For more than 50 years, physicians worldwide have relied on antibiotics for rapid and effective management of many of the most common infections. Antimicrobial agents have changed the way both physicians and the public perceive bacterial infections and their treatment.

For most of the antibiotic era, antimicrobials have been hailed as "miracle drugs." By 1954, two million pounds of antibiotics were manufactured annually in the U.S. - a figure that has climbed dramatically to more than 50 million pounds today.^[1] In the euphoria surrounding these "magic bullets," little thought was given to the adverse consequences of their indiscriminate use. Rather, the drugs were embraced as a panacea, capable of eradicating infectious micro-organisms without causing much harm to the cells of the patients being treated. Because these drugs often literally saved lives, any potentially serious problems associated with them were downplayed.

Today, antibiotics remain the front-line therapy for conquering bacterial infections. However, their indiscriminate use is no longer viewed as benign. Treatment with these drugs is acknowledged to be a two-edged sword. As antimicrobial agents have been misused and overused, bacteria have fought back with a selection process by which certain strains are now no longer susceptible to one or more agents. Each new use of these drugs, in fact, contributes to the evolution of resistant microorganisms. As a result, bacteria that once seemed to be losing the battle for survival have reemerged to create therapeutic dilemmas with resulting increased risks of treatment failure and disease complications.

There presently are more than 100 antimicrobial agents available in the U.S. They eradicate infections by either destroying microorganisms, or by undermining the ability of these microorganisms to reproduce.

But even when a new antimicrobial drug is introduced, infectious bacteria may be able to evade it by developing resistance through mechanisms such as these:^[2]

• Chromosomal mutations may occur in the genes of bacteria.
• Bacteria may acquire genetic material from other bacteria that confers resistance to antimicrobial compounds.
• Antibiotic use creates an environment for selective pressure that favors the emergence of resistance.

Through natural selection, "bacteria will develop resistance to virtually every antibiotic if given enough time and enough antibiotic use," said Stuart B. Levy, MD, President of the Alliance for the Prudent Use of Antibiotics (APUA), sponsor of the Summit. "Resistance may eventually occur to every antibiotic." The time to resistance, however, can vary considerably. For example, penicillin-resistant Streptococcus pneumoniae took 25 years to emerge as a clinical problem.^[3] Fluoroquinolone-resistant Enterobacteriaceae became problematic after 10 years.^[3] With some bacteria, resistance to new drugs has emerged much more rapidly. For that reason, clinicians need to limit their use of antibiotics to clinical circumstances where these compounds are clearly necessary and known to be efficacious.

Researchers have also learned that organisms resistant to one antimicrobial agent are likely to become resistant to others. For instance, the first gonococcus that was tetracycline-resistant emerged among strains that had already demonstrated resistance to penicillin.^[3] Resistance tends to be progressive as well - that is, it moves gradually from low to intermediate, and then to a high level. Thus, the first pneumococci that became resistant to penicillin initially demonstrated a small decline in susceptibility that eventually increased to high-level resistance. This same pattern has been documented in resistance associated with many other microorganisms. Early in the process, even though resistant bacteria may be present in the environment, they pose a relatively limited threat, and the likelihood of an individual acquiring a resistant infection is low; but with time, as the number of resistant bacterial organisms increases, and the degree of resistance rises, the odds begin to favor the bacteria. Low but increasing levels of resistance among pathogenic bacteria portend high levels of resistance in the future. As drug susceptibility declines, clinicians will be wise to reduce their use of antibiotics to decrease selection of drug-resistant strains.^[3,4]

Because it is such an unusual genetic feature, resistance will not disappear once established. No counterselective measures exist against microorganisms that are resistant. Even so, after resistance emerges, it may decline slowly. This gradual decrease in resistance is associated with poorly reversible genetic and environmental factors.^[3]

Antibiotic resistance was once a concern associated primarily with hospitals. But it has become problematic in all environments, including outpatient settings and even homes. More than ever, antibiotics are being recognized as agents that are truly societal drugs, since their use in individual patients can also affect the family, the community, and society as a whole. As each patient is treated, there is an influence upon the entire normal bacterial flora shed into his or her surroundings.

As the incidence of antimicrobial resistance rises, so do costs associated with its consequences. According to estimates, the cost of resistance ranges from $75 million to $7.5 billion per year.^[5] One study by the Centers for Disease Control and Prevention (CDC) concluded that for both nosocomial and community-acquired infections, those involving drug-resistant strains were at least twice as likely to be associated with morbidity, hospitalization, and increased length of hospital stay as those with drug-susceptible strains.^[6] Although it can only be roughly quantitated, antimicrobial resistance clearly is an important health problem and an economic burden to society.^[6]

A particularly disturbing report, issued by the CDC in MMWR in 1999, described four pediatric deaths associated with methicillin-resistant Staphylococcus aureus (MRSA) that occurred in community settings in Minnesota and North Dakota.^[7] "Our investigation demonstrated an increasing number of community-acquired cases of MRSA among patients without any established risk factors," said Michael T. Osterholm, PhD, Chairman and CEO of the Infection Control Advisory Network, whose team at the Minnesota Department of Health was one of those investigating the cases. "In the last two years, we've documented more than 300 cases of MRSA in Minnesota that are clearly community-acquired." In all four deaths, the strains of MRSA were multidrug-susceptible, except to the beta-lactams. This is very unusual since most strains of MRSA are resistant to multiple antimicrobials.

In light of these fatalities, public health officials expressed concern that a "superbug" had made its way into environments such as schools and day-care facilities, claiming the lives of children from diverse backgrounds - a 7-year-old African-American girl from urban Minnesota, a 16-month-old Native-American girl from North Dakota, a 13-year-old Caucasian girl from rural Minnesota, and a 12-month-old Caucasian boy from rural North Dakota. These patients had presented with symptoms that included high-grade fever, hemoptysis, seizures, bronchiolitis, vomiting, and/or irritability, and all were treated initially with a cephalosporin (cefazolin, ceftriaxone). "But all four went downhill so fast, so far, that by the time they were finally treated with vancomycin, it was too late," Dr. Osterholm told the Summit. "The average physician wouldn't think of an illness like this. It's not picked up in an antimicrobial resistance surveillance picture."

S. aureus is among the most common pathogens associated with hospital- and community-acquired infections. Reports that preceded the deaths described above had indicated increases in community-acquired MRSA. For example, a study at the University of Chicago Children's Hospital found that the number of children hospitalized with community-acquired MRSA climbed from 8 in 1988-90, to 35 in 1993-1995; at the same time, the prevalence of community-acquired MRSA in children without identified risk factors rose from 10 per 100,000 admissions (1988-90) to 259 per 100,000 admissions (1993-1995).^[8]

Antibiotic prescriptions have been on the rise for many years, and continue to climb. In the U.S., about 190 million daily-defined doses of these drugs are prescribed in hospitals annually. The numbers are also high in community settings - a total of 145 million courses (110 million in outpatient settings; 35 million in emergency departments).^[9]

Each time an antibiotic is used, it may contribute a little to the environmental pool of resistant bacteria. Not surprisingly, as the number of prescriptions has risen, so has the incidence of resistance. As a result, the empiric management of many infections has become more difficult in some geographic regions where resistance to organisms has become more prevalent. Some community- and hospital-acquired bacterial strains have developed resistance to so many antibiotics that choosing an effective agent for certain serious infections is becoming more challenging.

Because each antibiotic use contributes to the selection of resistant forms of bacteria, the unnecessary use of an antimicrobial is particularly troubling. Yet unneeded antibiotics are prescribed millions of times each year. For example:

In community settings, 20 to 50 percent of antibiotic use is deemed inappropriate.^[9]

In hospital settings, 25 to 45 percent of antibiotic use is deemed inappropriate.^[9]

According to 1992 data from the National Center for Health Statistics, antibiotics were given inappropriately to large numbers of patients with conditions that commonly have a viral etiology, and for which these drugs lack efficacy. For instance, more than 70 percent of non-streptococcal pharyngitis cases were prescribed an antibiotic. So were more than 50 percent of patients with rhinitis.^[10]

What are the reasons for this overprescribing? A number of factors may play a role. According to one recent report, physicians often acquiesce to patient demands for these drugs.^[11] Patients often do not understand the possible harm of taking antibiotics without restraint, and doctors may feel too pressed for time to explain why an antibiotic is unnecessary - so a prescription is written instead. Some physicians also overprescribe because of concerns that they may misdiagnose a bacterial infection for which an antibiotic is appropriate.^[11]

When the APUA collaborated with the Massachusetts Department of Public Health and the Massachusetts Infectious Diseases Society on a survey of primary care physicians, it found that increases in outpatient antibiotic prescribing were due primarily to patient requests for these agents, as well as the physician's hope to keep the patient satisfied with the office visit.^[12] In another recent study, researchers at the CDC conducted focus groups with primary care physicians, pediatricians and parents to determine their attitudes about antibiotic use. The physicians in private practice estimated that they could reduce their own prescribing of antibiotics by 10 to 30 percent without negatively affecting patient care.^[13]

Economic Concerns and Other Factors

Additional factors have been cited as contributors to inappropriate antibiotic use and antimicrobial resistance. For instance, physicians may worry about losing patients if they decline to prescribe. They might prescribe antibiotics inappropriately due to pressure from patients or parents who want to return to work or school sooner. Some doctors could have inadequate knowledge about who should or shouldn't receive these drugs. Physicians in managed care settings might feel pressure to cut costs by providing drug therapy rather than ordering diagnostic tests.^[9]

Patients may add to the problem of antibiotic resistance when they don't take the full course of a prescribed drug. Many people stop taking antimicrobial agents when their symptoms improve, even though the infectious organisms may not have been eradicated completely. Then they will store the remaining medication for future use when they (or a family member) develop another illness, even though that new ailment may not be one for which antibiotics are appropriate - particularly in a shortened course that is not therapeutically effective. Incomplete treatment can lead to treatment failure or a recurrence of symptoms, while also encouraging the growth of resistant strains.

Antimicrobial Products

One problem area often overlooked involves antibacterials (disinfectants and antiseptics) that have been incorporated into household products such as soaps, dishwashing detergents, lotions, and even toys and mattress pads. The public presumes that these antibacterials can sterilize the home environment and perhaps even fight off infections. However, studies have shown that these agents can produce changes in hospital flora; thus their presence in many household products may be contributing to antibiotic resistance.^[14]

In excess of 40 percent of the antibiotics produced in the U.S. each year are used in animals - which ultimately has consequences for the management of human disease.^[3,14] They are administered for the treatment or prevention of infections in animals, and are employed at low levels as growth enhancers in cattle and poultry.

Antibiotics are also applied as aerosols to fruit trees to control or prevent bacterial infections, and they are used in trout and salmon farms. According to one estimate, 40 to 80 percent of antibiotics used on farms are unnecessary.^[9]

"In agricultural use, these antibiotics are sprayed on fruit trees from planes or dusters in states such as Georgia, Louisiana and Florida," said Dr. Levy, who co-chaired the Summit. "So the people in those communities could be receiving small but repeated doses of antibiotics. Of course, in these situations, they aren't called antibiotics; they're called pesticides."

Does this use of antibiotics actually lead to resistance? "The evidence is undeniable," Scott A. McEwen, DVM, Professor of Veterinary Medicine at the University of Guelph in Ontario, Canada, told the Summit. "Of course it leads to resistance." Long-term exposure to low concentrations of antibiotics creates the environment for the development of resistant strains of bacteria that can be passed to a broad human population.^[14] When antimicrobial agents are applied to farm products, their residues can stimulate the growth of resistant bacteria that colonize the products during processing. When antibiotics are used for growth promotion, resistant microbes may eventually make their way to people who prepare or consume undercooked meat.^[14]

Recent reports in the New England Journal of Medicine have raised further concerns about emerging infections through veterinary use of antibiotics. For example, one study described a ceftriaxone-resistant salmonella infection acquired by a 12-year-old boy, most probably from direct or indirect contact with infected cattle on a farm in Nebraska.^[15]

At the Summit on Antimicrobial Resistance, participants discussed in depth many of the worrisome trends in resistance, including the growing number of drugs to which some organisms are resistant. Over 90 percent of strains of S. aureus demonstrate resistance to penicillin and related antimicrobial agents.^[9] It is not uncommon for certain micro-organisms to become multidrug resistant, sometimes insensitive to more than 10 antibiotics.^[5] For example, certain strains of three species - Enterococcus faecium, Mycobacterium tuberculosis and Pseudomonas aeruginosa - are resistant to nearly every available antibiotic, which is particularly ominous because they are associated with potentially life-threatening diseases.^[14]

"There are organisms that, 10 years ago, we could treat by choosing from among an assortment of antibiotics," said Dr. Levy. "Today, in some cases there may be only one antibiotic that proves effective. For tuberculosis and, in certain parts of the world even E. coli, you would now be hard pressed to find the right antibiotic to use."

Strains of Streptococcus pneumoniae with declining susceptibility to penicillin were actually quite low in prevalence until the late 1980s (according to one estimate, the odds of finding a multiresistant pneumococcal infection in a child may be millions of times higher today than it was 15 years ago).16 Between 1979 and 1987, only 0.02 percent of isolates had high-level resistance (MIC: 2 mg/ml or greater); but the percentage has increased since then.^{[10 ]}From January through October 1994, pneumococcal isolates from 431 patients with invasive disease in Atlanta were tested to determine their susceptibility to a number of antibiotics. Isolates from 25 percent of patients were resistant to penicillin, while 26 percent were resistant to trimethoprim-sulfamethoxazole (TMP-SMX); 9 percent were resistant to cefotaxime and 25 percent were resistant to multiple drugs.^[17] Now, with the emergence of S. pneumoniae that is resistant to multiple antibiotics, the treatment of conditions such as acute otitis media, sinusitis, and pneumonia has become more complicated.

"Antibiotic resistance now pervades all communities," Maurice A. Mufson, MD, Professor and Chairman of Medicine at Marshall University School of Medicine, told the Summit. "It complicates treatment choices and potentially places affected patients at increased risk of an adverse outcome."

In light of the worsening crisis, Dr. Mufson called for "more rational treatment of antibiotic-susceptible and antibiotic-resistant infections, and the appropriately restrained use of antibiotics to avoid production and selection of resistant strains."

Some intervention programs directed at reducing antibiotic use have proven successful. In a study of four primary care practices in Denver belonging to a group-model health maintenance organization, researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients, aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, as well as a clinician intervention involving education, practice profiling and academic detailing. In the practice profiling, for example, clinicians were given site-specific antibiotic prescription rates for acute bronchitis, using data from the prior winter. They were also provided education on the evidence-based management of acute bronchitis, and received guidance on how to say "no" to patients who demand antibiotics. The results: The program produced substantial declines in the rates of antibiotic prescribing (from 74 to 48 percent) when the complete intervention was employed. Moreover, return office visits for bronchitis or pneumonia did not change significantly as a result of the intervention.^[18]

At the Summit, participants agreed that the use of antibiotics could be reduced significantly in treating certain infections, which in turn could slow the emergence of resistant organisms.

Urinary Tract Infections

A recent study documented the increasing prevalence of antimicrobial resistance among uropathogens in women with an outpatient diagnosis of acute cystitis between 1992 and 1996. Researchers found significant increases in the prevalence of resistance to TMP-SMX, cephalothin and ampicillin. For example, among isolates of E. coli, the predominant uropathogen in acute uncomplicated cystitis, the prevalence of resistance to TMP or TMP-SMX increased from about 9 percent in 1992 to over 18 percent in 1996; resistance also doubled - from 8 to 16 percent - among all isolates combined. The two agents with the best in vitro susceptibility profiles were nitrofurantoin and ciprofloxacin; resistance to these drugs was uncommon over the course of the study, occurring in 0 to 2 percent of E. coli isolates, and less than 10 percent among all isolates combined.^[19]

Thomas M. Hooton, MD, Professor in the Division of Infectious Diseases at the University of Washington School of Medicine and co-chair of the Summit, reviewed the current status of UTI therapy, and noted that one potential adverse outcome of the increasing prevalence of TMP-SMX resistance is that physicians will start prescribing fluoroquinolones for everyone. In reviewing the current practice guidelines of the Infectious Diseases Society of America, he pointed to the recommendation of short-course therapy for acute uncomplicated cystitis.^[20] The current standard is a three-day regimen of TMP-SMX. Other drug options - such as a three-day course of a fluoroquinolone - can be considered when resistance rates exceed 10 to 20 percent (fluoroquinolones are not advised for universal first-line empiric treatment for acute uncomplicated cystitis).^[20] Nitrofurantoin (a seven-day course) or fosfomycin (a single dose) are other antibiotic alternatives. The prevalence of resistance among uropathogens to amoxicillin and sulfa drugs is too high to recommend these agents for empiric therapy of acute uncomplicated cystitis. Moreover, if beta-lactams are used for acute uncomplicated cystitis, treatment duration should be longer than three days.^[20]

Acute Otitis Media

Acute otitis media (AOM) is the most common illness for which children visit physicians' offices. Antimicrobial drugs have been shown to have a significant effect on AOM, and are routinely prescribed and recommended by most guidelines.^[21] According to therapeutic principles published recently in Pediatrics, "antimicrobials are indicated for the treatment of AOM; however, diagnosis requires documented middle ear effusion and signs or symptoms of acute local or systemic illness."^[22] The same guidelines state that antibiotics are not indicated for the initial therapy of otitis media with effusion (OME), but they may be advisable if effusions persist for three or more months.^[22]

The number of prescriptions for AOM in office-based settings has soared. For example, prescriptions for amoxicillin climbed from 4.2 million in 1980 to 12.4 million in 1992. Significant increases also occurred in prescriptions for cephalosporins - from 876,000 in 1980 to 6.9 million in 1992.^[23]

Excessive or inappropriate use of antimicrobials for AOM has produced selective pressure that has increased the percentage of infections caused by multidrug-resistant strains of Streptococcus pneumoniae.^[24] Such resistance is associated with poorer clinical outcomes. For example, in a study of children (ages 6 to 36 months old) with pneumococcal otitis media, intermediately penicillin-resistant S. pneumoniae was associated with a decline in bacteriologic and clinical response of AOM to cefaclor and cefuroxime axetil (see Table 1).^[25]

Table 1. Treatment Failures in Otitis Media Patients with Intermediately-Resistant Pneumococci

% of patients with bacteriologic failure (by penicillin MIC)
	<.1 mg/ml	.125 - .25 mg/ml	.38 - 1 mg/ml	p value
Cefuroxime (n = 41)	9%	8%	50%	0.084
Cefaclor (n = 37)	4%	43%	80%	<0.001

Source: Dagan R, et al., Pediatr Infect Dis J, 1996

Ironically, studies have shown that in approximately 80 percent of cases, AOM will resolve in 7 to 14 days without drug therapy and with only observation (compared to 95 percent resolution in patients who are managed with antimicrobial agents).^[21,22] Withholding of antibiotic treatment from all but the sickest children over two years old is a common practice in some Western European countries. In such circumstances, management is directed primarily at relieving symptoms (e.g., analgesics for pain relief, acetaminophen for fever reduction); antibiotics are prescribed only if signs and symptoms continue after 1 to 3 days of observation.^[26]

"There is ongoing research of AOM in children as young as six months old, and the preliminary findings suggest that observation in this age group may be an effective approach, with antibiotic therapy used if there is no resolution in two days or if drainage occurs," said S. Michael Marcy, MD, pediatrician at Kaiser Foundation Hospital.

In the U.S., high-dose amoxicillin (80-90 mg/kg/day) remains the drug of choice for initial empiric treatment of AOM in most communities. If pain, fever, and an inflamed tympanic membrane persist after two days of therapy, this may indicate the presence of antibiotic resistance, and a second-line drug should be considered, including high-dose amoxicillin/clavulanate, cefuroxime axetil, or intramuscular ceftriaxone.^[26]

Colds/Upper Respiratory Infections/Pharyngitis

Antimicrobial drugs have no demonstrated efficacy in the management of viral upper respiratory infections. Thus, they should not be prescribed for the common cold, nor should they be used to treat mucopurulent rhinitis that accompanies a cold unless it persists for more than 10 to 14 days.^[27]

Despite these guidelines, antibiotic prescriptions for colds, URIs and bronchitis accounted for 21 percent of all the antibiotic prescriptions written for adults in 1992. A total of 51 percent of patients diagnosed with colds, 52 percent with upper respiratory infections, and 66 percent with bronchitis were treated with antibiotics.^[28] This study convincingly demonstrated the overuse of antibiotics for infections caused predominantly by viruses.

Likewise, most episodes of sore throats are caused by viral agents. Clinical findings, however, cannot reliably distinguish between viral and streptococcal pharyngitis. Therapeutic principles for pharyngitis recently advised that antimicrobial drugs not be used in the absence of diagnosed group A streptococcus or another bacterial pathogen.^[29] A penicillin remains the drug of choice for treating group A streptococcal pharyngitis.

"For the parent who says, 'Are you going to let my child suffer with this sore throat pain by not giving him penicillin?', there is research indicating that the use of acetaminophen or an anti-inflammatory drug is able to reduce the pain and fever as rapidly as penicillin," said Dr. Marcy. "So when a child has a sore throat, I tell the parent, 'Give him acetaminophen today and tomorrow, and by then we'll have the throat culture back and we'll treat as necessary.' In terms of both symptoms and rheumatic fever complications, there is no reason to treat with antibiotics immediately - and of course a negative throat culture is an indication to stop antimicrobial therapy if it has been started." However, he added, two-thirds of family physicians and 40 percent of pediatricians continue therapy even when the throat culture is negative. "Their thinking is, 'You've done so well on penicillin, I am really reluctant to stop it, even though the culture is negative.' Well, why take the culture if you're not going to listen to it? It makes no sense."

Lower Respiratory Infections: Bronchitis and Pneumonia

Acute bronchitis is a common clinical problem that causes considerable morbidity and presents a diagnostic dilemma to physicians. As noted above, about two-thirds of patients with bronchitis receive antibiotics. However, a critical review of studies of acute bronchitis concluded that the existing literature does not support antibiotic therapy for this condition.^[30]

Recent guidelines in Pediatrics stated, "Regardless of duration, nonspecific cough illness/bronchitis in children rarely warrants antimicrobial treatment.... Antimicrobial treatment for prolonged cough (>10 days) may be indicated occasionally."^[31]

In the U.S., pneumonia ranks among the ten leading causes of death. The incidence of invasive pneumonia is increasing, and with an aging population its numbers may continue to escalate. "The emergence of widespread antibiotic resistance among the leading bacterial pathogens of the respiratory tract - particularly Streptococcus pneumoniae and Haemophilus influenzae - is a growing concern among physicians," said Dr. Mufson.

Knowledge of resistance patterns in the community can assist the physician in gauging the likelihood that a community-acquired pneumonia is due to resistant pneumococcus. According to Dr. Mufson, S. pneumoniae that is susceptible or intermediately resistant can be treated successfully with penicillin or a cephalosporin, for example. However, for highly resistant pneumococci, patients should be treated with antibiotics to which the pathogen is susceptible. Fluoroquinolones with good activity against S. pneumoniae (levofloxacin, gatifloxacin, moxifloxacin) are reasonable empiric alternatives.^[32] All pneumococci are susceptible to vancomycin, and thus the indiscriminate use of this drug must be avoided to prevent the emergence of vancomycin-resistant isolates. While good surveillance systems are needed, there is no way to know what is going on in an individual patient without a culture, which is not generally recommended in the outpatient setting.

Sexually Transmitted Diseases (STDs)

For the treatment of some STDs, the emergence of resistance has forced a reevaluation of optimal drug management. For example, therapy for gonorrhea has undergone several changes in recent decades. In the early 1970s, a single injection of penicillin (and later, oral tetracycline) was an effective means of treating this STD. But with the development of resistance, treatment choices shifted to cephalosporins or fluoroquinolones.^[33,34] Recently, quinolone resistance has been reported in some gonococcal strains; this disturbing trend may force another change in treatment recommendations.

The CDC has published STD treatment guidelines for community physicians.^{[34 ]}"In general, most providers are following these guidelines," said Gail Bolan, MD, of the San Francisco Department of Public Health. However, she added, practitioners often believe that patients with a recurring STD have been reinfected by an untreated partner, whereas it may be a case of resistance-related treatment failure. Thus, clinicians need to become more aware of resistance patterns, and the role that resistance may play in symptom recurrence.

At the Summit on Antimicrobial Resistance, primary care physicians and infectious disease specialists drafted a blueprint for action, incorporating a series of recommendations for community physicians to help turn the tide on antibiotic resistance. These strategies include the following:

1. Do not indulge patient demands for unneeded antibiotics.

Patient expectations for antibiotics have been one of the biggest obstacles to rational prescribing. Not surprisingly, patients are eager to recover from illness as rapidly as possible so they can return to their daily routines. When children are ill, their parents may push for antibiotics so they can return their youngsters to day-care or school (in one study, a parent complained that her day-care provider pressured her to get medical treatment for her youngster's upper respiratory symptoms).^[13] In recent years, as patients have assumed a more active role in their own health care, they are less hesitant to be assertive in their doctors' offices. But their requests for antibiotics are often inappropriate, such as in the presence of a viral illness, or when they ask for specific antibiotics with a broader spectrum than is needed for their particular infection.

Physicians need to recognize that there is support for their non-prescribing of antibiotics when dictated by the circumstances of a particular case. Not only does that support come from their peers and the medical literature, but even from patients themselves in a number of studies. In research by the CDC in which focus groups of patients were questioned on the prescribing practices of physicians, most parents stated that doctors should decide who gets antibiotics, and that they would accept that decision if physicians took the time to answer questions and explain the reasons for not prescribing these drugs.^[13]

2. Educate patients (and parents) on appropriate antibiotic use.

Education is part of the process of resisting patient demands for antibiotics when they are inappropriate. Patients need to be told that these drugs are not "cure-alls," and that they should be taken only when needed (e.g., for a known bacterial infection). They must learn that antibiotics should not be used for symptomatic relief (for example, at the first sign of a cough or scratchy throat), and that the emergence of resistance has public-health implications that extend far beyond the patient being treated.

In order for patient education to be successful, one must not dismiss a patient's concern or minimize his or her illness. To build trust, don't discount the condition as "only a viral infection." A parent who enters the doctor's office with a sick child wants the best care for his or her child. As part of the educational process, explain the inappropriateness of prescribing an antibiotic, and then say something like, "Let's think of what we can do." To help ease demands for these drugs to treat viral illnesses, inform patients of other therapeutic options for relieving symptoms, which may include decongestants, cough medicine, or antipyretics. Do not use antimicrobials as antipyretics.

It is true that in today's healthcare delivery system, physicians have less time than ever to spend with each patient. But Dr. Marcy told the Summit, "It takes me only one to two minutes to explain why I am not prescribing antibiotics for a particular patient. Most parents will accept it if you give them a good reason."

Although patients tend to see their physician as the primary provider of education, some have said that in addition to their doctors, reliable information is also often communicated by nurses and health educators, who may be on the doctor's staff.^[13] The CDC has also developed "prescription pads" that physicians can hand to their patients; this printed material explains the reasons why an antibiotic is not being prescribed, and offers guidelines for symptomatic treatment.^[35,36]

3. Identify the pathogen.

When there is uncertainty about the diagnosis of a particular illness, it can lead to the unnecessary use of antimicrobials. Before prescribing an antibiotic, physicians should conduct a clinical evaluation and use diagnostic techniques, when appropriate, to identify the causative microorganism. For example, in the diagnosis of AOM, pneumatic otoscopy may be indicated. For pharyngitis in which group A streptococcus is suspected, a throat culture or rapid antigen test for group A streptococcus should be performed. Urethral, cervical or urine specimens should be collected for appropriate tests for Neisseria gonorrhoeae or Chlamydia trachomatis if an STD is suspected.

A sputum Gram stain may be helpful in directing empiric therapy in community-acquired pneumonia. Likewise, urinalysis is helpful in the diagnosis of a UTI. However, sputum and urine cultures are generally not thought to be cost-effective in the management of lower respiratory infections and acute uncomplicated cystitis, respectively.

4. Choose short-course, narrow-spectrum antibiotics.

When appropriate - in simple infections, for example - physicians should prescribe antibiotics targeting a narrow range of bacteria. This will help preserve the normal susceptible flora in patients, while also slowing the buildup of resistance in patients and in the community. Broad-spectrum drugs should be reserved for more serious or suspected polymicrobic infections. Also, prescribe shorter courses of antibiotics when this choice is supported by clinical data, such as in acute uncomplicated cystitis.

5. Complete the full course of therapy.

When antibiotics are prescribed, patients must be instructed to take all of the pills, regardless of when symptoms resolve. Explain that this will ensure that all bacteria are destroyed, and that the growth of resistant strains will not be encouraged. Patients should be discouraged from saving unused antibiotics for use at a later date.

6. Use antibiotics for prophylaxis prudently.

Physicians should eliminate excess prophylactic use. In general, the biggest problem with prophylaxis is using broad-spectrum antibiotics unnecessarily and not discontinuing the drugs when it is appropriate to do so.

In situations where prophylaxis is prudent - in certain patients undergoing surgery or dental procedures - the drug, dose and duration of therapy should be chosen carefully. The American Heart Association (in collaboration with the American Dental Association and the Infectious Diseases Society of America, among other organizations), has published guidelines on antimicrobial prophylaxis for dental procedures.^[37] Likewise, there are published guidelines for surgery-related prophylaxis.^[38]

7. Follow proper hygiene procedures.

Physicians and other healthcare professionals should adhere to recommended hygienic practices. These include washing hands often and thoroughly with soap and water, especially between patient visits. Such steps can lower the risk of transmitting infections to patients, and thus reduce the need for antibiotic use and the likelihood of promoting antibiotic resistance.

Patients should also be encouraged to adopt proper daily hygiene. However, they should limit their use of soaps and other products with antibacterial chemicals; these should be reserved for ill individuals with a weakened immune system who may benefit from the additional protection of these products.

8. Encourage patients to get vaccinated.

Patients at risk for pneumonia should be immunized with the 23-valent pneumococcal polysaccharide vaccine. Current recommendations call for immunization of the elderly, as well as persons ages 2 to 64 years with an increased likelihood of an adverse outcome from serious pneumococcal pneumonia (such as the immunocompromised).^[39] Wider use of this vaccine can help prevent penicillin-resistant pneumococci and multidrug-resistant pneumococci from infecting people at high risk of serious pneumococcal disease.

The Food and Drug Administration recently approved a conjugate heptavalent pneumococcal vaccine for use in infants and children. The Advisory Committee on Immunization Practices has recommended vaccination of all infants less than two years old (and high-risk children between two and five years of age).^[40]

9. Improve resistance surveillance systems.

Although community-based physicians feel responsible for knowing about the local milieu of antimicrobial resistance and tailoring their practice to respond effectively to it, the tools are not there to do so. The current network for determining antibiotic resistance at the community level and making those data available to clinicians is very limited.

The Summit participants urged the establishment of a sophisticated surveillance and reporting system in every community to update physicians on the presence of resistant organisms in their locality. The foundation of these networks should be state-of-the-art laboratories and equipment for detecting, monitoring and investigating microbial infections, as well as trends in resistant organisms in both hospital and community settings. These data will help clinicians make rational antibiotic treatment decisions.^[14,36]

"The fundamental goal of surveillance is to gain as much information and knowledge as possible to make strategic decisions in a timely fashion," Daniel F. Sahm, PhD, Chief Scientific Officer at MRL Pharmaceutical Services, told the Summit. "The electronic surveillance approach establishes a dynamic and highly interactive antimicrobial susceptibility database. The technology now exists for rapid dissemination of information throughout the clinical community."

10. Use antibiotics judiciously in non-human settings.

Many antibiotics that are used for veterinary medicine or agriculture select for resistance to drugs used in human medicine. In the late 1970s, when a multidrug-resistant strain of Salmonella typhimurium spread from animals to humans, legislation in Europe and elsewhere instituted guidelines on the use of antibiotics as growth promoters.^[3] Since then, European countries have imposed tighter restrictions on the use of some agents, including the outright banning of certain compounds for growth promotion.^[3]

There are similar calls for bans in the U.S., including those by scientists and public interest groups petitioning the Food and Drug Administration. To date, however, there has been little movement in this direction.

11. Advocate new drug development.

Linezolid, a novel antimicrobial agent recently approved by the FDA, has demonstrated activity against many antibiotic-resistant strains. Most certainly, however, linezolid is only a beginning. Further efforts at developing new agents must be pursued aggressively.

New classes of antibiotics should circumvent existing resistance mechanisms or have new targets. Once these original compounds are available, they must be used prudently to ensure that they won't develop resistance problems as well.

Through efforts by clinicians, patients and public health officials, the antimicrobial resistance crisis can be slowed. Although some resistance is inevitable with the use of antibiotics, steps can be taken to curtail practices that cause and propagate resistance. Thus, it should be possible to maintain or prolong the efficacy of existing drugs.

Despite the international scope of antimicrobial resistance, action at the local level - including in physicians' offices - can make an enormous difference. The consensus of the meeting participants was expressed by Dr. Marcy. "I think we can reduce the use of antibiotics dramatically," he said. "I believe we can reduce the number of resistant organisms dramatically. Yes, it seems overwhelming at times. But if each of us does a little, all of us can do a lot."

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