Antibiotics and Outpatient Infections

Antibiotics and Outpatient Infections

David Kramer, M.D.

Antibiotic Therapy

Factors in Choosing an Antibiotic

Clinical syndrome

Host characteristics

Focused history

Antibiotic characteristics

When you are choosing an agent to use, you are looking at

what clinical symptoms the patient has, who is this patient, an

immunocompromised or normal host. You are taking a little bit

more of a detailed history to include infectious risks, and you

are thinking about the antibiotic itself.



3 Assessment of Clinical Syndromes

Identify predominant symptoms and signs

Determine the site of infection

Identify disease process

Determine likely causative organisms

Identify likely susceptibility pattern

In a clinical syndrome, you are trying to identify what is the

predominant symptom and signs. You are trying to see where

the site of infection is. Is this infection in the joint? Is this

infection in the bone? Where are we treating this infection?

Does this patient have a central nervous system infection?

Then, identify the disease process because if you identify that

this is osteomyelitis, it is a little bit different than if you think that

the patient has pyogenic arthritis. The causative organisms

might change and then what you need do, is you need to think

of what the disease is, what are the most likely pathogens

associated with this disease and what is their susceptibility

pattern in the area where you practice. This is essential. To pick

a drug, you have to know what organism you are dealing with.

Because if not, you are really doing it blindly. So you have to

have an idea of what organisms cause what specific diseases

so that then you can make a good choice about antibiotic

therapy.



4 Host Characteristics

Age

Underlying conditions

Medical devices

Nutritional status

When you look at hosts, you need to know the age of the

patient. A 10-year-old is different from a neonate. The patho-

gens are different. Think about underlying conditions. Is this a

patient with cystic fibrosis with pneumonia, or is this a well child

with pneumonia? Different pathogens. So you are thinking

about that host. Does this patient have an indwelling catheter?

Does the patient have a prosthetic heart valve? All these things

make it a little different to know which antibiotic to choose.

Then, is the patient malnourished because that might be a

cause for immunodeficiency.



5 Focused History

Travel

Exposures

Immunizations

Drug abuse

Sexual activity

When you are looking at a focused history, you need to know if

the patient you are seeing with fever for 10 days has just come

back from a safari in Africa, or is this a patient who has just

been in the community where there is a lot of influenza. So you

are going to ask about travel, about exposure to people who

have contagious diseases such as tuberculosis, or whether the

child is exposed to more infections because he is in daycare.

Are immunizations up to date? That is very important. That

patient may have measles if they have never been immunized

and there is an increase in your community of Hemophilus

influenza type E,. which is now very rare but can occur. Is this

adolescent an IV drug abuser? Unfortunately, this happens

occasionally and it brings in another set of organisms and

diseases we have to think about, and then sexual activity brings

up another whole host of organisms and disease processes.



6 Antibiotic Selection Factors

Spectrum of activity

Absorption

Distribution

Metabolism

Excretion

Adverse Effects

Safety

Routes of administration

Drug-drug interactions

Cost

Palatability

Effect on Resident Flora

Selective Pressure on environment

When we finally make that decision to select an antibiotic, we

must ask, Does the antibiotic cover the organisms that I am

thinking about? Is it well absorbed? Does it get to the site of

infection? Oral vancomycin is not good to treat Staph aureus

because it does not get absorbed from the GI tract. What are

the adverse effects? How safe is this drug? Do I have to

monitor drug levels? What is the route of administration? Can

I give it orally? Is it as good orally as it is IV? Are there other

interactions with other drugs, I might not want to use

erythromycin because it might change the levels of the

cyclosporin? How much does it cost? Is there a cheaper

alternative? Does it taste good? Because if it doesn't taste good

nobody, is going to take it. And no matter how good the

antibiotic is for that infection, if it is not taken, it is not of use.

Then, things that we think of in a more global setting are what

will this do to the patient's flora, and will this alter the flora and

then transmit resistant organisms? So, usually when you are

selecting an antibiotic, you are looking at all of these factors

and then making the decision based on the best antibiotic.



7 General Principles of Antibiotic Therapy

May initiate with broad spectrum awaiting culture results

Obtain pertinent cultures to narrow therapy

Use narrowest spectrum antibiotic as possible

The general principle is that you initiate broad spectrum

antibiotics awaiting culture results, then based on culture

results, you can narrow therapy. It is really best to use the

narrowest spectrum antibiotic possible for the infection,

especially now in the era of increasing antimicrobial resistance.

We really want to keep the very broad spectrum antibiotics for

when we need them. Ceftriaxone for treatment of otitis should

not be used because we have other, much narrower, alterna-

tives for otitis media and I want to save ceftriaxone to have an

antibiotic to treat the patient who comes in with meningitis. If

you don't use it in this fashion, I think that we are going to end

up with a lot of ceftriaxone resistance, and you are going to

have a lot of patients for which we have no antibiotics. So use

the narrowest spectrum possible.

The ideal antibiotic would be one that would be broad enough

to cover everything we want to cover, but very narrow to also

not cause resistance. It would have a very good absorption. It

would have a long half life, preferably that could be given in a

once a day or b.i.d. dosing. I actually prefer a b.i.d. dosing

schedule. Once a day, if a patient forgets to take it, then you

could be without an antibiotic for a long period of time. I want an

antibiotic that has no side effects. I want one that is very cheap

and one that has a great taste that the child will actually say,

Mom. It s my antibiotic time. I want to take it. Unfortunately, it

doesn t exist. There is no perfect antibiotic. Unfortunately, there

are good antibiotics or there are better antibiotics, but there is

no perfect one. There is no magical antibiotic for every infection.



8

Penicillins

Agent Activity Clinical Uses

Penicillin G oral anaerobes Gp A streptococcus

pharyngitis

Penicillin V streptococci RF prophylaxis

Benzathine Eikenella Syphilis

Procaine Pasteurella

Treponema

aspiration

pathogen specific

The different classes of antibiotics. I am starting with the

penicillins and they are divided into the name of the antibiotic,

their activity and then the clinical uses. Penicillin is a very useful

antibiotic still. Very active against oral anaerobes, streptococci

and the treatment of choice for Eikenella infections. Eikenella

is an organism that lives in the mouth, and with boxers or

people who punch each other in the mouth, you can get

infections with Eikenella in the hand. That is not uncommon.

Occasionally bites from animals can have Eikenella.

Pasteurella. Bites from animals. Penicillin is also for syphilis.

Penicillin is still very useful. We use it as the treatment of

choice for group A strep pharyngitis. We use it for rheumatic

fever prophylaxis. It is the therapy of choice for syphilis. For

aspiration pneumonia, it is still a very good agent to use initially

in that patient that may have aspirated in the community, not

the patient that has aspirated and has hospital acquired

organisms. But definitely, that patient coming from the commu

nity with an aspiration pneumonia. If you have a specific

infection with any of these pathogens, then that is when you

would use the penicillin.



9

Penicillin - Adverse Effects

Allergic reactions

Hemolytic anemia

Interstitial nephritis

Seizures and hyperkalemia in patients with underlying renal

disease

Adverse effects. The one that you most commonly hear about

is allergic reactions. A lot of people say that they are penicillin

allergic. I think that if you are penicillin allergic, you re really

going to take out all of the penicillins and most of the

cephalosporins if you are truly allergic with anaphylaxis. So

when the patient says they had a rash from penicillin or a rash

from amoxicillin, I investigate it further. I would hesitate to label

a patient as allergic to penicillin. Is it hives, not hives? I try to

bring pictures so the patient can see if it was hives or not. Or

was there wheezing, no wheezing? Was it true anaphylaxis? Try

to limit the labeling of patients as penicillin allergic if they just

had a rash.



10

Penicillinase-Resistant Penicillins

Agents Activity Clinical Uses

Methicillin

Nafcillin

Oxacillin

Cloxacillin

Dicloxacillin

S. aureus

S. epidermidis

less active for

penicillin suscepti-

ble bacteria

S. aureus infec

tions

After the penicillins were introduced, Staph aureus became very

rapidly resistant to penicillin. The penicillinase-resistant

penicillins were developed basically for treatment of Staph

aureus infections. These include methicillin, nafcillin, oxacillin

and oral agents such as cloxacillin and dicloxacillin. Their

activity is for Staph aureus. Occasionally, some Staph

epidermidis may be susceptible but the penicillinase resistant

penicillins are less active against penicillin susceptible bacteria,

especially anaerobes. The clinical uses are limited to Staph

aureus infections.



11

Adverse Effects of Penicillinase Resis-

tant Penicillins

Neutropenia - dose and duration related

Cholestasis and cholestatic jaundice

Interstitial nephritis - most common with methicillin

Poor palatability of oral preparations (dicloxacillin and

cloxacillin)

Adverse effects. Neutropenia is very common and it really

depends on how prolonged the usage is. In patients that we

treat for four or six weeks for Staph aureus osteomyelitis with

nafcillin, we frequently see neutropenias, and we have to stop

that agent and switch to something different like clindamycin.

So you should look for neutropenia with prolonged use. If it is

going to be a short course, it is very unlikely to produce

neutropenia. The other one that I just wanted to mention is

interstitial nephritis which is much more common with methicillin

than it is with nafcillin or oxacillin. Methicillin may not be

available any more.

The oral preparations of dicloxacillin and cloxacillin. There is no

child who has taste buds that would actually take this prepara-

tion because it tastes so terrible. The use of dicloxacillin and

cloxacillin is limited to the adolescent who can take a pill and

not worry about an aftertaste. But in a child, this becomes a

very big problem because they are really terrible tasting.



12

Aminopenicillins

Agents Activity Clinical Uses

Ampicillin

Amoxicillin

Penicillin suscep

tible

Some GNR

Enterococcus

Listeria

H influenzae

Borrelia

Otitis media

Sinusitis

UTI

Lyme disease

The aminopenicillins, ampicillin and amoxicillin, were developed

so that they could have a broader spectrum of activity than

penicillin. This broader spectrum includes all of the penicillin

susceptible ones, some gram negative rods, such as E. coli or

occasionally Proteus, enterococcus that is not resistant,

Listeria. Listeria in the neonate can cause infection in neonatal

meningitis. You cannot use a cephalosporin alone for neonatal

meningitis because Listeria would not respond. So ampicillin is

the drug of choice for Listeria. If H. influenza is susceptible, you

could use ampicillin, although we know that there is increasing

resistance. For Lyme disease amoxicillin is a good choice.

Clinical uses for amoxicillin. We know it is the drug of choice for

otitis and sinusitis. If you have an E. coli that is susceptible in

the urinary tract or you have enterococcal urinary tract infection,

it is useful, although most people would not start with amoxicillin

for a UTI because E. coli is becoming amoxicillin resistant and

is the most frequent cause of UTI. Lyme disease is one of the

uses you can use it for.



13

Adverse Effects of Aminopenicillins

Allergic reactions

Non-allergic mediated rashes associated with viral infections,

particularly EBV

Diarrhea

C difficile colitis

Seizures in patients with renal disease

The adverse effects are really non-allergic mediated rashes.

The rash from amoxicillin, if it is not hives, is usually not an

allergy. Remember that it is particularly evident in patients with

EBV. It can cause diarrhea. It can cause C. difficile. Seizures

are a very rare side effect.



14

Extended Spectrum Penicillins

Agents Activity Clinical Uses

Mezlocillin

Piperacillinn

Ticarcillin

Carbenicillin

Ampicillin suscep

tible

More GNR

Pseudomonas

GNR infection

Extended spectrum penicillins cover more Gram-negative rod

infections, and these include, mezlocillin, piperacillin, ticarcillin

and carbenicillin. Their activity is the same as ampicillin but they

include more Gram negative rods, and particularly piperacillin

and ticarcillin and orally carbenicillin are quite good for Pseudo-

monas infections if they are susceptible. So their clinical uses

are really Gram-negative rod infections. These are frequently

antibiotics that are used in hospitalized patients, except for

carbenicillin which is a p.o. preparation.



15

Adverse Effects of Extended Spectrum

Penicillins

Allergic reactions

Thrombophlebitis

High sodium load

Hypokalemia

Platelet dysfunction and bleeding

The extended spectrum penicillin have the same kind of

adverse profile. Ticarcillin has a high sodium load so we don't

use it in patients that have congenital heart disease or any

propensity to go into failure. Ticarcillin can also cause platelet

dysfunction and bleeding even with a normal platelet count.



16

Penicillins + Beta Lactamase Inhibitor

Agents Activity Clinical Uses

Amoxicillin +

clavulanate

ticarcillin +

clavulanate

Ampicillin +

sulbactam

Piperacillin +

tazobactam

Ampicillin suscep

tible

S. aureus

Anaerobes

H influenzae

M catarrhalis

Polymicrobic In

fections

Bites

Otitis media

Sinusitis

Nosocomial infec-

tions

Penicillin plus a beta lactamase inhibitor. We have come up

with amoxicillin + clavulanate, ticarcillin + clavulanate, ampicillin

+ sulbactam and piperacillin + tazobactam. These are all

ampicillin susceptible, but because of the clavulanate and the

addition of this beta-lactamase inhibitor, they get Staph aureus

as well as very good anaerobe coverage. Then because we

have ampicillin and the beta-lactamase, we now get H. influ-

enza and Moraxella catarrhalis included in the spectrum. The

clinical uses are usually polymicrobic infections. One of the

major clinical uses in pediatrics is bites. So that for cat bites,

extensive dog bites and even human bites, Augmentin or one

of these extended spectrum plus the beta-lactamase inhibitors

are the ones that are used in the hospital as well for bites. It is

a second line agent for otitis media and sinusitis. And they can

be used for nosocomial infection for Gram-negative rods that

are susceptible, or in patients infected with Gram-negative rods

plus Staph aureus and anaerobes, as in the hospitalized patient

who may have an aspiration pneumonia.



17

Adverse Effects of Penicillin +Beta

Lactamase Inhibitors

Gastrointestinal effects, especially diarrhea

All adverse reactions of the penicillin component can occur with

combinations

The adverse effects are an increased incidence of diarrhea.

Then remember that all the adverse effects of penicillin can

occur with the combination of preparations.



18

Cephalosporins

Cephalosporins are divided into first, second and third genera-

tions.



19

First Generation Cephalosporins

Excellent activity against Gram-positive organisms

Good activity against enteric Gram-negative bacilli

No CNS penetration

The first generations have excellent activity against Gram

positive organisms and their mainstay is for Staph aureus

infections. They have okay activity against enteric Gram

negative bacilli, so occasionally you will see that there is an E.

coli or Klebsiella that s susceptible to Keflex. But remember that

first generation agents have no central nervous system penetra-

tion so do not use Ancef or Keflex if meningitis is a possibility.

That is one of the major reasons we use them very infrequently

in neonates or preterm neonates where we can't easily exclude

central nervous system infection.



20

Second Generation Cephalosporins

Retain activity against Gram-positives

Enhanced activity against Gram-negatives

Some with good anaerobic coverage

Limited CNS penetration

Second generation cephalosporins retain activity against Staph

aureus and the Gram-positives. They have enhanced activity

against Gram-negatives, especially Hemophilus and Moraxella.

Some of them, especially cefoxitin, have good anaerobic

coverage and you may see them used for pelvic inflammatory

disease or for abdominal infections because of their anaerobic

coverage. Second generation cephalosporins have limited

central nervous system penetration and should not be used for

meningitis.



21

Third Generation Cephalosporins

Decreased activity against Gram-positives

Much enhanced activity against Gram-negatives

Some with antipseudomonal activity

Excellent CNS penetration

The third generations have much decreased activity against the

Gram-positive, so we do not use the third generation

cephalosporins, like cefotaxime or ceftriaxone, for infections

that are due to Staph aureus. They have much enhanced

activity against Gram-negatives. Some, like ceftazidime

particularly, have anti Pseudomonal activity and they have

excellent CNS penetration. Therefore, that is why we use them

for meningitis.



22

First Generation Cephalosporins

Agents Activity Clinical Uses

cephalothin

cephalexin

cefazolin

cefadroxil

Penicillin suscep

tible

S. aureus

GNR (some)

S. aureus infec

tions

First generation cephalosporins include cephalexin (Keflex),

cefazolin (Ancef) and cefadroxil (Duricef) with b.i.d. preparation.

Their activity is really for Staph aureus. Their clinical uses are

for Staph aureus. Remember that group A strep is also suscep-

tible. So for lacerations or cellulitis or osteomyelitis, where you

think Staph aureus is a player, these are good alternative drugs.



23

Second Generation

Activity Clinical Uses

Cefaclor

Cefuroxim

e

Cefprozil

Loracarbe

f

Cefoxitin

1st gen suscep-

tible

H. influenzae

M. catarrhalis

GNR (more)

Anaerobes

Second-line therapy for

otitis media and sinus

itis

Intraabdominal infections

Pelvic inflammatory disease

Second generation cephalosporins include cefaclor, cefuroxime,

cefprozil, loracarbef. They have the activity of the first genera-

tion and they include Hemophilus and Moraxella. Some to a

better degree than others. The clinical uses are really as

second line agents for otitis media and sinusitis. Cefoxitin is a

second generation that has increased activity against

anaerobes, and is used for intra-abdominal infections and pelvic

inflammatory disease.



24

Third Generation Cephalosporins

Agent Activity Clinical Uses

Cefotaxime

Ceftriaxone

Ceftazidime*

GNR

Streptococci

Nosocomial infections

Meningitis

*increased antipseudomonal activity

Third generation cephalosporins include cefotaxime,

ceftriaxone, and ceftazidime. They truly are Gram-negative rod

drugs. They are good for Strep pneumoniae, and that is why we

use them for meningitis. But we are seeing increased resis

tance to cephalosporins and their clinical uses should be

reserved for nosocomial infections and serious meningitis.

Other clinical uses of these can be for Gram-negative rod

infections, such as Salmonella in sickle cell patients or Salmo-

nella infections in general.



25

Oral Third Generation Cephalosporins

Agent Activity Clinical Uses

Cefixime

Ceftibuten

GNR

Poor coverage

against S. aureus,

pneumococcus

Resistant urinary tract infec

tions

Limited pediatric use

Oral third generation cephalosporins include cefixime (Suprax),

ceftibuten (Cedax). Their activity is really very good for Gram

negative rods. They have extraordinarily poor Staph aureus

activity and very poor pneumococcus activity. These basically

should really be used for Gram-negative rod infection. This

limits their pediatric use because otitis, pharyngitis and sinusitis

are not commonly caused by Gram-negative rods. I think that

one of the good uses for these agents is for resistant UTIs. So

our nephrologists use them quite frequently for complicated

UTIs with resistant Gram-negatives that they don't want to put

into the hospital and this is a very good oral alternative. Using

it routinely for otitis and sinusitis in patients where it really has

poor pneumococcal activity really doesn't make much bug-

drug" sense.



26

Fourth Generation Cephalosporins

Agent Activity Clinical Uses

Cefepime S. aureus

GNR

Pseudomonas

Undetermined

Cefepime is a new fourth generation. I really have not used it at

all yet. Its activity is said to be good for Staph aureus, Gram

negative rods and for Pseudomonas and I am really not sure

what clinical uses it will have in pediatrics. This is really a

relatively new drug that we don't have experience with.



27

Oral Cephalosporin Activity

PSP PRP H/M GAS SA

Cepha

lexin

Keflex + + +

Cefad

roxil

Durice

f

+ + +

Cefpr

ozil

Cefzil + +/ + +

Cefacl

or

Ceclor + +/ +

Cefur

oxime

Ceftin + + + +

Cefpo

doxim

e

Vantin + + + +/

Lorac

arbef

Lorabi

d

+ +/ +

Cefixi

me

Supra

x

+/-+ +

Ceftib

uten

Cedax +/ + +

Activity of antibiotics for otitis. Really you have to distinguish

between all of these oral cephalosporins and pick the ones that

you think have the best activity for the organisms that are

prevalent in your community and make a decision according to

that. Don t switch between these for second line drugs. There

is really no reason to switch. New information on Cedax

indicates that it is not very good for pneumococcus, so I think

it had a plus there before. You want to change that to a +/- as

well as cefixime. Loracarbef and Cefzil as well as cefaclor

really are +/- against Hemophilus and none of them are

better than high dose amoxicillin for resistant

pneumococcus.



28

Adverse Effects of Cephalosporins

Allergic reactions - 15% cross reactivity in penicillin allergic

patients

Serum sickness reaction (cefaclor)

Interstitial nephritis

Autoimmune thrombocytopenia

Biliary cholestasis and cholelithiasis (ceftriaxone)

Fungal overgrowth and infections

The adverse effects of cephalosporins. Cross reactivity may be

as high as 15% with penicillin allergic patients. It is said that the

cross reactivity is much greater with first generation

cephalosporins than with second generations and thought to be

really not very high at all in third generations. I am very conser

vative. If the patient truly has an anaphylaxis to penicillin I really

do not use any of the cephalosporins. However, some people

say that you could very safely use the third generations

because they are so different. Ceftriaxone is very unique in that

it causes biliary cholestasis and cholelithiasis. Then I really

want to point out that these are very a broad spectrum agents,

especially the third generations. We do see a lot of fungal

overgrowth and this may be a precipitating factor of the

nosocomial fungal infections in patients who are hospitalized.



29

Disadvantages of Cephalosporins

Not cure all drugs

Pneumococci may be resistant

Increasing resistant of hospital GNR

Broad spectrum

May lead to changes in normal flora and superinfection

High cost

Disadvantages. Pneumococci may be resistant. There is

increasing resistance of some hospital Gram-negative rods

such as Enterobacteriaceae, that are hospital acquired flora

may be resistant to cephalosporins. They are very broad

spectrum. They lead to especially fungal superinfection and

they are relatively high cost.



30

Causes of Cephalosporin Failure

Methicillin resistant S. aureus

Coagulase negative Staphylococcus

Listeria monocytogenes

Enterococcus spp.

C. difficile

Rickettsia

Chlamydia

Cephalosporin failure. The instances where it can fail include

methicillin-resistant Staph aureus or coagulase negative

Staphylococcus infections because you have an indwelling

catheter or a ventriculoperitoneal shunt. Listeria is resistant. For

Enterococcus they are not good at all. C. difficile and then

Rocky Mountain Spotted fever and chlamydia, especially

chlamydia pneumonia.



31

Carbapenems

Agent Activity Clinical Uses

Imipenem

Meropenem

Ceftriaxone

susceptible

Resistant GNR

anaerobes

Resistant infec-

tions

Carbapenems. Imipenem, and meropenem are really extraordi

narily broad spectrum drugs that have their use in pediatrics

really for resistant infections and particularly have been used for

meningitis. For pneumococcus that is resistant to ceftriaxone,

sometimes they are susceptible to imipenem or to meropenem.

Its activity is really against ceftriaxone susceptible plus resistant

Gram-negative rods as well as anaerobes.



32

Adverse Effects of Carbapenems

Allergic reactions - cross reactivity in PCN allergic parents

Diarrhea

Lowers seizure threshold (imipenem)

Adverse effects are that if you are penicillin allergic you are

going to be allergic to meropenem and imipenem. So it is not an

alternative for the penicillin allergic patient. Remember that

imipenem lowers the seizure threshold so that for use in

meningitis this might become a problem and it is better to use

meropenem in those instances. It is really nice to reserve this

for when you have a ceftriaxone resistant organism, this is a

good alternative.



33

Macrolides

Erythromycin

Clarithromycin

Azithromycin

Roxithromycin

Dirithromycin

Macrolides. Erythromycin is the prototype but now we have

clarithromycin, azithromycin. There is increasing use of

clarithromycin and azithromycin.



34

Erythromycin - Activity

Spectrum Clinical Uses

Penicillin susceptible

S. aureus

Mycoplasma

Legionella

B. pertussis

Campylobacter

Chlamydia

Penicillin allergic ptatients

Specific pathogens

The spectrum of activity. It is the penicillin susceptible organ-

isms. Then you have Staph aureus, although there is an

increase in Staph aureus that is resistant to erythromycin and

if they're resistant to erythromycin, they're going to be resistant

to azithromycin and clarithromycin as well. Organisms that are

covered include Mycoplasma pneumoniae, Legionella which is

an infrequent cause of infection in children but may occasionally

happen, Pertussis. It is our drug of choice for pertussis,

Campylobacter, and also chlamydia pneumoniae. So the

erythromycins are really good alternatives. The clinical uses are

for penicillin allergic patients for pharyngitis. They can be used

as second line agents for otitis and sinusitis and against,

specific pathogens, it is the drug of choice for pertussis

infections.



35

Macrolides - Adverse Effects

Gastrointestinal disturbances

Hepatotoxicity

IV erythromycin - cardiotoxicity hepatotoxicity venous irritation

Many drug interactions

The adverse effects are really gastrointestinal disturbances and

this is why the new macrolides exist. Because clarithromycin

and azithromycin have less gastrointestinal intolerance than

erythromycin. They may be hepatotoxic and remember that IV

erythromycin is a very dangerous drug to use. It can be

cardiotoxic and hepatotoxic and causes a lot of venous irritation.

It should not be given IV unless you have an infectious disease

consult and a very good reason such as Legionella infection in

a child. Remember that there are many drug interactions with

the erythromycins and these interactions don't go away be-

cause you are using the newer preparations. It is terrible for

cyclosporin levels but it also interacts with theophylline.



36

New Macrolides

Activity Clinical Uses

Clarithromyc

in

azithromycin

Erythromycin sus

ceptible

H influenzae

M catarrhalis

Non-tuberculous

mycobacterium

Toxoplasma

Cryptosporidium

N gonorrhoeae

Second line therapy

for otitis media and

sinusitis

Pathogen specific

Clarithromycin and azithromycin. Their activity is that of

erythromycin susceptible. They have better Hemophilus and

Moraxella coverage than penicillin, but they may not achieve

adequate middle ear concentrations. It is very interesting that

this is a very good use for non-tuberculous mycobacteria.

Those patients that have cervical lymphadenitis that we think

are secondary to non-tuberculous, might respond to

clarithromycin. I may use clarithromycin initially for these

patients. Also in patients with HIV with MAI, clarithromycin is a

good drug. Toxoplasma also in immunocompromised patients.

Azithromycin has the same activity in Cryptosporidium and

gonorrhea. The clinical uses are really as second line agents for

otitis and sinusitis and for pathogen specific infections.



37

Advantages of New Macrolides

Retain spectrum of activity of erythromycin

Increased spectrum against H. influenzae and nontuberculous

mycobacteria

Improved pharmacokinetics

Decreased gastrointestinal side effects

The advantages are that they retain the spectrum of

erythromycin, they increase the spectrum against these things,

they have improved pharmacokinetics, but really the main

advantage of clarithromycin and azithromycin is in their dosing

and their improvement in altered side effects. So that b.i.d. or

once a day dosing is preferable to four times a day dosing, and

the decrease in side effects is really the major advantage.



38

Disadvantages New Macrolides

Broader spectrum of activity

Does not broaden spectrum for erythromycin resistant

pneumococcus

High cost

Adverse effect of clarithromycin headache, neurologic changes

The disadvantage is that they have a broader spectrum of

activity. It does not really broaden the spectrum for

erythromycin resistant pneumococcus. So, if your

pneumococcus is resistant to erythromycin, it is equally

resistant to clarithromycin and azithromycin. The relative cost

is higher, and azithromycin is extraordinarily expensive, but

because it s been used for half of the time for five days rather

than the usual 10 day course, it is pretty equivalent to

clarithromycin, but it is about 10 or 12 times higher in cost than

erythromycin. The uncommon effects of clarithromycin such as

headache and neurologic changes are uncommon but can

occur.



39

Clindamycin

Activity Clinical Uses

PCN susceptible

S. aureus

Anaerobes

Toxoplasma

No H. influenzae

or M.

catarrhalis

Penicillin allergic

Resistant pneumococci

Intraabdominal infections

Toxoplasmosis

Clindamycin. Clindamycin is a drug that we had not used

previously as much as we are using now, but now with resistant

infections, we are seeing new uses for clindamycin. It has

activity against penicillin susceptible organisms, Staph aureus,

anaerobes, Toxoplasma. It doesn't have activity against

Hemophilus or Moraxella catarrhalis. Especially in bite wounds,

it doesn't cover Eikenella, so that it cannot be used as a single

agent in this. That is why we use amoxicillin-clavulanate or the

combination ones for bite wounds. The clinical uses of

clindamycin are in the penicillin allergic, in the resistant

pneumococcal infection, intra-abdominal infections, not alone

but with other Gram negative rod agents, and then in patients

with toxoplasmosis.



40

Adverse Effects of Clindamycin

Clostridium difficile colitis

Hepatotoxicity

Stevens-Johnson syndrome

Eosinophilia

Clindamycin adverse effects are C. difficile colitis. It definitely

has been associated with colitis, but I am not really sure that it

is more associated than any of the other antibiotics. Amoxicillin

is the one that is used the most, and amoxicillin is the antibiotic

that is most associated with C. difficile by the sheer numbers of

its usage. Clindamycin can cause hepatotoxicity. It can cause

Stevens-Johnson, and it may cause eosinophilia. Overall, it is

used a lot and it is a safe alternative.



41

Quinolones

Nalidixic Acid

Ciprofloxacin

Norfloxacin

Quinolones have been increasingly used in pediatrics, and

although they are not approved for use in pediatrics, we do

have an increasing experience with the quinolones and may

choose them as alternatives in some patients for specific

reasons.



42

Quinolones

Spectrum of Activity

Gram positives +/- S. pneumoniae

+/- S. aureus

Gram negatives Pseudomonas aeruginosa

Other Chlamydia, Mycoplasma,

Mycobacterium, Bartonella,

Plasmodium

They are not wonderful for pneumococcus or for Staph aureus,

these are not drugs for resistant pneumococcal infections or for

Staph aureus infections. But they are good for Gram negatives,

particularly Pseudomonas. That is one of the areas of major

use is as an outpatient drug for pseudomonal infection. Other

uses include Bartonella henslae which is the agent of cat

scratch disease.



43

Potential Uses of Quinolones

Pulmonary infections in cystic fibrosis

Complicated urinary tract infections

Chronic suppurative otitis media

Complicated osteomyelitis

Resistant nosocomial infections

Prophylaxis for N. meningitidis

Gastrointestinal infections

The potential uses for the quinolones. We have lots of experi

ence in the cystic fibrosis patients, with very little adverse

effects that we can attribute to the quinolones. Complicated

urinary tract infections caused by Gram-negative rods that are

resistant to other drugs. For chronic suppurative otitis media

when Pseudomonas may be one of the pathogens. Compli

cated osteomyelitis such as that associated with decubital

ulcers with Gram-negative rods and where resistant Pseudomo

nas may be a problem. Resistant infections. There are theoreti

cal risks of growth problems with quinolones. It is also used for

gastrointestinal infections such as Salmonella.



44

Adverse Effects of Quinolones

Diarrhea

Arthralgias and tendon rupture

Increased liver enzymes

Possible effect human cartilage growth

Adverse effects. Quinolones do cause diarrhea. It has been

reported to cause arthralgias and there was recently a report of

an Achilles tendon rupture associated with quinolone use,

particularly ciprofloxacin. But the question of the effect on

human cartilage growth is becoming more and more of a

question. This is definitely seen in animals, but in cystic fibrosis

patients where we use large quantities of ciprofloxacin, in doing

MRIs of their joints there is really no detectable damage to the

cartilage. So I think we are getting more and more comfortable

with quinolones. Obviously not as a first choice. But their

potential uses in pediatrics are going to be becoming more and

more prevalent.



45

Sulfonamides

Agent Activity Clinical Uses

TMP/sulfamethoxaz

ole (Bactrim, Septra)

PCN susceptible,

except Gp A

strep and

anaerobes

GNR Salmonella,

Shigella

H. influenzaee

Pneumocystis

Second-line therapy

for otitis media and

sinusitis

Bacterial enteritis

Pneumocystis

Erythro/sulfamethox

azole Pediazole)

Erythromycin sus

ceptible

H. influenzae

M. catarrhalis

Second-line therapy

for otitis media and

sinusitis

Sulfonamides. TMP/sulfa does not have activity against group

A strep. It has no anaerobic activity at all. The Gram-negative

rods, that it is very good for are Salmonella, shigella,

Hemophilus influenza. It is the drug of choice for Pneumocystis

carinii pneumonia infections. Its clinical uses are as a second

line agent for otitis and sinusitis. For bacterial enteritis and for

Pneumocystis. Erythro/sulfa (Pediazole) takes the activity of all

the erythromycin and increases activity for Hemophilus and

Moraxella. It is a second line agent for otitis and sinusitis.



46

Adverse Effects of Sulfonamides

Gastrointestinal disturbances

Skin rashes - more common in HIV infected patients

Erythema multiforme and Stevens-Johnson syndrome

Adverse effects of the sulfonamides. Skin rashes are very

prominent and are more common in HIV patients than in non-

HIV infected patients. Erythema multiforme and Stevens

Johnson syndrome seem to have a higher association with

sulfonamides than with other antibiotics, although it can occur

with other antibiotics. But there seems to be somewhat of a

higher association with sulfonamides and Stevens-Johnson.



47

Vancomycin

Activity Clinical Uses

PCN susceptible

MRSA

S. epidermidis

Enterococcus sp

C. difficile

pathogen specific

infection of medical devices

Vancomycin. The activity of vancomycin is that it is penicillin

susceptible. It includes methicillin resistant Staph aureus and

is really the best drug for methicillin resistant Staph aureus

infections. It is the drug that we use when Staph epidermidis

infection is thought of, such as in patients with indwelling

devices and indwelling venous catheters. Enterococcus is

usually susceptible, although now we know that enterococcus

has the ability to develop vancomycin resistance, and this is an

increasing problem that is going to becoming even more of a

problem in pediatric institutions. Then we use the oral prepara-

tion for C. difficile. Really the clinical uses are for infection of

medical devices and truly pathogen specific when you have

MRSA or if you have a susceptible Enterococcus. The routine

use of vancomycin for C. difficile colitis is not recommended

because we do not want to encourage Enterococcus resistance.

Metronidazole should be used instead.



48

Adverse Effects of Vancomycin

Ototoxicity - in patients with renal disease or concurrent

aminoglycosides

Red man syndrome

Hypotension associated with infusion

The infusion of the intravenous vancomycin can cause a red

man syndrome that is not an allergy. It responds very nicely to

decreasing the rate of infusion or stopping it for a little bit and

starting up again at a lower rate. It also responds nicely to

antihistamines. There have been patients with hypotension

associated with the infusion, which readily gets better with

stopping it.



49

Aminoglycosides

Agents Activity Clinical Uses

Gentamicin

Netilmicin

GNR GNR infections

Amikacin Resistant GNR Hospital GNR

Tobramycin P. aeruginosa

Aminoglycosides. Their activity is for Gram-negative rods and

Gram-negative rods only. It is a little bit better for resistant

Gram-negative rods, so some are no longer using gentamicin

but have switched to amikacin because they have a problem

with a particular Gram-negative rod that may be resistant.

Tobramycin is specific for Pseudomonas aeruginosa. They are

used for Gram-negative rod infections, and apart from urinary

tract infections, should not be used as the sole agent.



50

Adverse Effects of Aminoglycosides

Nephrotoxicity

Ototoxicity

Reversible neuromuscular blockade

Need to monitor levels

Adverse effects. They have nephrotoxicity and ototoxicity. It can

cause neuromuscular blockade, which is an important factor in

patients with botulism because this small neuromuscular

blockade becomes clinically significant in those patients, and it

may precipitate respiratory arrest in that patient. There is new

information that once daily dosing of aminoglycosides may be

as effective as the three times a day dosing, with less side

effects. More pediatric information is coming forward with that.



51

Tetracyclines

Agents Activity Clinical Uses

Tetracycline

Doxycycline

Chlamydia

Mycoplasma

Rickett-

sia/Ehrlichia

Borrelia

Brucella,

Francisella

Propionobacteria

Eikenella

Pathogen specific

Not for Gp A

Strep

Tetracyclines are really pathogen specific. It includes very

broad pathogens that are kind of unusual. It really is not for

group A streptococcus.



52

Adverse Effects of Tetracycline

Gastrointestinal disturbances

Deposition of drug in bones and teeth

Contraindicated in children <8 years

Photosensitivity

Hepatotoxicity - especially with IV tetracycline

Bacterial overgrowth

They are not used often in pediatric patients because they are

contraindicated because they deposit in bones and teeth and

stain the teeth. Remember if you are using it for patients for

acne, tell them that it causes photosensitivity so that they can

get ready when they get out into the sun.



53

Chloramphenicol

Activity Clinical Uses

Penicillin susceptible

H. influenzae

Anaerobes

Salmonella

Shigella

Rickettsia

Rocky mountain spotted fe

ver in children less than 8

years old

Chloramphenicol is something that has a very good spectrum

activity, but it is not used very much because we have very

good alternatives. But remember one of the main clinical uses

is for Rocky Mountain Spotted fever in that patient that is less

than eight years of age. There have been failures when it has

been used for resistant pneumococcus despite its good in vitro

activity. So it is not recommended.



54

Adverse Effects of Chloramphenicol

Idiosyncratic aplastic anemia

Bone marrow suppression

Gray baby syndrome

Hepatotoxicity

Need to monitor levels

Adverse effects include bone marrow suppression and aplastic

anemia; these have precluded its use in pediatrics.



55

Rifampin

Activity Clinical Uses

S. aureus

Streptococci

N. meningitidis

H. influenzae

Mycobacterium

Synergy device infection

Mycobacterial infection

Prophylaxis for H. influenzae

and N. meningitides

Rifabutin has better activity for MAI than rifampin

Rifampin. We use it a lot as synergistic for microbacterial

infections and prophylaxis. It really should not be used to treat

infections alone because organisms become rapidly resistant

to rifampin.



56

Rifamycins - Adverse Effects

Hepatotoxicity especially with other drugs or pre-existing

liver disease

Changes color of all body secretions to orange

It does change the color of all body secretions. It makes them

a bright orange. That is how you know the patient is getting

rifampin but you have to warn the patient about this.



57

Metronidazole

Activity Clinical Uses

Anaerobes

G. vaginalis

Entamoeba

Trichomonas

Giardia

Anaerobic infections

C. difficile

Pathogen specific

Metronidazole is good for anaerobes, and that includes all of

these organisms as well as Giardia. Its clinical uses are

anaerobic infections, C. difficile, and pathogen specific infec

tions.



58

Adverse Effects of Metronidazole

Neurotoxicity

Peripheral neuropathy

Gastrointestinal disturbances

Metallic taste

Mutagenic and carcinogenic in lab animals

A peripheral neuropathy and neurotoxicity can occur, which is

more frequent in adults. I has a metallic taste. We use it quite

frequently for anaerobes and for C. difficile colitis.



59

References

1. Jacobs RF, Schutze GE, Young RA, et al. Antimicrobial

Agents In: Principles and Practice of Pediatric Infectious

Diseases. Eds: Long SS, Pickering LK, Prober CG New

York, Churchill Livingstone 1997

2. Spect WT, Blumer I (eds). The Pediatric Clinics of North

America: Symposium of Anti-Infective Therapy. Philadel

phia, WB Saunders Co, 1983

3. Smith AL (ed). Antibiotic Update. Pediatric Annals 1993;

22. 155-200