DR. ARMITAGE is a professor of medicine, department of medicine, division of infectious diseases, at Case Western Reserve
University, Cleveland, Ohio.
DR. McMILLAN is professor of pediatrics, vice chair for pediatric education, director of the pediatric residency program at
Johns Hopkins University School of Medicine, Baltimore, iMd, and editor-in-chief of Contemporary Pediatrics.
DR. BESSER is director, Coordinating Office for Terrorism Preparedness and Emergency Response, Centers for Disease Control
and Prevention, Atlanta, Ga.
MS. ASCH-GOODKIN is a contributing editor of Contemporary Pediatrics.
The authors, manuscript reviewers, and staff editors have nothing to disclose in regard to affiliations with, or financial
interests in, any organization that may have an interest in any part of this article, which is adapted from Patient Care, an Advanstar publication.
The number of pathogens that resist treatment with antibiotic agents has risen steadily during the past decade, spreading
the problem of increasing resistance from hospitals, nursing homes, and other closed settings into the community, complicating
the treatment of acute otitis media (AOM), community-acquired pneumonia (CAP), skin and soft tissue infections, and cystitis.
Pneumococcus species that are resistant to both penicillins and cephalosporins are becoming more common; by 1998, 24% of invasive isolates
in the United States were resistant to penicillin and 14% were resistant to three or more drug classes.1 Although widespread use of the 7-valent conjugate pneumococcal vaccine (PCV7) has been associated with a steep decline in
the incidence of invasive pneumococcal disease and in the number of cases involving resistant isolates, pneumococcal resistance
continues to complicate management of many common infections, and resistance is becoming more frequent in other bacterial
pathogens. Most recently, the late 1990s saw the emergence of methicillin-resistant Staphylococcus aureus (MRSA) in the community.2,3
The adverse consequences of increasing bacterial resistance include:
- More frequent treatment failures
- Increased resistance among pathogens, caused by clinicians switching from one antibiotic to another
- Increased costs due to the use of more expensive second- and third-line antibiotic agents
- The lack of effective drugs to treat some infections.
The causes of resistance
Key Points: Bacterial resistance
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Increasing bacterial resistance is largely the result of overuse of antibiotics, particularly broad-spectrum drugs. Although
judicious use of antibiotics can minimize the incidence of resistant disease at both the population and the individual levels,
a physician is likely to prescribe an antibiotic that has the greatest likelihood of providing a cure for a sick patient who
expects safe and effective treatment.
The roots of overuse
Patient misconceptions about the role of antibiotics in medicine contribute to overprescribing. The results of a 1998-1999
survey, for example, found that 27% of respondents believed that antibiotics could end a cold more quickly, 32% thought that
taking antibiotics for a cold prevented more serious illness, and 48% expected to receive a prescription when they were sick
enough from a cold to seek medical care. In the same survey, 58% of respondents were unaware that antibiotic use posed any
dangers at all to themselves or to the health of the community.4
Although many clinicians believe that patients expect a prescription for an antibiotic, studies indicate that the perception
of dissatisfaction may be mistaken or that dissatisfaction can be mitigated.5-7 Patients want both sympathy and reassurance that their office visit is a reasonable reaction to their distress. Although
some patients may be satisfied only with a prescription for an antibiotic, others may be satisfied by expressions of concern
and support. Time constraints on patient visits may lead some clinicians to believe that prescribing an antibiotic is easier
and faster than educating patients about, for example, the difference between viral and bacterial infections.
Drug manufacturers also share the blame for inappropriate prescribing, by promoting expensive, patent-protected drugs. In
addition, the current malpractice climate gives rise to the perception among physicians that prescribing an antibiotic is
safer than taking the chance—however remote—of a treatment failure that could lead to a malpractice complaint.
Dearth of new drugs.
Market economics has resulted in the lack of new antibiotics. A recent search of FDA databases revealed that approvals of
new antibacterial agents decreased by 56% over the past 20 years, and, of 506 drugs under development at the time of the search,
only six were antibacterial agents. This situation is serious, especially for infections with gram-negative pathogens, and
because of the reported increase in the number of infections that lack effective treatments.8
From the manufacturers' perspective, developing new antimicrobials—typically used to treat acute disease—lacks the return
of a drug for chronic diseases such as arthritis or hypertension. Paradoxically, the practice of conserving antibiotics that
remain effective against otherwise resistant organisms is another financial disincentive to invest in developing a sparingly
used drug.
Educate and innovate
The medical and public health communities have responded to antibiotic overuse with consensus guidelines on disease management,
the Appropriate Antibiotic Use campaign spearheaded by the CDC, and a recent push by the Infectious Diseases Society of America
(IDSA) for federal incentives to promote research and development of new anti-microbial agents.
Guidelines.
Specialty organizations and the CDC publish consensus guidelines designed to codify best practices, including choice and
dosage of antibiotics, in the treatment of common infections. Although extremely useful, guidelines are often lengthy, comprehensive
documents that address many more situations than a physician is likely to see. Locally developed hospital or practice-based
guidelines or care paths for specific diagnoses, however, are also available to physicians, and typically provide local specificity
and usefulness. Most hospitals have such care paths for specific diagnoses. A care path for CAP, for example, involves performing
a standardized workup and initiating a standardized antibiotic regimen.
The CDC Get Smart: Know When Antibiotics Work campaign.
The CDC aimed this 1995 campaign at both providers and consumers to promote the appropriate use of antibiotics using educational
materials such as waiting room posters and patient education brochures, continuing education courses for providers, partnerships
with state health agencies, and development of medical school curricula.
Although antibiotic prescribing has declined 40% since the campaign began, the declines have been in prescriptions for narrow-spectrum,
older agents such as amoxicillin and erythromycin, while prescriptions of broad-spectrum, newer and more expensive drugs increased
for both children and adults.9-13 By 1999, 22% of adult and 14% of pediatric prescriptions for broad-spectrum antibiotics were for the common cold, unspecified
upper respiratory infection (URI), and acute bronchitis—conditions that typically have a viral cause.14 CDC officials are now considering how the program can effectively promote targeted therapy.
Creating incentives for antibiotic R&D.
Acting on its position that federal incentives are needed to spur pharmaceutical research and development in the field of
new antimicrobial drugs, the IDSA launched a campaign titled "Bad Bugs Need Drugs" to draw public and government attention
to the public health crisis created by stagnating antibiotic discovery. IDSA is urging Congress to pass legislation to encourage
the pharmaceutical industry to re-enter this field: Companies that develop novel antimicrobials should be rewarded with market
exclusivity rights, and research, development, and manufacturing should be encouraged through tax credits. (See in this issue
for more on the IDSA's actions.)
A modern approach to choosing antibiotics
Web resources
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Comprehensive guidelines on the use of first-line and alternative antibiotic treatment choices and dosages are available on
the Web (see "Web resources"). Selected practical tips on prescribing antibiotics for those illnesses seen most frequently
in primary care are listed there.
Colds and other URIs.
Although antibiotic therapy is inappropriate for colds and most mild URIs, which typically have a viral cause, antibiotic
prescriptions are written for 52% of uncomplicated URIs. In addition, URIs account for 10% of all antibiotic prescriptions
written each year in ambulatory practice.15 Reforming the treatment of uncomplicated URI may be the best opportunity for clinicians to reduce bacterial resistance and
to help control health care costs.
Patients who believe an antibiotic is necessary for a cold or URI may benefit from education about the differences between
viral and bacterial infections and why an antibiotic is unwarranted, supported by handouts, brochures or posters; patient
education materials are available at the CDC Web site (www.cdc.gov/getsmart). In addition to education, patients often need their clinician to acknowledge their discomfort and validate their decision
to seek medical attention. Many patients are satisfied with an "alternative prescription" for rest, diet, and simple remedies
such as saline nose drops and OTC analgesics—and an invitation to call or return if symptoms do not resolve in seven to 10
days.
Pharyngitis.
The typical sore throat usually requires only symptomatic treatment to help patients feel better, and education is often
sufficient.16 Pharyngitis caused by Streptococcus pyogenes (a group A streptococcus), however, does require antibiotic therapy. Diagnosing pharyngitis is aided by the in-office rapid
antigen-detection test (RADT). The most recent guidelines from IDSA accept the validity of the RADT and recommend antibiotic
treatment for patients with signs and symptoms of acute pharyngitis and positive test results.17 Recommended treatment is a 10-day course of oral penicillin V or a single dose of penicillin G benzathine, IM. Patients
who are allergic to penicillin can be given a 10-day course of erythromycin or a first-generation cephalosporin. Penicillin
resistance has not been reported for S pyogenes.
Acute bacterial rhinosinusitis.
Acute bacterial rhinosinusitis (ABRS) shares many symptoms of viral URIs, such as runny or stuffy nose, postnasal drip, sore
throat, cough, and facial pain or pressure.15,18 Symptoms of ABRS also include nasal drainage, fever, dental pain, and ear pressure or fullness. As a rule of thumb,
viral URI symptoms that have not improved after 10 days or have worsened after five to seven days suggest the presence of
ABRS.19 Clinical judgment is key to the diagnosis; imaging is not recommended in uncomplicated cases. The most common bacterial
isolates are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis—all of which have shown some degree of resistance in recent years. About half of pediatric patients will experience spontaneous
resolution of symptoms without antibacterial treatment.
Recent antibiotic use is a major risk factor for resistance; therefore, tailor accordingly treatment recommendations for those
patients who have received antibiotics in the preceding four to six weeks. Specific recommendations are available in the Sinus
and Allergy Health Partnership guidelines. The American Academy of Pediatrics (AAP) recommends treating acute bacterial sinusitis
in children with antimicrobials for a more rapid clinical cure; children with complications should be treated promptly and
aggressively.20
Acute otitis media.
Antibiotics are prescribed more often for AOM than for any other childhood infection. The three pathogens most often responsible
for AOM—S pneumoniae, nontypeable H influenzae, and M catarrhalis—have all demonstrated some degree of antibacterial resistance. Most children with AOM recover completely without antibiotic
therapy, suggesting that the condition is a prime candidate for judicious use of antibiotics. Treatment guidelines from the
AAP and the American Academy of Family Physicians for managing uncomplicated AOM in otherwise healthy children 2 months of
age or older with no other signs of systemic illness or underlying condition that might alter the course of AOM suggest that
clinicians:
- Assess and manage pain
- Confirm the rapid onset of illness, presence of middle ear effusion, and signs and symptoms of middle ear inflammation
- Consider observation for 48 to 72 hours for otherwise healthy children 6 months to 2 years of age with nonsevere illness
at presentation and an uncertain diagnosis, and for children 2 years of age and older without severe symptoms at presentation or with an uncertain diagnosis.21
Drugs mentioned in this article
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An antibiotic is warranted either initially or when symptoms fail to resolve after the observation period; first-line therapy
is high-dose amoxicillin, 80 to 90 mg/kg/day. Intermediately resistant organisms usually are susceptible to high-dose penicillin.
In severe illness or when additional coverage for beta-lactamase-positive H influenzae or M catarrhalis is desired, initial therapy is with high-dose amoxicillin/potassium clavulanate. Although the number of resistant pneumococcal
isolates has decreased, the emergence of other resistant organisms is possible.2,22 Community acquired pneumonia.
If CAP is suspected, empiric treatment should be initiated before testing or culture results are known. Although pneumococcus
is the most common causative pathogen, initial therapy with a macrolide such as azithromycin or clarithromycin is recommended
in case atypical organisms are involved. High-dose amoxicillin is usually adequate against drug-resistant S pneumoniae. CAP is more often viral than bacterial in children.
Ketolides are a new class of antibiotics that are related to macrolides for use in treating respiratory infections and may
offer an advantage for the treatment of macrolide-resistant S pneumoniae. The FDA approved telithromycin for use in 2004.
Methicillin-resistant S aureus. Once found only in hospitals, prisons, and nursing homes, MRSA is now found elsewhere in the community, requiring clinicians
to adjust their antibiotic prescribing practices. Infection with MRSA typically manifests in skin and soft tissue. Mild or
moderate disease in children often responds to trimethoprimsulfamethoxazole (TMP-SMX), clindamycin, or doxycycline. In severe
pediatric illness, treatment is empiric vancomycin or vancomycin plus nafcillin or gentamicin.3 (See "Fighting a rising tide of MRSA infection in the young " in the July 2005 issue.)
Treatment options for community-acquired MRSA demonstrate the way increasing resistance increases health care costs. The cost
of treating mild MRSA infection with TMP-SMX is approximately $16. More resistant infections can be treated at reasonable
cost using generic versions of doxycycline ($22.80) or clindamycin ($73.60). In contrast, the cost of treating a severe, highly
resistant MRSA infection with linezolid is $1208.23
Urinary tract infections.
Uncomplicated urinary tract infections (UTIs) are among the most common infections in females and have been managed empirically.
The drug of choice for most patients with uncomplicated disease remains TMP-SMX, despite growing resistance to it and other
antibiotics.
Infectious diarrhea.
Increasing resistance to traditional antibiotics has also complicated the treatment of diarrhea caused by bacterial enteropathogens.24,25 Antibiotic therapy is unnecessary for many of the bacterial causes of enterocolitis, and may be harmful.
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