapy and hormonal therapy

with clindamycin. Some bad things can happen; cardiac arrest,

elevated liver function tests, which are very uncommon. Again, it

can potentiate non-depolarizing neuromuscular blockade. There

has been raised, this questionable interaction of gentamycin and

clindamycin in increased nephrotoxicity and you don’t see that

combination a whole lot.



Agents Soon to be Available

. Streptogramins: dalfopristin/quinupristin (Synercid); associated with

arthralgias, myalgias, hyponatremia, jaundice, phlebitis

..Oxazolidones: Associated with bone marrow hypocellularity and lymphoid

tissue atrophy. Weight loss, soft stools, anorexia, and distended cecum have

also been described

The Streptogramins, which are Synercid again for vancomycin-

resistant pneumococcus. There is very little data on what some of

the side effects are. The ones that have been described so far are:

arthralgias, myalgias, hyponatremia, jaundice, phlebitis.

Oxazolidones are a class of compounds that are coming out. Good

oral compounds that work very well against resistant

pneumococcus. Bone marrow hypercellularity, lymphoid tissue

atrophy, weight loss, soft stools, anorexia and distended cecum

have been described. But these are in small numbers.