Antibiotic To Xi Cities New Agents

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Antibiotic Toxicities

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

Most of them have some gram-positive activity, but you w

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

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

also tobramycin, not much with kanamycin, even less w

mycin. Pulmonologist are using inhaled tobra for some C

The main type of toxicities that we see from aminoglyc

ototoxicity and nephrotoxicity.

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

actually destruction of the cochlear hair cells and it p

high-frequency, irreversible hearing loss. This can occ

can occur late. It can occur after you've gone thro

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

The vestibular dysfunction, which causes damage to th

hair cells is most commonly seen with gentamicin and

cin. 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 ma

people to worry about. Ototoxicity is usually directly re

peak level that you get. So, if you give 10 x th

aminoglycoside, that's the kind of patient that I would w

their ears. If something could happen to their ears. P

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

having high peaks for whatever reason you're not follo

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

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

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

patient had renal disease that you didn't pay attention

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

which also have Ototoxic potential in combination vanc

other loop diuretics. Prior exposure to aminoglycosid

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

tendency for any ear problems you need to be conc

aminoglycosides and the exact amount of ototoxicity

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

premature infants. All premature infants should get th

screened usually before they leave the premature nurse

about the micro-preemies. The 500 to 1000 gm infants

have hearing loss was it to the multiple courses of amino

they got or the fact that they had intraventricular hemo

brain abscess or was it the fact that they were exposed

loud noises. So the exact mechanism is not well know



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 troug

not clearing their aminoglycoside. They really need to be

a day which is clearly just enough to get their peaks do

maintains a very high level which is hurting their kidne

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

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

or hypertension and excessive urine protein.

Risk for nephrotoxicity. Again, high doses or prolonged

therapy, especially for hemoglobin. Liver disease, con

of other nephrotoxic medications, again, vancomyci

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 adve

and drug interactions. The interactions, mostly we w

increased nephrotoxicity. Again, increased nephrotoxicit

use aminoglycosides in combination with all othe

nephrotoxicity drugs. Cyclosporine, amphotericin B, s

loop diuretics, indomethacin, most people don't r

cephalothin is one of those. One of the interes

aminoglycosides do or potentially potentiate is the

suppression of nondepolarizing neuromuscular agents

think about it too, in the old days before the cephalosp

we used ampicillin and gentamicin exclusively when th

babies came in or you had the baby that presented

constipation, some cranial nerve findings, just kind of be

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

lot worse, so it potentiates that neuromuscular blocka

think anybody's going to use a lot of oral kanamyci

kanamycin and methotrexate can increase methotrexa



Tetracyclines

$ Short acting: Oxytetracycline, tetracycline

$ Intermediate acting: Demeclocycline

$ Long acting: Doxycycline, minocycline

The tetracyclines. There are short acting, intermediate

long acting. Tetracycline hydrochloride has such a bad

with teeth staining and other side effects. Very short a

with Oxytetracycline, the long acting Doxycycline, actual

best CNS penetration of any of the tetracyclines. This

tetracycline of choice. Minocycline which dermatolog

bad acne.



Tetracyclines

$ Nausea and vomi t ing are$

Photosensitivity

most common $ Decreased prothrombin activity

$ Hepatotoxicity occurs following$ Over-

growth of resistanthigh 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 alm

the oral antibiotics that we use. We can see in hep

usually following high doses or especially in pregnant

who have been prescribed. Nephrotoxicity in pre-ex

disease. What we all worry about is the tetracycli

orthophosphate complex that inhibits bone growth and

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

tetracycline hydrochloride, and Oxytetracycline is the lea

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

the number of times that you got tetracycline and for t

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

at risk for teeth staining. Doxycycline given for a short c

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

probably not going to see this. Dentists can f ix staining

ally. Oversensitivity, a question of whether to give your p

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

tologists probably do when they use Minocycline bec

dermatologists use sun block. I tell my patients who a

Africa that use Doxycycline for malaria prophylaxis tha

to be concerned about that and consider that. The e

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,

magnesium containing things to settle your stomach

getting oral tetracyclines, that can interfere with your p

There has been some data suggesting that the effective

contraceptives can be reduced by tetracyclines and

make you worry when you are given ten days of tetracyc

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

we do, just maybe counsel them that that is a possibili

need to be aware of that. There can be some incre

toxicity with loop diuretics. A lot of the drugs we're g

about interfere with warfarin or Coumadin levels one

other and this is not different. The reason why tetracyc

digoxin toxicity is probably an interference with metabo

digoxin when it is absorbed by the bacterial overgrowth

tetracycline. Again, with rifampin or anticonvulsants yo

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 chlora

probably because in most every instance there are

drugs which are just as good or better. I think chloram

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

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

brain abscesses. The most common kind that we see, w

on chloramphenicol for longer than about seven days

developing some of these kind of symptoms. Classica

elevated serum iron, low reticulocyte count, and low h

Once you stop your chloramphenicol these correct by th

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



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

anytime you start chloramphenicol. It's classically des

seen mostly with oral chloramphenicol, but it could be s

chloramphenicol as well. Again, the mechanism is tho

the direct toxicity of the nitrosochloramphenicol on the

amount that we saw here is anywhere from 1 in 40,0

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

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

complication. Other kinds of less common adverse effe

might see or things you should probably think abou

pseudomembranous colitis, encephalopathy, hemolyti

patients with G6PD, and ototoxicity which is classically

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



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 potentialfor aplastic anemia

$ Concurrent use of acetaminophen may increase chloramphenicol metabo-

lism

Drug interactions, again commonly given with

cyclophosphamide, or warfarin. If you have elevated leve

because of chloramphenicol with an inhibition to m

hepatic enzymes. Phenobarbital and rifampin, would st

liver so you clear the chloramphenicol a lot faster. You

have increased levels of chloramphenicol in the face of

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

see with chloramphenicol are associated with peak le

twenty-five, usually greater than thirty, some with thi

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

problems at least with co-administration of chloramph

cimetidine and increased risk for aplastic anemia. Con

of acetaminophen has been reported to increase chlora

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

was a direct myocardial metabolic derangement at the

with decreased tissue oxygenation and shock. Other thin

can see are abdominal distention, emesis, respirat

hypotension, metabolic acidosis, which can occur at any

beyond the neonatal period. Again, usually associate

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 humancytochrome P450, found predominately in the liver and small intestine

Rifamycins. The main ones that we have now which ar

for us are rifampin and rifabutin. Most of the rifabutin

MAI or MIC prophylaxis in pediatric HIV patients. Rifa

still using for prophylaxis for meningococcal. We use it o

in combination with some of our Staphylococcal medic

of course in tuberculosis. It is contraindicated in pregn

breast-feeding. There are four absolute contraindication

feeding antibiotics as you can get. The complete absolu

dications to breast-feeding among antibiotics

metronidazole, sulfonamides, and chloramphenicol. The

can work around or they say are not absolute contrai

However, in pregnancy it is contraindicated. Rifampin

colored urine. It will stain and can destroy your contac

well. Rapid and potent inducers of CYP3A4, the mos

human cytochrome P450 are found predominately in th

small intestine.

The adverse reactions you can see with rifampin really a

shock-like syndrome, acute hemolytic anemia, especia

partum women, African-American women, Hispanic w

teenagers etc. Hepatic toxicity is enhanced by chronic li

or concurrent administration of isoniazid or pyrazina

individuals say if you're using it in combination with the

with 10 mg per kg per day. You can see liver dysfunct



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 rifamp

leukopenia, thrombocytopenia, arthralgia, myalgia, fev

been reported.

Drug interactions. With erythromycins, what they do

reduce the serum concentration, increase the plasma

and decrease the elimination half-life of a bunch of dr

end up with low serum concentration. You have a lot o

interactions that you need to worry about if you are us

mycins. Mostly what you are going to do is lower

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

look at aerobic susceptibilities now, in most studies clin

not really the gold-standard drug anymore that we tho

About 25% of Bacteroides fragilis or fragilis group is r

clindamycin now. I think metronidazole has really step

the drug of choice when you have a patient who has ha

abdominal catastrophe. So we're using it a little m

pediatric patients. Only about 2 to 3% of Bacteroides

resistant to that particular drug. It can however,

neurotoxicity with seizures, headaches, encephalopat

these are in patients with chronic neurological problem

certainly use it in brain abscesses as one of our gol

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

amount of seizure discharges that we think, at leas

metronidazole. But in most cases it's going to be t

neurological disorders. It can cause a peripheral n

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

high doses. Especially a lot in the young, gastrointest

This is a very common scenario. It does leave a meta

your mouth or can. You have some rare adverse s

rashes, pain, discoloration of the urine. It can also ca

pancreatitis and gynecomastia. This is a common form

will see with gastrointestinal upset too, acute pancre

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

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

effects in lab animals but we've never seen that in p

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 concentra-

tions 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 in

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

plasma clearance or some people will get an increase

that. Phenobarbital and corticosteroids will reduce

concentrations of metronidazole. Cimetidine may inh

metabolism and increase serum concentrations of met

Remember if you have a patient taking Flagyl you ma

them to drink, because they may end up vomiting

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

of side effect. Metronidazole is contraindicated in preg

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

you may get a 2 gm dose of metronidazole. All you ne

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

patient who is taking metronidazole chronically everyd

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 hypersensi-

tivity

Most of what we talked about with trimethoprim fro

related to the sulfa content. The sulfa components th

most commonly are sulfadiazine, sulfamethoxazole, su

and sulfisoxazole. Again, skin manifestations are the mo

side effects that you will see with sulfonamides. Eryth

form major, which we call Stevens-Johnson syndrome

epidermal necrolysis are the most severe hypersens

tions. Patients with HIV have a two to seven fold i

hypersensitivity to the sulfonamides or to a sulfonamide

with trimethoprim. So again, these patients have a lot o

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

hypersensitivity, a serum-like sickness syndrome. You c

a drug-induced lupus erythematosus reaction. Yo

granulocytopenia. We've had a couple of patients

trimethoprim sulfate who have developed granulocyto

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

usually the sulfa compound there that we see. Renal

crystalluria and reversible hepatocellular dysfunction w

has been described with sulfamethoxazole. Mostly in c

with trimethoprim. There are a few patients who h

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,

methotrexate, oral hypoglycemic agents. You get

anticoagulant effect. You can get depression because y

levels go way high and you may get hypoglycemic be

oral hypoglycemic agents work a little bit better. So you

concerned about that. They do that by competing for b

on human albumin. Potentially you will also see eleva

bilirubin in these patients as well. There is an associat

has been described as an increased nephrotoxicity of c

in combination with cephalomide. So that would be so

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. Mo

going to see is in combination with sulfamethoxazole, s

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

trimethoprim that does it or the sulfamethoxazole th

Gastrointestinal upset and again, skin rashes occur in

5% of the patients. It's the most common thing that w

fatal hypersensitivity reactions like the skin rashes ca

occur, but again it's hard to differentiate which compon

here. It's contraindicated in pregnancy due to possible

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 canbe enhanced by non-steroidal anti-inflammatory drugs

The quinolones are not used much for kids, especial

have problems with puberty. The FDA says we can't u

kids less than eighteen. I personally use them some

kids have gone through their growth spurt. The reason

because of the studies with beagle puppies who got the

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

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

know. There is very good data in cystic patients an

outside the United States that show that with these

human patients do just fine. Obviously, if you have a fo

whose quadriplegic with microcephaly and a G-tub

chronic UTIs and you keep them in the hospital forev

sent him home on Cipro, their parents probably don't r

there's a theoretical risk they may not grow two inches

would use it in certain situations. They are actually

absorbed and very well tolerated. My cut off is if the

through puberty or seem to have gone through pube

drugs will probably never be first line drugs for k

because at least most of these have very poor pne

activities. So some of the newer ones are getting

pneumococcus, but pneumococcus is such a big dea

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

are very well tolerated; diarrhea and skin rashes are

seen. You can have neurologic effects; very bad headac

certainly can see neurologic manifestations in rare occ



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 re

serum sickness like syndromes, eosinophilia. Eosinop

kind of common on anybody that is having drug reacti

human studies in the United States and across the w

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



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 t

drugs with them and you get reduction of metabolis

medications by inhibiting the cytochrome P450, taking

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, ampicillin-sulbactam

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

mezlocillin, piperacillin, piperacillin-tazobactam

Penicillins. If you have meningococcal men

meningococcemia, if you give their entire course w

generation cephalosporin you don't need to give the

prophylaxis. Still in this country penicillin is the drug of c

of the penicillin side effects and adverse effects that w

going to be consistent. Natural penicillins are penicillin G

penicillin, benzathine penicillin. Penicillinase-resistant

those things that are fairly specific for Staph and Strep

activity against anything else. Aminopenicillins;

ampicillin, ampicillin-sulbactam, which you use for

Extended spectrum penicillins, extended to include diffi

gram-negatives, to include Pseudomonas and their co

of Timentin, which is ticarcillin and clavulanate, and Zo

is piperacillin and tazobactam. Remember that the Beta

inhibitors here actually might have some antibacterial

it's best to think of them as having none. They just reall

Beta-lactamase production, which then takes those thin

resistant based upon Beta-lactamase and makes them s

again. The majority of Pseudomonas resistance is not b

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 supposed

one in every thousand exposures. Fatal anaphylaxis is

hypersensitivity reactions are serum-like sickness,

rashes, and contact dermatitis. With natural penicillin

allergic problems we see tend to be with procaine

specifically and 80 to 90% of those are specific t

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

you more susceptible to that. Other less common rea

hemolytic anemia; interstitial nephritis; seizures; this re

be with high dose penicillin, if you are approach

20,000,000 units a day, yes you may have seizures o

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

kilo per day of third generation cephalosporin, you

enough Beta-lactamase there to cause you a seizu

penicillin is fairly safe. Penicillin is pretty specific for

Strep. If you have patients that you treat as outpatients

file weekly CBCs, watching their neutrophils, because w

we can watch them break down and this is pretty much

Beta-lactam antibiotic. Remember there are some othe

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

problems with the liver, especially cloxacillin. The kind

form in adults is why methicillin is not used much i

interstitial nephritis. Nafcillin competes with your biliru

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

life of the newborn or a sick neonate you maybe w

something that goes through the kidney. We didn

problems with interstitial nephritis with nafcillin, but the

get the more problems you have nafcillin. Methicilli

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 peni

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

hypersensitivity to penicillin? Or is it the fact that real

have otitis media and he may have Epstein-Barr virus a

potentiated this rash and that's what makes it so diffic

true hypersensitivity reaction or allergic reaction to som

penicillins just based upon a rash. I usually ask for ot

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

diarrhea, especially with the old preparation of

clavulanate, since they've lowered the amount of clavu

has certainly gone away or at least it has in the patient

That seems to be the most common reason for patients

much diarrhea. If you look at cases of antibiotic associ

you will see more attributable now to ampicillin

cephalosporins than you will the clindamycin, but you h

at their case rates, because we are using more am

cephalosporins now than we are clindamycin. If

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 hype

reactions just like the other penicillins. Thrombophle

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

piperacillin. I don't use much carbenicillin. It's still the o

that you can actually still give orally. If they can take a bi

you can still give them carbenicillin. Congestive he

precipitated by carbenicillin due to a high sodium

piperacillin and ticarcillin will give you platelet dysfunc

have a patient who already has thrombocytopenia, you m

stay away from some of these extended-spectrum

because if you have small numbers already and you

slick they may not work as well. So you may have som

problems. There is a risk for pseudomembranous colitis

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.

along with aminoglycosides can potentiate that neu

blockade. In a few patients it's been described. Theoret

is some data suggesting ticarcillin in combin

aminoglycosides may inactivate that aminoglycoside if y

doses of ticarcillin for prolonged periods. So keep tha

you are using piperacillin or ticarcillin in combin

gentamicin and tobramycin and your patient is kind of

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

combination. Cefotaxime is a pretty safe drug as far as

go. Azlocillin and mezlocillin can increase cefotaxime

patients with renal impairment secondary to decr

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

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 gra

coverage, not much gram-negative coverage. Some, b

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

positive, Staph, Strep coverage. Cephalosporins d

enterococcus. Good gram-positive, except for ent

Second generation; gram-positive coverage, a little bit le

first generation, but still fairly good and better gram

coverage. Third generation; less gram-positive covera

the most part covers pneumococcus very, very well.

Staph aureus but Pseudomonas coverage in some inst

new fourth generation cephalosporins. Cefepime or M

the one that's coming out that we are using some in k

supposedly has the coverage of the first generation as f

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

to include Pseudomonas. So fourth generation cephalos

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

tis at this time, but that doesn't mean it's not out there,

recall it at this t ime. The second generation cephalosp

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

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 ar

allergic is probably somewhere around 10 to 20% woul

cephalosporin allergic. Some hypersensitivity rea

compound specific. For instance with Cefaclor. We've

a long time that with Cefaclor that we've seen an increas

like sickness syndromes or Stevens-Johnson synd

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

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

There are some studies out there indicating that actual

a genetic predisposition. Some people may be more p

to have problems with this class of drug of second

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

tive reaction it may actually be compound specific. Ju

you get Stevens-Johnson with Cefaclor doesn't mean yo

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

Cefprozil, also second generation cephalosporin, we a

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

class specific to this second generation cephalosp

Anything the penicillins can do, the cephalosporins c

interstitial nephritis etc. Seizures and nephrotoxicity

doses. Gastrointestinal upset. Ceftriaxone, we'll

ceftriaxone for a minute. Two things with Ceftriaxone; re

newborns ampicillin-gentamicin or ampicillin-cefot

acceptable combinations in the first three months of life

really want to use ampicillin-ceftriaxone in the first we

Really because it competes with bilirubin binding sites a

see some problems with hyperbilirubinemia at that tim

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

has GC that has not been treated give the baby on

ceftriaxone and you're not going to interfere with anyt

upon one dose. But for prolonged therapy in the ne

group, cefotaxime is a better choice than ceftriaxon

patients who receive ceftriaxone for any amount of time

a reversible biliary pseudolithiasis or you get sludge in th

der. Most all patients are asymptomatic with this. The o

really been found is by doing studies with ultrasound.

patients on ceftriaxone. For the most part it's clinicall

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

however, there have been three or four cases now

rapidly fatal immune-mediated hemolytic anemia with c

These are patients who hemolyze and die within twenty

receiving ceftriaxone. These have been patients who ha

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

have seen ceftriaxone before and at least one of them

has had antibodies to ceftriaxone that were measurable

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

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

kids who have seen ceftriaxone before.

I mentioned to you that Cefotetan, cefoxitin, or merope

are not cephalosporins, they actually are cephamycins.

lump them together with second generation cephalospo



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 serumtransaminases and alkaline phosphatase

€ Disulfiram-like reactions with alcohol

why these drugs actually work for anaerobes where

really don’t. Anything that cephalosporins can do, thes

you have a cephalosporin problem, you can have a pr

these as well. This does, however, give you a metron

reaction with alcohol.

Loracarbef is actually a carbacephem. It is a version o

They’ve taken it and modulated it and made it a little b

compound with is. It really has fewer side effects than c

we haven’t seen acute hypersensitivity reaction with this

seen with cefaclor. It is the best-tasting drugs in all th

comparisons. Loracarbef is number one, cefaclor is n

It is expensive. Again, same kind of drug reactions that w

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 andcephalosporins

Carbapenems: imipenem-cilastatin, trimaxim or m

which is Merum. Meropenem has come out in the last

and really does have indications for meningitis. There

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

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

disease. We had some problems with patients havin

especially if they had a seizurogenic-type illnesses like

and it seemed to be potentiated by the use of this c

Meropenem certainly has less seizures than Primaxin d

usually say we don’t see seizures like this does, and tha

should use it in meningitis. Actually they do see seizure

it’s no greater rate than you see seizures with cefo

anything else. I really think that this class of drugs ha

anaerobic coverage. I think you have very good activity

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 withlonger 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 pr

with Primaxin when you use the bigger doses. Yo

hypersensitivity reactions and nausea again, which can

with longer infusion times. Remember you still have

lactamase ring here, so anything that you can see with

you can see with these. All the bad adverse side effe

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

meropenem. Again there is this potential cross-sensitivi

IgE medicated and mediated anaphylaxis with penicillin

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 orcephalosporins

Monobactams: monobactams again still has part of

lactamase so you can still see some cross-sensitivi

mediated anaphylaxis that we talked about. The one d

aztreonam. Think of aztreonam as an aminoglycoside

necessity for levels. Mostly gram negative coverage, Pse

etc. You can see some liver toxicity or some eosinophi

Long bleeding times. Rash, phlebitis, diarrhea, alteratio

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 ( <30-45 minutes)

$ Hypotension can be related to histamine release, direct myocardial depres-

sion, and peripheral vasodilation

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

compromise

The glycopeptides: remember, vancomycin and t

Teicoplanin is not available, but it does have som

obviously, with vancomycin and pneumococcus.

glycopeptide we have in this country is vancomycin. Oto

vancomycin is well described. Again, in patients with

renal function or co-administration of other nephrotox

toxic drugs, like the aminoglycosides. Toxic levels grea

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

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

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

release and you can decrease that by increasing the

infusion time. I certainly try to get an antihistamine so

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

tration of this drug, especially if you need it. You jus

through it. Piperacillin aminoglycosides can potentiate s

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, clar

azithromycin, troleandomycin. By far one of the mos

complications is gastrointestinal discomfort and nause

You can get reversible cholestatic jaundice. Some oth

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

erythema multiforme. Also seen with large doses in patie

with renal complications. In patients that we might use i

erythromycin products, or macrolides on: for instance

or if you are in an NICU that you are worried about u

urealyticum. There have been associated cardiac tox

this; prolonged QT interval, ventricular tachyca

hepatotoxicity and it is very irritating to the veins.

doxycycline is.



Clarithromycin and Azithromycin

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

$ Headache, reversible neurologic change, glossitis, stomatitis, taste perver-

sion, elevated transaminases have been rarely reported

Clarithromycin and azithromycin. GI upsets are less tha

erythromycin but that they still occur but to a much less

Headache, reversible neurologic changes can be s

perversion is common, such as metallic taste. Azithr

the suspensions are the same price. Once a day for

makes it very appealing for families. And I think it do

role. Probably otitis media as a secondary agent or ter

I think it does have a role in adolescents that have pn

etc. that you worry about microplasia and Chlamydia.

the one good thing that azithromycin has done, bes

antibiotic one time a day, is really show efficacy for man

five days of therapy instead of ten days of therapy. An

we’ll start backing down everything else to about fiv

therapy for otitis and uncomplicated pneumonias. We

things ten days because prevention of rheumatic

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



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 diffe

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

thing, the main complications that have occurred re

we’ve taken great notice with is with terfenadine and ast

Seldane and its new components, where patients

erythromycin were actually - some of the oral azoles - th

problems with ventricular tachycardia, cardiac arrest an

variant, of ventricular tachycardia, (torsade de pontes

variant form of ventricular tachycardia.

The newer macrolides are safer but we haven’t used

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, pseudom

colitis is the classic one that you think about, especial

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

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

with clindamycin. Some bad things can happen; card

elevated liver function tests, which are very uncommo

can potentiate non-depolarizing neuromuscular block

has been raised, this questionable interaction of genta

clindamycin in increased nephrotoxicity and you don

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 va

resistant pneumococcus. There is very little data on wh

the side effects are. The ones that have been described

arthralgias, myalgias, hyponatremia, jaundice,

Oxazolidones are a class of compounds that are coming

oral compounds that work very well against

pneumococcus. Bone marrow hypercellularity, lymp

atrophy, weight loss, soft stools, anorexia and disten

have been described. But these are in small numbers.

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