Pediatr Infect Dis J, 2003;22:1143–51 Vol. 22, No.

12
Copyright © 2003 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A.

Appropriate antibiotic use and why it is

important: the challenges of bacterial
resistance
JAY M. LIEBERMAN, MD

After the introduction of antibiotics in the
mid-20th century, clinicians soon witnessed clin-
ical failures secondary to bacterial resistance.
Despite scientists’ efforts to synthesize more po-
tent antibiotics during the last five decades, bac-
terial resistance continues to evolve, in large
part because of the overuse and misuse of anti-
biotics. The treatment of several pathogens, in-
cluding methicillin-resistant Staphylococcus au-
reus, penicillin-resistant Streptococcus
pneumoniae and vancomycin-resistant entero-
cocci, is problematic. New solutions are needed
to preserve the activity of our current antibiotic
armamentarium, to lower the overall risk of bac-
terial resistance and to successfully treat pa-
tients with resistant bacterial infections. Options
include: development of new antibiotics to treat
resistant organisms; vaccination to prevent in-
fections; and improved use of antibiotics. Be-
cause bacteria will eventually develop means to
avoid being killed by antibiotics, judicious use of
antibiotics by all clinicians is imperative. Appro-
priate antibiotic use involves selection of a “tar-
geted spectrum” antibiotic, as well as an appro-
priate dose and duration.
INTRODUCTION
The emergence of antimicrobial resistance among a
number of bacterial pathogens changes the way we
practice medicine and places some of our patients at
risk of dying from their infections. The overuse and
misuse of antibiotics are major contributing factors to
bacterial resistance; therefore it is incumbent on each
of us to use antibiotics appropriately.
This article reviews some of the clinical problems we
face as a result of bacterial resistance and then dis-
cusses potential solutions, with an emphasis on appro-
Miller Children’s Hospital, Long Beach, CA; and University of
California, Irvine, CA.
Key words: Bacterial resistance, quinupristin/dalfopristin, lin-
ezolid, fluoroquinolones.
Address for reprints: Jay M. Lieberman, M.D., Miller Chil-
dren’s Hospital, 2801 Atlantic Avenue, P.O. Box 1428, Long
Beach, CA 90801-1428. Fax 562-997-9634; E-mail
jay_lieberman@hotmail.com.
1143
priate antibiotic use and a focus on the fluoroquinolo-
nes.
RESISTANT ORGANISMS
As examples of the clinical challenges posed by
bacterial resistance, three Gram-positive organisms
are highlighted in this review: Staphylococcus aureus;
Streptococcus pneumoniae; and Enterococcus.
Methicillin-resistant Staphylococcus aureus. In
1941 all S. aureus organisms were susceptible to pen-
icillin, and relatively low doses of penicillin were highly
effective for staphylococcal infections. However, by
1944 S. aureus isolates were described that produced
penicillinase,1 an enzyme that inactivates penicillin
and renders S. aureus resistant to its effects. By the
1960s most S. aureus isolates were penicillin-
resistant.2 Because most S. aureus organisms were no
longer susceptible to penicillin, new antistaphylococcal
drugs were developed, and the semisynthetic penicil-
lins such as methicillin, nafcillin and oxacillin became
the mainstays of therapy. However, S. aureus soon
developed resistance to these drugs as well. In distinc-
tion to penicillin, resistance to the semisynthetic pen-
icillins is not caused by inactivation of the antibiotic
but rather is mediated by a change in the target of the
antibiotic, an enzyme on the bacterial inner membrane
called a penicillin-binding protein. Because the mech-
anism of resistance is an alteration in the target of the
antibiotic, these so-called “methicillin-resistant S. au-
reus” (MRSA) are resistant clinically to all beta-lactam
antibiotics, even though a drug such as cefazolin may
appear to be active in vitro. It is also important to note
that MRSA are often multidrug-resistant and are re-
sistant to antibiotics such as the macrolides and ami-
noglycosides, even though the mechanisms of action of
these antibiotics are different than that of the beta-
lactams.
MRSA became prevalent by the late 1970s, but
MRSA infections usually were confined to the large
hospital setting. Community-acquired methicillin-
resistant S. aureus (CA-MRSA) infections were very
unusual, particularly in children, until the 1990s,
when CA-MRSA emerged in the United States. Chi-
cago Children’s Hospital reported that the number of
children hospitalized with CA-MRSA increased from 8
1144 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
in the 3-year period from 1988 to 1990 to 35 in the
3-year period from 1993 to 1995.3 In south Texas, 53
CA-MRSA infections were identified between 1997 and
2000, compared with just 7 cases between 1990 and
1996.4 The proportion of community-acquired S. au-
reus infections in children hospitalized at Texas Chil-
dren’s Hospital in Houston that was methicillin-
resistant increased from 35% in February 2000 to 67%
in January 2002.5 In 1999 the CDC reported 4 pediatric
deaths from CA-MRSA in Minnesota and North Dako-
ta.6
The emergence of CA-MRSA as a significant pediat-
ric pathogen in many parts of the US has important
clinical implications. Physicians need to know the
prevalence of CA-MRSA in their communities and, in
areas where CA-MRSA is prevalent, children hospital-
ized with potentially life-threatening staphylococcal
infections, such as endocarditis, should be empirically
treated with vancomycin until susceptibilities are
available. For non-life-threatening infections, such as
lymphadenitis, cellulitis, osteomyelitis or pneumonia
in nontoxic patients, clindamycin is usually an appro-
priate choice.7 Community-acquired MRSA are much
more likely to be susceptible to clindamycin than are
hospital-acquired MRSA.2– 4
To further complicate matters for clinicians, MRSA
that are clindamycin-susceptible but erythromycin-
resistant may exhibit inducible resistance to clindamy-
cin (i.e. on exposure to clindamycin, such isolates may
develop resistance to clindamycin). At the University of
Illinois in Chicago, 33 of 88 clindamycin-susceptible
MRSA isolates were erythromycin-resistant.8 Evalua-
tion for inducible clindamycin resistance using the “D
test” showed that 31 of the 33 isolates exhibited indu-
cible resistance. There was one clinical failure caused
by such an isolate; a 9-month-old boy with empyema
caused by a clindamycin-susceptible, erythromycin-
resistant MRSA developed a clindamycin-resistant iso-
late during clindamycin therapy. Therefore clindamy-
cin should not be prescribed for long term therapy of
significant MRSA infections, such as osteomyelitis or
empyema, unless the organism is documented to lack
inducible resistance to clindamycin.
In contrast to the report from Chicago,8 the preva-
lence of MRSA with inducible clindamycin resistance
appears to be lower in other geographic regions.7
Penicillin-resistant Streptococcus pneumoniae.
Clinical isolates of S. pneumoniae are reported as
susceptible (MIC ⱕ 0.06 ␮g/ml), intermediate (0.12
␮g/ml ⱕ MIC ⱕ 1 ␮g/ml), or resistant (sometimes
referred to as highly resistant; MIC ⱖ 2 ␮g/ml) to
penicillin. The clinical significance of these breakpoints
is that infections caused by intermediate strains of
pneumococcus, with the exception of meningitis, are
likely to respond to third generation cephalosporins or
even high dose penicillin. Commonly used beta-lactam
Vol. 22, No. 12, Dec. 2003
antibiotics therefore will often be effective for pneumo-
nia, otitis media or sinusitis caused by an intermediate
strain of pneumococcus. On the other hand if the
pneumococcus is highly resistant, penicillin will not be
effective, and these organisms may also be resistant to
cefotaxime and ceftriaxone.
Penicillin-resistant pneumococci, like CA-MRSA,
emerged in the US in the 1990s. In a study of invasive
pneumococcal isolates from eight sites around the US
in 1998, 24% were nonsusceptible (either intermediate
or highly resistant) and 14% overall were highly resis-
tant.9 Similarly a national surveillance study per-
formed in 1999 through 2000 showed that 34% of
clinical isolates (invasive and noninvasive) were peni-
cillin-nonsusceptible and 22% overall were highly re-
sistant.10 Resistance had increased markedly com-
pared with a similar study from 1994 through 1995
when 24% of isolates were nonsusceptible and 10%
overall were highly resistant.10
As with CA-MRSA the emergence of drug-resistant
pneumococci has changed pediatric practice. A child
who is hospitalized with a potentially life-threatening
pneumococcal infection, such as definite or probable
bacterial meningitis, should be treated with an empiric
antibiotic regimen that includes vancomycin in addi-
tion to cefotaxime or ceftriaxone.11 Importantly vanco-
mycin is not indicated for all children hospitalized with
possible or probable pneumococcal infections, such as
pneumonia, unless they are critically ill. The treatment
for documented resistant invasive pneumococcal infec-
tions, such as meningitis, should be based on suscepti-
bility results and may require vancomycin plus another
agent such as ceftriaxone or cefotaxime, meropenem
and/or rifampin. Some fluoroquinolone antibiotics (e.g.
moxifloxacin, gatifloxacin) have excellent activity
against penicillin-resistant pneumococci and, although
these agents are not yet approved for use in children
⬍18 years of age, they may have a role in the manage-
ment of serious, resistant pneumococcal infections in
children. Consultation with an infectious disease spe-
cialist should be strongly considered to assist in the
management of invasive pneumococcal infections
caused by nonsusceptible organisms.
For the more common pneumococcal infections, such
as acute otitis media and sinusitis, therapy can be
problematic because no oral agent is active against all
resistant strains. A consensus statement on otitis me-
dia by a CDC working group and clinical practice
guidelines for sinusitis from the American Academy of
Pediatrics (AAP) provide some recommendations for
the management of these infections in an era of pneu-
mococcal resistance.12, 13 Amoxicillin is the drug of
choice for uncomplicated acute otitis media or sinusitis
regardless of the local prevalence of resistant pneumo-
cocci. Even when pneumococci are resistant to penicil-
lin, sufficient concentrations of amoxicillin can often be
Vol. 22, No. 12, Dec. 2003 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
achieved in middle ear and sinus fluid to successfully
treat the infection. For children with ear infections who
are at increased risk of having a resistant pneumococ-
cal infection (i.e. young infants and those who have
recently received antibiotics or who attend day care),
high dose amoxicillin (80 to 90 mg/kg/day) is recom-
mended, and many experts recommend high dose
amoxicillin for all children with acute otitis media. For
children with otitis media who do not respond clinically
after 2 to 3 days of amoxicillin therapy, several drugs
may be useful as secondary agents, including high dose
amoxicillin/clavulanate, cefdinir, cefuroxime axetil,
cefpodoxime proxetil or a single intramuscular dose of
ceftriaxone. Some data, however, suggest that three
once daily doses of ceftriaxone may be required for
penicillin-nonsusceptible pneumococcal ear infec-
tions.14
It is important to emphasize that some antibiotics
commonly used to treat children with ear and sinus
infections are unlikely to be effective against nonsus-
ceptible strains of pneumococcus.12 Cefaclor, loracarbef
and cefixime, for example, are poorly active against
these organisms and therefore should not be used as
first line therapy for acute otitis media or sinusitis.
It might be thought that other oral antibiotics, such
as trimethoprim-sulfamethoxazole and the macrolides,
would maintain their activity against penicillin-
resistant pneumococci because they have a mechanism
of action different from that of penicillin. However, as
with MRSA, penicillin-resistant pneumococci are usu-
ally multidrug-resistant. More than 80% of penicillin-
resistant pneumococci are also resistant to tri-
methoprim-sulfamethoxazole and more than one-half
are resistant to the macrolides.9
Vancomycin-resistant Enterococcus. Enterococci
are normal inhabitants of the human gastrointestinal
tract. These bacteria, which are intrinsically resistant
to most antimicrobials, including cephalosporins, gen-
erally do not cause significant infections in otherwise
healthy children. However, enterococci are common
causes of hospital-acquired infection, in large part
because the widespread use of cephalosporins in hos-
pitalized patients kills most Gram-negative enteric
bacteria and leaves enterococci as the predominant
organism.15
Therapy of enterococcal infections has become in-
creasingly problematic because of the emergence of
resistance. Before 1983 all strains were susceptible to
ampicillin, and the recommended therapy for serious
enterococcal infections was a synergistic combination
of ampicillin and gentamicin. With the emergence of
ampicillin resistance, vancomycin became the drug of
choice for serious ampicillin-resistant enterococcal in-
fections. In 1986, however, vancomycin-resistant en-
terococci (VRE) were first reported,16 and rates of
isolation of VRE in hospitals increased steadily
1145
through the 1990s.17 From the clinical perspective the
emergence of VRE was important because these iso-
lates were often resistant to all available antibiotics,
meaning that some patients had untreatable bacterial
infections.
Vancomycin resistance among enterococci is also
important because it is plasmid-mediated. The capac-
ity for vancomycin resistance, therefore, could be trans-
ferred in the laboratory to other Gram-positive bacte-
ria. The major concern was the clinical consequence
when S. aureus or Streptococcus pneumoniae became
vancomycin-resistant.
Vancomycin-resistant Staphylococcus aureus.
Clinical isolates of MRSA that were intermediate to
vancomycin, called vancomycin-intermediate S. aureus
(VISA), were first identified in patients in Japan in
199618; as of June 2002, 8 VISA infections had been
documented in patients in the US.19 The mechanism of
vancomycin resistance among VISA is not the same as
it is for VRE.
In June 2002 the first clinical isolate of vancomycin-
resistant S. aureus (VRSA) was reported from a patient
in Michigan.19 The patient was a 40-year-old woman
with multiple medical problems, including diabetes
mellitus, peripheral vascular disease and chronic renal
failure. She had recurrent infections of foot ulcers and
received multiple courses of broad spectrum antibiotics
to treat these infections. In April 2002 the patient
developed MRSA bacteremia and was treated with
vancomycin. In June 2002 cultures from a suspected
catheter exit site infection grew VRSA that contained
the vanA gene that confers vancomycin resistance on
VRE. A second documented VRSA infection was re-
ported from Pennsylvania in September 2002. This
patient also had chronic foot ulcers, and the VRSA
isolate contained the vanA resistance gene.20
For these two patients with VRSA infection, there
were other therapeutic options, but the threat of un-
treatable S. aureus infections looms closer on the
horizon. It seems only a matter of time before children
develop common infections, such as staphylococcal cel-
lulitis or lymphadenitis, that are resistant to all rou-
tinely used oral antibiotics.
Why bacterial resistance? Microbes have genetic
plasticity, which means that they have the capacity to
evolve in response to their environment. The major
impetus for developing resistance is selective pressure
resulting from antibiotic use. The bacteria that survive
are those that develop mechanisms to avoid being
killed by antibiotics.
What is this antibiotic pressure? In the United
States, an estimated 126 million courses of antibiotics
were prescribed in the ambulatory setting in 2000.21
Pediatricians have a special responsibility for control-
ling this problem because children account for a dis-
proportionate share of the antibiotics used. Ear infec-
1146 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
tions alone resulted in almost 30 million office visits in
1997.
With all this selective pressure from antibiotic use,
bacterial resistance emerges. Because of bacterial re-
sistance, patients present with more serious infections
or with infections that are more difficult to treat. This
leads to more antibiotic use and the use of more broad
spectrum agents. And so a vicious cycle develops. For
example it is necessary to limit vancomycin use be-
cause of VRE and concerns about the emergence of
vancomycin resistance among staphylococci and strep-
tococci. However, because of the increasing prevalence
of MRSA and drug-resistant pneumococci, we use more
vancomycin. The place to break this vicious cycle is to
decrease antibiotic use and thereby decrease the pres-
sure on bacteria to develop resistance.
Three major approaches are advocated to combat
bacterial resistance: (1) develop new antibiotics to treat
resistant organisms; (2) vaccinate to prevent infec-
tions; and (3) improve our use of antibiotics.
NEW ANTIBIOTICS
Quinupristin/dalfopristin. Quinupristin/dalfo-
pristin (Synercid) is a semisynthetic antibiotic that
combines two streptogramin compounds and is the first
licensed antibiotic in its class.22 It inhibits bacterial
protein synthesis and is available only as an intrave-
nous product. Its spectrum of activity is similar to that
of vancomycin, with excellent activity against Gram-
positive pathogens, including many resistant strains.
Quinupristin/dalfopristin is active against staphylo-
cocci, including MRSA, pneumococci, including penicil-
lin-resistant strains, and Enterococcus faecium, includ-
ing VRE (but not Enterococcus faecalis). Its major
value is that it provides a therapeutic option for infec-
tions caused by vancomycin-resistant E. faecium, VISA
or VRSA. In addition quinupristin/dalfopristin may be
useful for treatment of serious Gram-positive infec-
tions in patients who are allergic to, or intolerant of,
beta-lactams and vancomycin. Unfortunately there are
already reports of VRE and MRSA resistant to quinu-
pristin/dalfopristin since its licensure in 1999.23, 24
Linezolid. Linezolid (Zyvox) is the first licensed
oxazolidinone antibiotic.25 The oxazolidinones, syn-
thetic compounds unrelated to other antimicrobials,
inhibit bacterial protein synthesis. Linezolid has lim-
ited activity against selected Gram-negatives and
anaerobes but is highly active against Gram-positive
bacteria, including resistant strains. Like quinupris-
tin/dalfopristin, linezolid is active against MRSA, pen-
icillin-resistant pneumococci and vancomycin-resistant
E. faecium. Unlike quinupristin/dalfopristin, linezolid
also is active against E. faecalis.
Linezolid is available in both intravenous and oral
preparations and is 100% bioavailable after oral ad-
ministration. As such it provides an oral therapeutic
Vol. 22, No. 12, Dec. 2003
option for patients with Gram-positive infections resis-
tant to other oral antibiotics. Therapy with linezolid
should be limited to patients with infections caused by
VRE, VISA or VRSA; for serious Gram-positive infec-
tions in patients who cannot tolerate vancomycin or
beta-lactam antibiotics; and for patients with resistant
Gram-positive infections who have been treated with
intravenous vancomycin and can be transitioned to
oral therapy. Since linezolid became available in 2000,
clinical isolates of VRE and MRSA resistant to lin-
ezolid have been reported from treated patients.26 –28
Quinupristin/dalfopristin and linezolid are two valu-
able additions to our antimicrobial armamentarium,
but resistance has already been described. To preserve
their value their use should be limited to those rare
cases where they are clearly needed.
Fluoroquinolones. Although the fluoroquinolones
are not new antibiotics, most pediatricians have lim-
ited experience with this class of antibiotics. Important
features of this drug class include excellent bioavail-
ability after oral administration, achievement of high
tissue concentrations and a broad spectrum of activity.
In general fluoroquinolones are active against many
Gram-positive bacteria (the “newer” quinolones, moxi-
floxacin and gatifloxacin, are particularly active
against Streptococcus pneumoniae) and many Gram-
negative bacteria. Some quinolones (ciprofloxacin be-
ing the most potent) have significant activity against
Pseudomonas aeruginosa.29 The quinolones are there-
fore attractive agents to use for treatment of selected
children with serious bacterial infections.
The quinolones have a unique mechanism of action;
they inhibit two bacterial enzymes, DNA gyrase and
topoisomerase IV, that are essential for bacterial DNA
synthesis. Because they target bacterial sites distinct
from the site of action of other antibiotics, it was
hypothesized by some that resistance might be less
likely to occur or slower to develop.30 Unfortunately
these hopes were not borne out.
Oral ciprofloxacin first became available in the US in
October 1987 and rapidly became a widely prescribed
antibiotic. By 1989 it was the fourth most prescribed
antibiotic in the country, with ⬎5 million prescriptions
filled.31 During the last decade a number of other
fluoroquinolones have become available, including
ofloxacin, levofloxacin, moxifloxacin and gatifloxacin.
With widespread use during the past 15 years, quino-
lone resistance has emerged among a number of bac-
teria. Four such organisms are highlighted here.
Neisseria gonorrhoeae. Fluoroquinolone antibiot-
ics, such as ciprofloxacin, ofloxacin and levofloxacin,
given as a single oral dose are among the recommended
therapies for uncomplicated gonorrhea. However, N.
gonorrhoeae isolates resistant to the quinolones
emerged in the 1990s and are now prevalent in parts of
Asia and the Pacific. Such isolates have been identified
Vol. 22, No. 12, Dec. 2003 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
only sporadically throughout the US, although in Ha-
waii the percentage of isolates that are ciprofloxacin-
resistant increased from 1.4% in 1997 to 14.3% in
2000.32, 33 As a result, before treating a patient with
gonorrhea, a travel history should be obtained from
both the patient and their sexual partner(s). If either is
likely to have acquired the infection in Asia, the Pacific
Islands or Hawaii, then a quinolone should not be used.
Because of an increased prevalence of quinolone resis-
tance among N. gonorrhoeae isolates in California, the
CDC has also stated that the use of fluoroquinolones in
that state “is probably inadvisable.”33
S. pneumoniae. The newer quinolones (e.g. moxi-
floxacin, gatifloxacin) are now among the recom-
mended agents for the empiric treatment of communi-
ty-acquired pneumonia in adults. 34 In Canada
prescriptions for quinolones in general increased al-
most 7-fold between 1988 and 1998 (from 0.8 to 5.5
prescriptions per 100 persons per year).35 Through
1993 pneumococci with reduced susceptibility to the
quinolones had not been identified but, by 1997
through 1998, the prevalence of S. pneumoniae strains
nonsusceptible to ciprofloxacin isolated from Canadian
adult patients had increased to 2.9%. All strains iso-
lated from children were susceptible. Furthermore pa-
tients with pneumococcal pneumonia who failed em-
piric levofloxacin therapy because of infections with
levofloxacin-resistant strains (including patients
whose isolates developed resistance during therapy)
have been reported.36, 37 Although the overall preva-
lence of quinolone-resistant pneumococci remains rel-
atively low, it is interesting to recognize that penicillin
was available for almost 50 years before clinically
significant penicillin resistance emerged. It took fewer
than 10 years for quinolone resistance to develop
among the pneumococci.
Campylobacter/Salmonella. The quinolones are
widely prescribed for the treatment of patients with
bacterial gastroenteritis because this class of drugs is
active against a broad range of bacterial pathogens
that cause diarrhea, including Salmonella, Shigella,
Campylobacter and Yersinia. In Minnesota, however,
the proportion of Campylobacter jejuni resistant to the
quinolones increased from 1.3% in 1992 to 10.2% in
1998.38 Many of these cases were associated with
foreign travel and recent quinolone use. This phenom-
enon is not limited to Minnesota; 40.5% of C. jejuni
isolates were fluoroquinolone-resistant in one Pennsyl-
vania health care system in 2001.39
Fluoroquinolone resistance also has emerged among
Salmonella species. In Taiwan, ciprofloxacin resistance
was not seen among Salmonella enterica serotype chol-
eraesuis until 2000. By the third quarter of 2001, 60%
of isolates in Taiwan were ciprofloxacin-resistant.40 An
analysis of S. enterica isolates from Finnish travelers
also showed that the proportion with reduced suscep-
1147
tibility to ciprofloxacin increased from 3.9% in 1995 to
23.5% in 1999.41
One reason quinolone resistance has emerged among
enteric bacteria is that, in some regions of the world,
these antibiotics are used in livestock and poultry not
only to treat infections in the animals but, more impor-
tantly, to promote growth after administration of sub-
therapeutic concentrations.42 This long term exposure
to low levels of antibiotics provides an ideal environ-
ment for the selection of resistant bacteria in the
animals. Although quinolones are not approved for
growth promotion, they are known to be misused,
especially outside the US.43 In the US quinolone anti-
biotics were approved for therapeutic use in poultry in
1995. In Minnesota C. jejuni was isolated from 74% of
91 retail chicken products in 1997, and 14% of these
isolates were ciprofloxacin-resistant.38 Many public
health experts want to prohibit the use of antibiotics in
poultry, especially those antibiotics that are used to
treat infections in humans.44 In 1999 the European
Union banned the use of four such antibiotics as
growth promoters.45 The US Food and Drug Adminis-
tration may soon follow suit.
The experience with the quinolones exemplifies the
lesson that inappropriate use of an antibiotic hastens
the development of resistance. The more an antibiotic
is used, the more pressure there is on bacteria to
develop resistance. If antibiotics are not used judi-
ciously, they can lose their value and thus not be
available for patients who really need them.
Appropriate use of fluoroquinolones in chil-
dren. Although the quinolones are not currently ap-
proved for use in patients younger than 18 years of age,
they already have an established role in certain high
risk pediatric populations. They are commonly used to
treat pulmonary exacerbations caused by P. aeruginosa
in children who have cystic fibrosis and may also have
a role in the prevention or treatment of infections in
children with cancer.
Several potentially appropriate uses for quinolones
in otherwise healthy children are listed in Table 1.
TABLE 1. Possible uses for fluoroquinolone antibiotics in
otherwise healthy children*
Infections caused by Pseudomonas aeruginosa or other
multidrug-resistant Gram-negative bacteria
Urinary tract infection
Chronic suppurative otitis media or malignant otitis externa
Chronic osteomyelitis
Complicated middle ear and mastoid infections
Bacterial gastroenteritis caused by a multidrug-resistant organism, e.g.
Shigella
Typhoid fever
Mycobacterial infections
Anthrax prophylaxis or treatment
* Fluoroquinolone antibiotics are not licensed for use in individuals younger than 18
years of age, except in the case of anthrax treatment. If use is recommended for a
patient younger than 18 years of age, the risks and benefits should be explained to the
patient, when appropriate, and parents.
1148 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
They should not be used to treat children with colds or
bronchitis or for children who have infections suscep-
tible to other oral antibiotics. In general the quinolones
should be reserved for treating specific bacterial infec-
tions (e.g. P. aeruginosa) that are resistant to com-
monly used antibiotics or when the use of an oral
quinolone allows outpatient management of a serious
infection for which no other oral agent is available.
IMMUNIZATIONS
New antibiotics will never completely solve the bac-
terial resistance problem because organisms eventu-
ally develop resistance. New vaccines, on the other
hand, may provide a solution.
By the 1970s a significant proportion of Haemophi-
lus influenzae type b (Hib) isolates was resistant to
ampicillin and chloramphenicol. It seemed inevitable
that Hib would develop resistance to ceftriaxone and
cefotaxime. However, antibiotic-resistant Hib meningi-
tis is no longer of concern because widespread use of
the Hib conjugate vaccines has eliminated the disease.
Similarly concerns about treating resistant pneumo-
coccal infections can be alleviated through use of the
pneumococcal conjugate vaccine.
Vaccination against viral diseases also can reduce
antibiotic use. Preventing chickenpox through use of
the varicella vaccine can avert secondary bacterial
infections caused by S. aureus and eliminate concerns
about possible MRSA infection. Preventing influenza
may thwart secondary bacterial ear infections and
pneumonia. In a study of a nasal spray influenza
vaccine in children, vaccinated children had 21% fewer
febrile illnesses and 30% fewer episodes of febrile otitis
media than did unvaccinated controls.46 Widespread
vaccination against influenza among young children,
as encouraged by the current recommendations,47 will
lead to fewer fevers and fewer antibiotic prescriptions.
Decreasing antibiotic use can reduce the emergence of
resistance.
IMPROVING ANTIBIOTIC USE
Judicious antibiotic use means that antibiotics are
prescribed only when indicated and that the drug
chosen is the most narrow spectrum agent that will be
effective. Appropriate use means choosing not only the
correct antibiotic but also the appropriate dose and
duration, factors that can influence the development
and carriage of resistant organisms.29, 48
In an observational study of children in France, the
use of an oral beta-lactam agent was associated with an
increased risk of pharyngeal carriage of penicillin-
resistant Streptococcus pneumoniae. The risk was
highest in those children who had been prescribed a
lower than recommended dose of the antibiotic and in
those who had received ⬎5 days of therapy.49 A ran-
domized trial conducted in Chile confirmed these find-
Vol. 22, No. 12, Dec. 2003
ings. The rate of carriage of penicillin-nonsusceptible
pneumococci was significantly lower in children pre-
scribed amoxicillin at 90 mg/kg/day for 5 days com-
pared with children prescribed 40 mg/kg/day for 10
days.50
Understanding that low dose and/or prolonged anti-
biotic usage selects for bacterial resistance can lead to
beneficial changes in physicians’ antibiotic prescribing
practices.51 The results of a metaanalysis suggest that
5 days of antibiotic therapy is effective for uncompli-
cated acute otitis media,52 and short course therapy is
recommended for children 2 years of age and older with
uncomplicated ear infections.11 Clinical research may
define other pediatric infections for which a shorter
course of antibiotics is appropriate.
The importance of appropriate antibiotic use is mag-
nified by the fact that these drugs have an impact on
the community as well as on the child for whom they
are prescribed. An antibiotic alters a child’s microbial
flora and, for example, increases the likelihood that the
child will be colonized with a penicillin-resistant pneu-
mococcus. Although that child may never develop
pneumococcal disease, children in the same day-care
center or a younger sibling may acquire that resistant
organism and develop an ear infection or meningitis.
After an 11-month-old child in a Georgia day-care
center developed refractory otitis media caused by a
multidrug-resistant pneumococcus, other children in
the center were evaluated for nasal carriage of the
organism. Of 21 children tested 10 (48%) carried the
same highly resistant pneumococcus.53
Similarly a child in an intensive care unit who is
treated with extended spectrum cephalosporins may
become colonized with resistant pathogens such as
VRE or multidrug-resistant Gram-negative bacteria.
These highly resistant pathogens can then be transmit-
ted via the hands of a health care worker to a child in
a neighboring bed who may develop a serious infection.
The implication is that every time an antibiotic is
prescribed, there is a multiplier effect. Every antibiotic
given to a child may adversely affect 2 or 5 or 10
children. However, this fact also empowers prescribers,
because it means that for every antibiotic not pre-
scribed, 2 or 5 or 10 children are protected from the
potential adverse consequences.
The good news is that bacterial resistance is to some
degree reversible. In response to an increase in eryth-
romycin resistance among group A streptococci in Fin-
land, nationwide recommendations were issued to re-
duce the use of macrolide antibiotics. As a result
macrolide consumption declined by ⬃40%, and the
frequency of erythromycin resistance among group A
streptococcal isolates subsequently declined by almost
one-half.54
Reducing antibiotic use should be effective, because
resistant bacteria have no competitive advantage in
Vol. 22, No. 12, Dec. 2003 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL 1149

the absence of antibiotic exposure and because coloni-
zation with resistant pathogens is usually transient. A
study of nasopharyngeal carriage of penicillin-
resistant pneumococci revealed that cultures were neg-
ative within 4 weeks in 68% of carriers, within 8 weeks
in 87% and within 12 weeks in 94%.55 Because carriage
of these resistant bacteria resolves spontaneously, sus-
ceptible strains eventually replace resistant strains in
the absence of antibiotic exposure.
Antibiotic restrictions do not guarantee that antimi-
crobial resistance will disappear, however, as demon-
strated by a report from the UK.56 Despite a marked
decrease in prescriptions for sulfonamides, the fre-
quency of sulfonamide-resistant Escherichia coli did
not decrease during an 8-year time period. The reasons
for this are not clear, although it may be because the
determinants of sulfonamide resistance are genetically
linked to other resistance determinants.
The AAP and CDC have published principles of
judicious antibiotic use for upper respiratory tract
infections.57 Key features of these recommendations
are highlighted in Table 2. Despite the guidelines
inappropriate antibiotic use is common. One report
evaluated 531 pediatric office visits in which the dis-
charge diagnosis was cold, upper respiratory tract
infection, or bronchitis and found that antibiotics were
prescribed for 44% of children with colds, 46% with
upper respiratory tract infections and 75% with bron-
chitis.58 None of these patients required antibiotics,
and yet these 3 diagnoses accounted for ⬎20% of all
antibiotic prescriptions.
In another study physicians were polled regarding
their antibiotic prescribing practices, and 38% of the
pediatricians and 58% of the family physicians indi-
cated that they routinely prescribed antibiotics for the
common cold.59 In addition 81% of the pediatricians
and 93% of the family physicians routinely prescribed
antibiotics for bronchitis. A review of their office charts
showed that these reported practices correlated with
actual practices, given that antibiotics were prescribed
for 31% of visits where the common cold was diagnosed.
In addition antibiotics were prescribed for 19% of
phone encounters and 49% of office visits, including
11% of well-child checkups. There was enormous vari-
ability among practitioners, with rates of antibiotic
prescribing ranging from 1 to 10 prescriptions per child
per year.
Pediatricians acknowledge that they sometimes pre-
scribe antibiotics for inappropriate indications60; their
reasons for this are multifactorial. Parental pressure is
a major factor cited by some clinicians. Parents often
desire a tangible product at the conclusion of a visit,
and the clinician may feel that they need to satisfy this
demand. It is clear that any educational campaign to
reduce inappropriate antibiotic use in children must
target parents as well as clinicians. Other factors that
can influence prescribing practices include concerns
about legal liability, economic pressures to evaluate
and examine patients quickly and incorrect percep-
tions about the effectiveness of antibiotics for certain
infections.60, 61
Changing physician (and parental) behavior is com-
plex and will require a multifaceted approach, but
there is some evidence to suggest this can be accom-

TABLE 2. Principles of judicious use of antimicrobial agents for upper respiratory tract infections*
Disease Principles

Otitis media 1. Antimicrobials are indicated for the treatment of AOM, but the diagnosis requires
documented middle ear effusion and signs or symptoms of acute local or systemic illness.
2. A narrow spectrum antibiotic (e.g. amoxicillin) should be used for initial episodes of AOM.
3. Antimicrobials are not indicated for initial treatment of otitis media with effusion, although
treatment may be indicated if effusions persist for ⱖ3 mo.
4. Antimicrobial prophylaxis should be reserved for control of recurrent AOM, defined as ⱖ3
distinct and well-documented episodes in 6 mo or ⱖ4 episodes in 12 mo.

Acute sinusitis 1. Clinical diagnosis of bacterial sinusitis requires: nasal discharge and daytime cough without
improvement for 10 to 14 days; or more severe signs and symptoms (i.e. fever ⱖ39°C, facial
swelling, facial pain).
2. Initial antimicrobial treatment of acute sinusitis should be with the most narrow spectrum
agent that is active against the likely pathogens.

Cough illness/bronchitis 1. Nonspecific cough illness/bronchitis in children, regardless of duration, does not warrant
antimicrobial treatment.

Pharyngitis 1. Diagnosis of group A streptococcal pharyngitis should be made based on results of

appropriate laboratory tests in conjunction with clinical and epidemiologic findings.
2. Antimicrobial therapy should not be given to a child with pharyngitis in the absence of
documented group A streptococcal infection. Other rare causes of bacterial pharyngitis, e.g.
diphtheria, may require therapy.
3. Penicillin remains the drug of choice for treating group A streptococcal pharyngitis.

Common cold
* Adapted from Reference 57, with permission.
1. Antimicrobial agents should not be given for the common cold.
2. Mucopurulent rhinitis (thick, opaque or discolored nasal discharge) frequently accompanies
the common cold and is not an indication for antimicrobial treatment unless it persists for
10 –14 days suggesting possible sinusitis.
1150 THE PEDIATRIC INFECTIOUS DISEASE JOURNAL
plished. One study evaluated an educational interven-
tion for pediatricians and family physicians.62 Princi-
ples of judicious antibiotic use were discussed with the
physicians twice over a 4-month period, and parents
were mailed a brochure on antibiotic use. Antibiotic
prescribing practices before and after the intervention
were compared, as they were in “control” practices in
which no intervention was done. In children 3 to 36
months of age, antibiotic dispensing decreased 18.6%
in the intervention group vs. 11.4% in the control
practices. In another study a community-based inter-
vention trial targeted parents and pediatric primary
care providers for education regarding judicious anti-
biotic use.63 The median number of prescriptions for
liquid antibiotics per clinician declined 11% in the
intervention region, whereas it increased 12% in the
control region. The median number of solid antibiotic
prescriptions (tablets and capsules) declined by 19%
and 8% in the intervention and control regions, respec-
tively. The results of these two studies should be
interpreted with some caution because of baseline
differences in antibiotic prescribing rates between the
intervention and control groups. Nonetheless they sup-
port the idea that educating physicians and parents
can positively impact antibiotic use.
It is interesting that antibiotic use decreased not
only in the intervention groups and regions, but also in
many of the control practices and regions. This is a
nationwide trend. From 1989 to 1990 through 1999 to
2000, overall antibiotic prescription rates (per patient
visit) by office-based physicians in the US declined by
29% for children younger than 15 years of age.64 For
children younger than 5 years, the group with the
highest antibiotic use, antibiotic prescribing dropped
by 41% between 1995 and 1999.65 The message that we
need to improve our antibiotic prescribing seems to
have been heard. Each of us must do what we can to
ensure that this trend continues, because our reward
will be less bacterial resistance and healthier children.
CONCLUSIONS
Bacterial resistance threatens our ability to treat
both common and serious infections in children. Al-
though new antibiotics can effectively treat some resis-
tant pathogens and more research is needed to develop
novel antimicrobials, bacteria will eventually develop
resistance to any antibiotic with time. The misuse and
overuse of antibiotics drive the emergence and spread
of resistance. Eliminating inappropriate antibiotic use
and promoting more judicious use are essential parts of
the solution.
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