Prevention and management of antibacterial resistance for primary care patients with respiratory tract infections.

Abstract: This review examines the problem of increasing antibacterial resistance among the pathogens commonly associated with community-acquired respiratory tract infections, particularly Streptococcus pneumoniae. Haemophilus influenzae, and Moraxella catarrhalis. The increases in morbidity, mortality, and treatment cost associated with increased resistance to available antibiotics are challenging prescribers to find more effective therapeutic strategies. A MEDLINE search of the literature from 1966 to the present was performed to seek data relevant to the issue of resistance, especially the negative effects on patient outcomes and costs of therapy. Several observations and conclusions emerged. Data are lacking on local resistance patterns, broad-spectrum agents are overprescribed when narrower-spectrum choices would be more appropriate, a need exists for educational programs to encourage restricting drug use and changing prescribing habits, and there is a need for new antibiotic choices. The best antibiotic options are agents with a tailored spectrum of activity that are targeted at particular respiratory tract pathogens and have low potential to select for resistant organisms.

**********

The issue of antibacterial resistance has received worldwide attention in the past few years, particularly in the United States, in the management of respiratory tract infections (RTIs), which encompass community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pediatric infections, such as acute otitis media, and streptococcal tonsillitis or pharyngitis. These conditions are among the leading infectious disease diagnoses that result in visits to health care providers in the United States. From 1980 to 1996, upper respiratory tract infections (URTIs), otitis media, and lower respiratory tract infections, including influenza, accounted for 200, 80, and 74 visits, respectively, per 1,000 population. (1)

The most common etiologic pathogens for bacterial RTIs are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. These three organisms and other less commonly encountered pathogens, such as Staphylococcus aureus, are among those demonstrating increasing resistance to various antibacterial agents. (2-5) Such resistance poses a challenge to prescribers because it limits the antibiotic choices available for effective treatment. (6,7) For some bacterial pathogens--resistant enterococci, for example--hospital in Europe and North America have documented that there are no effective, first-line therapeutic options remaining.

Antibiotics represent the second-largest category of drugs prescribed by primary care physicians (261 million courses prescribed in ambulatory settings in 1998), and treatment of RTIs accounts for 67% of antibiotic use in adults and 87% in children. (2) Simultaneously, decreased efficacy, due in large part to increased antibacterial resistance, has resulted in increased inpatient and outpatient morbidity and mortality rates. (4,9,10) The widespread use of expensive, broad-spectrum agents and multiple courses of therapy due to treatment failures are also resulting in rising treatment costs. (2,11)

Primary care physicians thus have a critical responsibility to better understand and effectively combat the problem of antibacterial resistance in the treatment of patients with RTIs. A more thorough appreciation of the factors involved in making appropriate therapeutic choices will increase the chances of treatment success and better safeguard the future utility of antibacterial agents. (3,12)

Development of Resistance by Clinically Important Respiratory Tract Pathogens

S. pneumoniae, H. influenzae, and M. catarrhalis account for the vast majority of community-acquired RTIs. (5,13) Other Gram-positive and Gram-negative pathogens are also causative agents, however. Although the data are still scarce, there is a worrisome trend toward antibacterial resistance among organisms commonly referred to as atypical or intracellular pathogens (Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae), especially in community-acquired pneumonia. Legionella species, in particular, are singled out. (5) Other pathogens are implicated in community-acquired RTIs in specific settings: S. aureus and Pseudomonas aeruginosa are usually found in nursing home patients and in those with structural lung disease, and anaerobes and Klebsiella pneumoniae are pathogens implicated in aspiration pneumonia. (13)

Antibacterial Resistance to Penicillin

After the debut of penicillins in the 1940s, many years passed before the first resistant pneumococcal strains emerged. The exquisite sensitivity of S. pneumoniae to penicillin began to erode in 1967, when the minimal inhibitory concentration (MIC) observed in a pneumococcal isolate was 20 times higher than that in any strain previously studied. In 1974, Forward (14) reported one of the first clinical failures of penicillin therapy for a pneumococcal infection (ie, to treat pneumococcal meningitis). Since the 1970s, the growing resistance of pneumococci to penicillin has been well documented throughout the world, with a high of 79.7% observed in a Korean survey between 1996 and 1997. (15)

The most rapid increase in pneumococcal resistance has been reported overseas. In Hong Kong, during a period of 18 months in the 1990s, the prevalence of drug-resistant S. pneumoniae increased from 6.6 to 55.8%; in Madrid, cerebrospinal fluid pneumococcal isolates went from a resistance rate of 25% in 1992 to 100% in 1996. (16)

The results of three surveillance studies of S. pneumoniae isolates collected from U.S. medical centers showed a trend of increasing high-level and intermediate resistance. (17-19) Resistance rates increased from 23.6 to 29.5 to 34.2% in studies in periods from 1994 to 1995, 1997 to 1998, and 1999 to 2000, respectively. (17-19) In another 3-year surveillance study of invasive pneumococcal disease, resistance to penicillin increased from 21 to 25% from 1995 to 1998. Overall, 24% of 3,475 available S. pneumoniae isolates were resistant to penicillin in 1998. (7)

Outbreaks of erythromycin-resistant streptococci, as well as resistance to [beta]-lactam antibiotics by H. influenzae and M. catarrhalis, have also been documented. Both of the latter pathogens express [beta]-lactamase, thereby disabling the effectiveness of [beta]-lactam agents. Whereas nearly all isolates of M. catarrhalis express the enzyme, (3) only approximately 30 to 35% of H. influenzae isolates are affected. (5,20) [beta]-lactamase expression in H. influenzae seems to be affected by the site of infection, patient age, type of Haemophilus infection, and country of origin. (21)

Development of Multidrug Resistance 

Multiresistant S. pneumoniae bacteria are defined as those strains that are resistant to penicillin plus two or more other drug classes. These classes can include macrolides, tetracyclines, chloramphenicol, and co-trimoxazole. (22) In the United States, the percentage of multiresistant strains has increased from 9.1% in the period from 1994 to 1995, to 16.9% in 1997 and 1998, to 22.4% in 1999 and 2000. A much smaller, slower, but steady increase in pneumococcal resistance to fluoroquinolones also has been observed. (22) The reduced susceptibilities of S. pneumoniae to various classes of antibiotics are shown in Table 1.

Although S. aureus causes less than 10% of community-acquired pneumonia, this pathogen is problematic because of the high rates of resistance found in hospitals. Multidrug-resistant (eg, methicillin, penicillin, amikacin, macrolides) strains of S. aureus are most common in nosocomial infections, with an estimated annual hospital cost of $122 million. (23,24)

Factors Contributing to Resistance in the Primary Care Setting

Antibiotic Overuse 

A number of factors, most notably the overuse of broad-spectrum antibiotics (Table 2), can contribute to the development of antibacterial resistance in the primary care setting. (25) Austin et al (26) assessed the impact of antibiotic consumption on frequency of resistance and verified that the volume of drug use provides the major selection pressure on the process. These investigators also found that reduction in antibiotic use restores susceptibility, although at a much slower rate than the rate at which resistance developed. (26) Despite the knowledge that colds, other URTIs, and bronchitis are usually caused by viruses, two surveys of office-based physicians, one of which surveyed doctors treating adults and the other of which surveyed those treating pediatric patients, showed that between 44 and 75% of patients were given prescriptions for antibiotics. Interestingly, physicians who took care of children but were not pediatricians were more likely than pediatricians to prescribe antibiotics for children with colds, URTIs, or bronchitis. (27) In a review of a wide range of studies assessing the practical implications of S. pneumoniae resistance, Wang et al (25) summarized the over-whelming numbers of prescriptions written for pediatric URTIs. More than 50% of children with uncomplicated nasopharyngitis received antibiotic prescriptions in one series; in another, 100% of those with sinusitis, 82% with bronchitis, and 81% with pharyngitis were prescribed antibiotics. Some of the prescriptions, of course, may have been given due to a belief that using antibiotics prevents secondary bacterial infections in cases of a preceding viral infection. (25)

Parental demand for antibiotics is also known to influence prescribing practices. In a survey of pediatricians regarding prescribing habits, 48% reported that parents pressured them for antibiotics for illnesses that were deemed not appropriate for the use of these drugs, and one-third of the respondents reported that they occasionally (or more frequently) complied with the request. (28) Other reports echo these data, with evidence showing that incorrect beliefs regarding the ability of antibiotics to treat symptoms of the common cold strongly influenced requests for antibiotic prescriptions during an office visit. (11) Physician compliance with such requests can perpetuate the belief that the antibiotic, not the natural course of the disease, is the reason for the patient's improved condition.

Increased use of broad-spectrum versus narrow-spectrum antibiotics has also contributed to increased community-based antibacterial resistance. The use of agents that affect more than the specific infecting pathogen also have an unintended effect on other organisms that constitute the normal bacterial flora and result in both overgrowth and resistant strains. (7,29) In a survey of prescription data from 1980, 1985, 1989, and 1992, office-based physicians wrote increasingly more prescriptions for expensive, broad-spectrum agents than for less expensive, narrower-spectrum drugs. (30)

Cephalosporins, particularly second- and third-generation agents, have a wide range of antibacterial coverage. Some have spectra of activity that include Gram-positive, Gram negative, and anaerobic organisms. Unfortunately, most drugs in this class are not as effective as the penicillin class against S. pneumoniae. A ninefold national increase in cephalosporin prescriptions from 1980 to 1992 has been demonstrated, along with evidence of treatment failures. In the latter instances, prescription records show that patients are then administered another cephalosporin or an agent with weaker activity, thereby adding to the increase in consumption. (11)

Unknown or Unavailable Local Resistance Patterns

Lack of knowledge of local resistance patterns, sometimes due to the unavailability of data, can misdirect prescribing. The 1998 surveillance study of S. pneumoniae cited above showed a wide range of prevalence rates. (25) In the United States, regional differences have been found to account for variances of 15 to 18% in penicillin-resistant S. pneumoniae from coast to coast and from north to south. These wide variations were true for multidrug-resistant strains as well. (7) Major geographic differences such as these illustrate the importance of examining resistance rates and patterns on hospital-to-hospital and region-to-region bases. Antibiotic choices could be more selective, allowing narrower-spectrum agents to target specific pathogens on the basis of susceptibility information.

Lack of Adherence

An important aspect in the development of antibacterial resistance is patients' nonadherence to antibacterial regimens, which can result in the selection of resistant strains. It is important for patients to complete their full treatment cycles, because the surest way to prevent the spread of resistance is to completely eradicate the infecting organism. Simplifying treatment regimens (ie, shortening the total course of therapy required and minimizing the number of doses per day), can encourage patient adherence and help control the development of resistance. (12)

Clinical and Economic Implications of Antibacterial Resistance

Increased Morbidity and Mortality

Infections with resistant pathogens can have significant adverse effects on both clinical and economic outcomes. Morbidity, mortality, and length of hospital stay, as well as the intensity, numbers, and types of therapies used, are all affected in patients who harbor resistant organisms. These factors, in turn, increase cost of treatment in both the hospital and community settings.

Various studies support a positive correlation between extent of antibacterial use and resistance rates in hospitals, in which up to 40% of patients receive antibiotics. (4) Neiderman et al(31) extensively reviewed the literature of antibiotic resistance in critical care areas and found increased morbidity and mortality owing to many different organisms, including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). In nosocomial infections, the presence of methicillin resistance in S. aureus seems to enhance its virulence and increase the likelihood of death for patients infected with this pathogen. (32) Feikin et al (33) found that the risk of death was significantly increased for patients who had S. pneumoniae that was highly resistant to penicillin or cefotaxime.

Investigators in several other studies have examined the potential relationship between pneumococcal resistance and increased morbidity and mortality rates. (34 37) In the early 1990s, clinical failures in patients with meningitis who were treated with cephalosporins were attributed to resistant pneumococcal strains. (35) In children with acute otitis media, increased rates of treatment failure were seen when cephalosporins were used in an attempt to eradicate resistant pneumococcal strains. (36,37) The emergence of S. pneumoniae with resistance to multiple antibiotics (including third-generation cephalosporins) has also complicated management and threatened treatment options for the practicing primary care physician. Turett et al, (34) after evaluating 462 cases of pneumococcal bacteremia, found that high-level penicillin resistance was one of the independent predictors of death, with a mortality rate of 17% in their population of inner-city inpatients and outpatients. Because office-based physicians most frequently provide the first line of treatment for RTIs, they must understand their patients' risk factors for acquiring resistant pathogens to make an informed choice of empiric therapy. The clinical consequences of failed treatment can be severe. For example, bacterial resistance to treatment with oral antibiotics may necessitate IV therapy, which, besides adding cost and inconvenience, can potentially increase the risk of patient morbidity. (38)

Increased Cost of Care

Numerous investigators have examined the effect of antibacterial resistance on the cost of care, particularly as it relates to length of hospital stay or increased number of antibacterial prescriptions written. In a review of repeated cephalosporin use, Steinberg et al (11) showed that increased costs were associated with more office visits and continued need for prescriptions. In hospitalized patients, Neiderman et al (31) showed that increased incidence of morbidity and mortality as a result of infection with resistant S. aureus, enterococci, and Gram-negative organisms resulted in increased length of stay and cost of care. Another study estimated that the annual cost to hospitals related to treatment of patients with multidrug-resistant S. aureus was $122 million. (24)

In a community-based study, Eandi et al (39) used a decision-tree model to analyze the effect of pneumococcal resistance on cost of care and determined that cost would increase by more than threefold when resistance was a factor. In addition to direct costs to the health care system, increased risk of treatment failure due to drug resistance results in considerable indirect costs to society through patients' lost productivity and prolonged absences from work.

In the managed care environment, with its focus on cost containment, requires that physicians do more with fewer resources. The emphasis on fewer and shorter hospital stays and limited use of expensive diagnostic tests has made the office-based physician's first choice of empiric antibacterial therapy of crucial importance. Increased resistance of primary respiratory pathogens has complicated this choice. For example, treatment with first-line antibiotics for acute exacerbations of chronic bronchitis has been shown to fail anywhere from 13 to 25% of the time. (40,41) This rate of clinical failure can lead to enormous additional costs, possibly related to the need for further diagnostic testing or additional courses of therapy. The least expensive antibacterial agent is not necessarily the most cost-effective, because cost must be weighed against the drug's efficacy against resistant organisms and the cost associated with treatment failure. Therefore, the issue of economics versus the increased potential for negative clinical outcomes has further complicated the primary care physician's treatment of respiratory infections.

Fighting Resistance in the Primary Care Setting

A growing number of studies show that modifying current prescribing practices for existing antibacterial agents can reduce the prevalence of resistant pathogens. This can be accomplished by restricting antibacterial use or cycling antibiotics with low potential for development of resistance, by issuing antibiotic stop orders or order forms, by enabling physician education initiatives for the development of treatment guidelines, and by using local resistance patterns to help guide prescription practices.

Antibiotic Restrictions

Cycling the use of antibiotics with lack of or low rates of resistance, or using restrictive policies for antibacterial agents in hospitals, has proved helpful in avoiding antibiotic overuse and restoring susceptibilities for both Gram-positive and Gram-negative organisms that had shown some level of resistance. (32,42,43) One study found that, during a 6-month period, ventilator-associated pneumonia owing to antibiotic-resistant, Gram-negative bacteria declined significantly when treatment with a third-generation cephalosporin was cycled with ciprofloxacin. (32) At Methodist Hospital in Indianapolis, IN, a 4-year antibiotic-restriction program was successful in decreasing the rate of VRE from 16 to 6% and the MRSA rate from 34 to 23%. (43)

Data supporting the success of such measures also exist in the community setting. Monitored prescribing after educational interventions was effective in improving susceptibilities in rural Alaska. In the target population of children younger than 5 years of age who had respiratory illnesses, there was a 22% decrease in the number of prescriptions generated and a 28% decrease in the carriage rate of nonsusceptible S. pneumoniae. In addition, carriage of fully resistant strains decreased from 25 to 11% (P = 0.007). (11)

Educational Initiatives

Developing and implementing physician education programs is an important way to alter prescribing practices. Passive interventions alone, such as mailings to physicians, are not as effective as live interaction. Effective teaching techniques include targeting specific categories of physicians and their opinion leaders, establishing credibility by referencing quality, unbiased sources of information, and presenting all aspects of controversial clinical issues. To engage prescriber participation, measures such as these should be reinforced with follow-up interactions. (44) To have physicians perceive education as assisting rather than restricting them, patient outcomes rather than cost should be emphasized. (42)

In a large study of a group model health maintenance organization, interventions with three groups of primary care practitioners focused on attempts to decrease the volume of antibiotics prescribed. One group received education with prescriber profiling, academic detailing, and treatment guidelines (full-intervention group), another received office materials only (limited-intervention group), and a third group served as a control group. Antibiotic prescribing decreased from 74 to 48%, from 82 to 77%, and from 78 to 76%, in the full-intervention, limited-intervention, and control groups, respectively. (45) In another study, face-to-face interventions were found to be most effective in changing physicians' prescribing habits for patients with tonsillitis and streptococcal pharyngitis. (46) Workshops aimed at reducing antibiotic prescribing also have been successful in reducing the number of prescriptions written for broad-spectrum antibiotics. (47)

Treatment Guidelines

A number of professional groups have compiled evidence-based recommendations to guide physicians in their efforts to better treat infectious diseases. The overall effect of these treatment guidelines may be viewed as disappointing because bacterial resistance continues to escalate; however, this may be caused by passive distribution of the guidelines through journal publication. As already noted, educational efforts are most effective when they are directly targeted (eg, face-to-face academic detailing from peers). (44)

Among the many groups that have developed guidelines for the treatment of infectious diseases is the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group of the Centers for Disease Control and Prevention (CDC), comprising practicing physicians, academicians, and public health professionals. (48,49) The group's published papers include documents on the treatment of acute otitis media and pneumonia. (48,50) The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America (IDSA) have addressed the serious problem of preventing antibacterial resistance in hospitals. (10) The CDC, IDSA, the American Academy of Family Physicians, and the American College of Physicians support guidelines for appropriate treatment of uncomplicated acute bronchitis, (51) and the IDSA and the American Thoracic Society have developed guidelines for the treatment of community-acquired pneumonia. (52,53)

Local Resistance Patterns

As recommended in the general guidelines by the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group, knowledge of local resistance patterns would help physicians tailor their prescribing practices. (49) Surveillance studies have documented variations in, for example, pneumococcal susceptibilities around the United States. In 1998, California and New York each had 15% penicillin-resistant isolates, compared with Georgia and Tennessee, which had 33 and 35%, respectively. (7) Although knowledge of local resistance patterns would obviously be useful in choosing effective drug therapy to treat RTIs and other infections, these data are difficult to obtain. Hospital laboratories routinely summarize their susceptibility data, but it is difficult to extrapolate these numbers to specific communities. Community-based laboratories in local and state health departments are probably the best places to obtain this type of information. (48)

In addition to geographic variability, bacterial susceptibility patterns can vary by patient age, race, and sex. The Drug-resistant Streptococcus pneumoniae Therapeutic Working Group guidelines give examples for local surveillance of S. pneumoniae susceptibilities, with emphasis on defining the population under study to include all possible variables. They suggest that MICs or zone-diameter values should be used to categorize susceptibility of isolates, and that consistent lists of drugs to be tested should be established, with new agents added as susceptibility patterns change. (49)

Meeting the Need for New Antibacterial Agents

With increasing resistance compromising the utility of older antibacterial agents, the need for new antibiotics is critical. The increasing incidence of infectious diseases, including RTIs like pneumonia and acute otitis media, adds urgency to the problem. (24) Although no new class of antibacterial agents had been approved for 25 years until the oxazolidones became available in 2000, improvements in the fluoroquinolone class, the availability of quinupristin/dalfopristin, and the soon-to-be-available ketolides now offer new choices. (24,54)

Oxazolidones

Linezolid is the approved oxazolidine. Its novel mechanism of action involves inhibition of protein synthesis by blocking formation of the initiation complex. It was developed as an agent for Gram-positive infections caused by S. aureus, particularly MRSA, VRE, and penicillin-resistant S. pneumoniae. It is indicated for treatment of nosocomial and community-acquired pneumonia caused by S. aureus and S. pneumoniae; bacteremia caused by vancomycin-resistant Enterococcus faecium; and complicated skin and skin-structure infections caused by S. aureus, Streptococcus pyogenes, or Streptococcus agalactiae. The agent lacks activity against Gram-negative and atypical (eg, Mycoplasma, Chlamydia) pathogens. Another drawback is that the agent, like all oxazolidones, is bacteriostatic and not bactericidal, thus having the potential for development of resistance. Resistance to E. faecium has been observed. Linezolid has also been associated with oral and vaginal candidiasis, skin lesions, and thrombocytopenia. (54-56)

Fluoroquinolones

Two newly available fluoroquinolones--gatifloxacin and moxifloxacin--have a methoxy substitution at the 8 position, which may restrict the selection of resistant mutants compared with older fluoroquinolones such as ciprofloxacin and levofloxacin, which share a primary antibacterial target in a subunit of the pathogen's topoisomerase IV gene. (57,58) Mutations in this gene create the potential for the development of cross-resistance. By primarily acting on a subunit of DNA gyrase, the newer fluoroquinolones are able to overcome the issues of cross-resistance that may affect the older agents. (59) Important activity includes an MIC necessary to kill 90% of the pathogen (MI[C.sub.90]) for S. pneumoniae of 0.06 to 4.0 [mu]g/ml for both penicillin-sensitive and penicillin-resistant strains; an (MI[C.sub.90])against H. influenzae ranging from 0.008 to 0.06 [mu]g/ml; and an (MI[C.sub.90]) against M. catarrhalis ranging from less than 0.001 to 0.03 [mu]g/ml. These values are similar for strains that are positive and those that are negative for [beta]-lactamase. The activity of moxifloxacin for S. pneumoniae has an (MI[C.sub.90] of 0.06 to 4.0 [mu]g/ml. For H. influenzae, moxifloxacin's (MI[C.sub.90]) ranges from 0.03 to 0.12 [mu]g/ml, and for M. catarrhalis, its (MI[C.sub.90]) ranges from less than 0.001 to 0.06 [mu]g/ml. (57)

Streptogramins

Quinupristin/dalfopristin is the first injectable streptogramin to be marketed in the United States. It is indicated for treatment of serious vancomycin-resistant E. faecium bacteremia and complicated skin and skin-structure infections caused by methicillin-susceptible S. aureus or S. pyogenes. It also has good activity against S. pneumoniae, with an (MI[C.sub.90]) ranging from 0.39 to 1.0 [mu]g/ml; its activity is independent of penicillin or erythromycin susceptibility. Although active in vitro against M. pneumoniae, L. pneumophila, and M. catarrhalis, quinupristin/dalfopristin is not useful against H. influenzae. (60)

Ketolides

Telithromycin, the first member of an innovative new class of antibacterials, the ketolides, has the same basic 14-membered macrolactone ring structure as erythromycin. Chemical modifications maintain acid stability of the ketolides but enhance microbiologic activity. The mechanism of antibacterial activity for telithromycin is similar to that of erythromycin. Both erythromycin and telithromycin bind to residues A2058 and A2059 in the central loop of domain V of the 23S ribosomal RNA (rRNA) in the 50S ribosomal sub-unit, and interact at residue A752 of hairpin 35 of Domain II of the 23S rRNA; however, telithromycin interacts more strongly than erythromycin at this site. (61-63) This may explain why telithromycin is less likely than the macrolides to induce resistance. (64)

Telithromycin provides potent activity against common and atypical or intracellular respiratory pathogens, including erythromycin- and penicillin-resistant strains of S. pneumoniae, for which neither clarithromycin nor azithromycin are useful. Its MI[C.sub.90] for H. influenzae ranges from 0.5 to 2.0 [mu]g/ml and from 0.06 to 0.12 [mu]g/ml for S. aureus. For M. catarrhalis, telithromycin has an MI[C.sub.90] of 0.06 [mu]g/ml. (65)

Potential for Development of Resistance to Newer Agents

Oxazolidones

Resistance to linezolid has been reported in S. aureus and E. faecium. (66,67) The duration of linezolid treatment and exposure to multiple antibiotics have been implicated in the development of linezolid resistance in vancomycin-resistant E. faecium. In the case of MRSA, mutations in the coagulase gene and 23S rRNA were associated with strains that were also linezolid-resistant.

Fluoroquinolones

The availability of the newer fluoroquinolones (eg, moxifloxacin, gatifloxacin) has introduced a new class of agents, with little or no pneumococcal resistance, recommended for empiric treatment of RTIs. (58) Data from the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) study revealed that resistance to fluoroquinolones is low in the United States. In 7,544 S. pneumoniae isolates from U.S. study sites, fluoroquinolones (levofloxacin and gatifloxacin) were effective against more than 98% of the isolates. (68) As the use of these drugs increases in the United States, however, pneumococcal resistance may also increase owing to selective pressure. Such resistance has already been noted in Canada, where the older agents (ciprofloxacin and levofloxacin) have been used more extensively than they have in the United States. (22,58) Furthermore, there may be a potential for cross-resistance. Resistance to ciprofloxacin in pneumococci from Northern Ireland has been reported to be higher among penicillin-resistant strains than among penicillin-susceptible strains. (69) It is speculated that the risk of developing pneumococcal resistance to moxifloxacin and gatifloxacin may be decreased by the fact that these agents bind to both the DNA gyrase and topoisomerase IV enzymes; thus, two simultaneous DNA mutations need to occur for resistance to develop.

Streptogramins

Target modification is the most common mechanism for development of quinupristin/dalfopristin resistance. Although, as a streptogramin B, quinupristin is cross-resistant with macrolides and lincosamides, dalfopristin is a streptogramin A and not part of this resistance pattern. This aspect of dual components may give this agent an advantage. (60)

Ketolides

As a member of the novel 3-keto class of ketolide antibacterials, telithromycin, unlike erythromycin A and other macrolides, does not induce resistance or cross-resistance to macrolide, lincosamide, or streptogramin B agents in vitro. (12) As shown in Table 3, telithromycin maintains activity against erythromycin-resistant isolates of S. pneumoniae, including strains showing the constitutive and inducible-resistance phenotypes (confirmed by presence of the ermB gene) and those showing the M-resistance phenotype (confirmed by the presence of the mefA/E gene). (70) In an investigation by Davies et al, (64) only three S. pneumoniae strains were resistant to telithromycin, whereas the comparator drugs fared considerably worse: 36 strains were resistant to azithromycin, 37 to clarithromycin, 36 to erythromycin, 45 to roxithromycin, and 20 to clindamycin.

As of June 2001, in the PROTEKT study, 7,544 isolates of S. pneumoniae from 171 sites across the United States had MIC determinations performed to evaluate susceptibilities. (68) Decreased susceptibility to penicillin was found in 53.5% of isolates, with 27.3% showing intermediate resistance and 26.2% showing full resistance. Erythromycin demonstrated an overall 30.7% rate of resistance, with 29.7% of intermediate-resistance strains and 78.3% of full-resistance strains. In contrast, 99.4% of all isolates were susceptible to telithromycin. Of note, clarithromycin and azithromycin were at or above their resistance breakpoints. (68) In the same study, which also evaluated the susceptibilities of S. pyogenes, telithromycin retained good activity against erythromycin-resistant strains of this pathogen. (71)

Thus, the new agents, linezolid and quinupristin/dalfopristin, are targeted at serious, Gram-positive nosocomial infections (eg, MRSA, VRE). For the treatment of patients with RTIs, the newer fluoroquinolones and ketolides show the most promise, although the very broad spectrum of gatifloxacin and moxifloxacin may promote resistance. In contrast, telithromycin, the first ketolide, is an agent with a tailored spectrum of activity against common and atypical respiratory tract pathogens and has low potential to select for resistance.

A Note on Prevention

Handwashing

It is known that glove use and conscientious handwashing with appropriate antiseptic solutions can help to prevent the spread and development of infection and antibiotic resistance in the health care setting. Such measures are also known to result in reductions in risk of patient morbidity and mortality from nosocomial infection. (72) Current guidelines, regulations, and standards regarding the topical use of antibacterial products for skin hygiene have been published by several agencies and organizations, including the Association for Professionals in Infection Control and Epidemiology, Inc., (72) the CDC, (73) and the U.S. Food and Drug Administration. (74) It would be advisable for all infectious disease health care professionals to familiarize themselves with these guidelines.

Vaccines

Other preventive approaches include the use of vaccines to not only reduce the incidence of disease but also curtail the development of antibacterial resistance. The H. influenzae type b vaccine reduced the incidence of invasive H. influenzae disease in children younger than 5 years of age by 97% between 1987 and 1999. (75) Other vaccines have shown mixed results. Current vaccines against S. pneumoniae have been most effective in preventing infection in young adults, although not in older adults. (76) Complications, such as the need for repeated dosing and the high cost of current vaccines, may further limit the usefulness of these approaches.

Conclusion

Antibacterial resistance is common among pathogens associated with community-acquired RTIs, particularly S. pneumoniae, H. influenzae, and M. catarrhalis. With negative effects on patient outcomes and costs of therapy, antibacterial resistance must be attacked with a wide range of approaches. These include educating prescribers about appropriate use and developing new agents with activity against resistant pathogens and low potential to select for resistance. The primary care physician must be aware of prescribing practices aimed at minimizing resistance development, and of new drugs effective against resistant pathogens associated with community-acquired RTIs.

Good thoughts bear good fruit, Bad thoughts bear bad fruit, And man is his own gardener.

--James Allen

Table 1.  Proportion of pneumococcal isolates resistant to various
antimicrobial agents according to their susceptibility to penicillin,
1998 (a)
                Penicillin resistance/susceptibility (% isolates)

Agent                 High-level resistance (b) ([mu]g/mL)

Amoxicillin                   [greater than or equal to]2
Cefotaxime                    [greater than or equal to]2
Cefuroxime                    [greater than or equal to]2
Erythromycin                  [greater than or equal to]1
Cotrimoxazole  [greater than or equal to]4, [greater than or equal to]76
Tetracycline                  [greater than or equal to]8
Levofloxacin                  [greater than or equal to]8

          Penicillin resistance/susceptibility (% isolates)

Agent          Susceptibility       High-level       P value (c)
                 (n = 2,636)   resistance (n = 483)

Amoxicillin          0.0                82.2          <0.001
Cefotaxime           0.0                42.4          <0.001
Cefuroxime           0.1               100.0          <0.001
Erythromycin         3.2                61.3          <0.001
Cotrimoxazole        6.6                92.3          <0.001
Tetracycline         1.3                25.5          <0.001
Levofloxacin         0.1                 0.7           0.007

(a) Adapted from, Whitney CG, Parley MM, Hadler J, Harrison LH, Lexau C,
Reingold A, et al. Increasing prevalence of multidrug-resistant
Streptococcus pneumoniae in the United States. N Engl J Med 2003;343:
1917-1924(7).
(b) The National Committee for Clinical Laboratory Standards (NCCLS)
defines resistance in terms of the minimal inhibitory concentration
(MIC) of the drug in micrograms per milliliter.
(c) P values were derived by the [X.sup.2] test for trend.

Table 2.  Factors promoting development and spread of bacterial
resistance in the community setting (a)

* Overuse or unnecessary use of antibiotics, especially with viral
 infections (including complying with patients or parental expectations)
* Overuse of broad-spectrum agents; reluctance to start with or change
 to narrower-spectrum drugs
* Unavailability of local resistance patterns
* Inadequate dosing
* Lack of compliance
* Recent hospitalization, recent use of antibiotics, and day-care
 exposure (promotes nasal carriage of resistant pathogens)
* Over-the-counter availability of antibiotics outside the United States
* Inadequate immunization

(a) Adapted from Steinberg (11) and Wang et al. (25)

Table 3. Comparison of in vitro activity of telithromycin against
erythromycin-resistant isolates of Streptococcus pneumoniae (a)

                                         MICs ([mu]g/L)

                                 MI[C.sub.50]  MI[C.sub.90]  Range

Constitutive resistance (n =21)
  Erythromycin A                    512        >512          16 >512
  Clindamycin                       128         256           32-512
  Telithromycin                       0.06        1         0.06-1

Inducible resistance (n = 9)
  Erythromycin A                    128         512            2-512
  Clindamycin                         8          64         0.25-64
  Telithromycin                       0.06        0.5       0.06-1

M-resistance (n = 3)
  Erythromycin A                     --           --           2-4
  Clindamycin                        --           --         all 0.06
  Telithromycin                      --           --        0.12-0.5

Adapted from, Descheemaeker P, Chapeele S. Lammens C. Hauchecorne M.
Wijdoogle M. Vandamme P, et al. Macrolide resistance erythromycin
resistance determinants among Belgian Streptococcus pyogenes and
Streptococcus pneumoniae isolates. J Antimicrob Chemother 2000;45:167
-173 (70).

Acknowledgment

I thank Martin Lipsky, MD, of Northwestern University Medical School for his valuable contribution to the content and review of this manuscript.

From the Department of Medicine, Danbury Hospital, Danbury, CT.

Supported by an unrestricted educational grant from Aventis Pharmaceuticals.

The author has no financial interest in the drugs, devices, or procedures described in this article.

Reprint requests to Paul Iannini, MD, Department of Medicine, Danbury Hospital, 24 Hospital Avenue, Danbury, CT 06810. Email: [e-mail]

Accepted June 20, 2002.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9610-1008

References

1. Armstrong GL, Pinner RW. Outpatient visits for infectious diseases in the United States, 1980 through 1996. Arch Intern Med 1999;159:2531-2536.

2. Jacobs MR. Emergence of antibiotic resistance in upper and lower respiratory tract infections. Am J Manag Care 1999;5(11 Suppl):S651-S661.

3. Cunha BA. Antibiotic resistance. Med Clin North Am 2000;84:1407-1429.

4. File TM Jr. Overview of resistance in the 1990s. Chest 1999;115(3 Suppl):3S-8S.

5. Jones RN. The impact of antimicrobial resistance: Changing epidemiology of community-acquired respiratory-tract infections. Am J Health Syst Pharm 1999;56(Suppl 3):S4-S11.

6. Hand WL. Current challenges in antibiotic resistance. Adolesc Med 2000;11:427-438.

7. Whitney CG, Parley MM, Hadler J, Harrison LH, Lexau C, Reingold A, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000;343:1917-1924.

8. Davies JE. Origins, acquisition and dissemination of antibiotic resistance determinants. Ciba Found Symp 1997;207:15-35.

9. Patterson JE. Antibiotic utilization: Is there an effect on antimicrobial resistance? Chest 2001;119(2 Suppl):426S-430S.

10. Shlaes DM, Gerding DN, John JF Jr. Craig WA, Bornstein DL, Duncan RA, et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: Guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997;25:584-599.

11. Steinberg I. Clinical choices of antibiotics: Judging judicious use. Am J Manag Care 2000;6(23 Suppl):S1178-S1188.

12. Leclercq R. Safeguarding future antimicrobial options: Strategies to minimize resistance. Clin Microbiol Infect 2001;7:18-23.

13. Lister PD. Emerging resistance problems among respiratory tract pathogens. Am J Manag Care 2000;6(8 Suppl):S409-S418.

14. Forward KR. The epidemiology of penicillin resistance in Streptococcus pneumoniae. Semin Respir Infect 1999;14:243-254.

15. Collignon PJ, Turnidge JD. Antibiotic resistance in Streptococcus pneumoniae. Med J Aust 2000;173(Suppl):S58-S64.

16. Ball P. Therapy for pneumococcal infection at the millennium: Doubts and certainties. Am J Med 1999;107:77S-85S.

17. Doern GV, Brueggemann A, Holley HP Jr, Rauch AM. Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: Results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996;40:1208-1213.

18. Doern GV, Brueggemann AB, Huynh H, Wingert E. Antimicrobial resistance with Streptococcus pneumoniae in the United States. 1997-1998. Emerg Infect Dis 1999;5:757-765.

19. Doern GV, Heilmann KP, Huynh HK, Rhomberg PR, Coffman SL, Brueggemann AB. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in the United States during 1999-2000, including a comparison of resistance rates since 1994-1995. Antimicrob Agents Chemother 2001;45:1721-1729.

20. Blondeau JM, Tillotson GS. Antimicrobial susceptibility patterns of respiratory pathogens: A global perspective. Semin Respir Infect 2000;15:195-207.

21. Goldstein FW, Acar JF. Epidemiology of antibiotic resistance in Haemophilus influenzae. Microb Drug Resist 1995;1:131-135.

22. Brueggemann AB, Doern GV. Resistance among Streptococcus pneumoniae: Patterns, mechanisms, interpreting the breakpoints. Am J Manag Care 2000;6(23 Suppl):S1189-S1196.

23. Witte W. Antibiotic resistance in Gram-positive bacteria: Epidemiological aspects. J Antimicrob Chemother 1999;44(Suppl A):1-9.

24. Cassell GH, Mekalanos I. Development of antimicrobial agents in the era of new and reemerging infectious diseases and increasing antibiotic resistance. JAMA 2001;285:601-605.

25. Wang EE, Kellner JD, Arnold S. Antibiotic-resistant Streptococcus pneumoniae: Implications for medical practice. Can Fam Physician 1998;44:1881-1888.

26. Austin DJ, Kristinsson KG, Anderson RM. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc Natl Acad Sci U S A 1999;96:1152-1156.

27. Nyquist AC, Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. JAMA 1998;279:875-877.

28. Bauchner H, Pelton SI, Klein JO. Parents, physicians, and antibiotic use. Pediatrics 1999;103:395-401.

29. Gould IM. A review of the role of antibiotic policies in the control of antibiotic resistance. J Antimicrob Chemother 1999;43:459-465.

30. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians. JAMA 1995;273:214-219.

31. Niederman MS. Impact of antibiotic resistance on clinical outcomes and the cost of care. Crit Care Med 2001;29(4 Suppl):N114-N120.

32. Kollef MH. Is there a role for antibiotic cycling in the intensive care unit? Crit Care Med 2001;29(4 Suppl):N135-N142.

33. Feikin DR, Schuchat A, Kolczak M, Barrett NL, Harrison LH, Lefkowitz L, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public Health 2000;90:223-229.

34. Turett GS, Blum S, Fazal BA, Justman JE, Telzak EE. Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high HIV seroprevalence. Clin Infect Dis 1999;29:321-327.

35. Goldstein FW, Garau J. Resistant pneumococci: A renewed threat in respiratory infections. Scand J Infect Dis Suppl 1994;93:55-62.

36. Dagan R, Abramson O, Leibovitz E, Lang R, Goshen S, Greenberg D, et al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis J 1996;15:980-985.

37. Dagan R, Abramson O, Leibovitz E, Greenberg D, Lang R, Goshen S, et al. Bacteriologic response to oral cephalosporins: Are established susceptibility breakpoints appropriate in the case of acute otitis media? J Infect Dis 1997;176:1253-1259.

38. Liu HH. Antibiotic resistance in bacteria: A current and future problem. Adv Exp Med Biol 1999;455:387-396.

39. Eandi M, Zara GP. Economic impact of resistance in the community. Int J Clin Pract Suppl 1998;95:27-38.

40. Ball P. Epidemiology and treatment of chronic bronchitis and its exacerbations. Chest 1995;108(2 Suppl):43S-52S.

41. MacFarlane JT, Colville A, Guion A, Macfarlane RM, Rose DH. Prospective study of aetiology and outcome of adult lower-respiratory-tract infections in the community. Lancet 1993;341:511-514.

42. Yates RR. New intervention strategies for reducing antibiotic resistance. Chest 1999;115(3 Suppl):24S-27S.

43. Smith DW. Decreased antimicrobial resistance after changes in antibiotic use. Pharmacotherapy 1999;19:129S-132S.

44. Dickerson LM, Mainous AG III, Carek PJ. The pharmacist's role in promoting optimal antimicrobial use. Pharmacotherapy 2000;20:711-723.

45. Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing antibiotic use in ambulatory practice: Impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults. JAMA 1999;281:1512-1519.

46. Zwar N, Wolk J, Gordon J, Sanson-Fisher R, Kehoe L. Influencing antibiotic prescribing in general practice: A trial of prescriber feedback and management guidelines. Fam Pract 1999;16:495-500.

47. McNulty CA, Kane A, Foy CJ, Sykes J, Saunders P, Cartwright KA. Primary care workshops can reduce and rationalize antibiotic prescribing. J Antimicrob Chemother 2000;46:493-499.

48. Dowell S, Butler JC, Giebink GC, Jacobs MR, Jernigan D, Musher DM, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance: A report form the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999;18:1-9.

49. Heffelfinger JD, Dowell SF, Jorgensen JH, Klugman KP, Mabry LR, Musher DM, et al. Management of community-acquired pneumonia in the era of pneumococcal resistance: A report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000;160:1399-1408.

50. Dowell SF, Smith T, Leversedge K, Snitzer J, Failure of treatment of pneumonia associated with highly resistant pneumococci in a child. Clin Infect Dis 1999;29:462-463.

51. Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JM, Hoffman JR, et al. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: Background, specific aims, and methods. Ann Intern Med 2001;134:479-486.

52. Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia. Clin Infect Dis 2000;31:347-382.

53. American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730-1754.

54. Plouffe JF. Emerging therapies for serious gram-positive bacterial infections: A focus on linezolid. Clin Infect Dis 2000;31(Suppl 4):S144-S149.

55. Bain KT, Wittbrodt ET. Linezolid for the treatment of resistant Grampositive cocci. Ann Pharmacother 2001;35:566-575.

56. Gleckman R. What do the new antimicrobials offer? Postgrad Med 2001;109:1-7.

57. Fish DN, North DS. Gatifloxacin, an advanced 8-methoxy fluoroquinolone. Pharmacotherapy 2001;21:35-59.

58. Talan DA. Clinical perspectives on new antimicrobials: Focus on fluoroquinolones. Clin Infect Dis 2001;32(Suppl 1):S64-S71.

59. Pestova E, Millichap JJ, Noskin GA, Peterson LR. Intracellular targets of moxifloxacin: A comparison with other fluoroquinolones. J Antimicrob Chemother 2000;45:583-590.

60. Delgado G Jr, Neuhauser MM, Bearden DT, Danziger LH. Quinupristindalfopristin: An overview. Pharmacotherapy 2000;20:1469-1485.

61. Bearden DT, Neuhauser MM, Garey KW. Telithromycin: An oral ketolide for respiratory infections. Pharmacotherapy 2001;21:1204-1222.

62. Depardieu F, Courvalin P. Mutation in 23S rRNA responsible for resistance to 16-membered macrolides and streptogramins in Streptococcus pneumonide. Antimicrob Agents Chemother 2001;45:319-323.

63. Vester B, Douthwaite S. Macrolide resistance conferred by base substitutions in 23S rRNA. Antimicrob Agents Chemother 2001;45:1-12.

64. Davies TA, Dewasse BE, Jacobs MR, Appelbaum PC. In vitro development of resistance to telithromycin (HMR 3647), four macrolides, clindamycin, and pristinamycin in Streptococcus pneumoniae. Antimicrob Agents Chemother 2000;44:414-417.

65. Felmingham D. Microbiological profile of telithromycin, the first ketolide antimicrobial. Clin Microbiol Infect 2001;7:2-10.

66. Tsiodras S, Gold HS, Sakoulas G, Eliopoulos GM, Wennersten C, Venkataraman L, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001;358:207-208 (letter).

67. Pai MP, Gonzales RD, Petrolati JM, et al. Risk factors associated with the development of enterococcal resistance to linezolid. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Dec 16-19, 2001 (abstract 1194).

68. Stratton C, Barry A, Yee YC. In vitro activity of telithromycin against clinical isolates of Streptococcus pneumoniae collected from medical centers across the United States during the winter of 2000/2001. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, December 16-19, 2001 (abstract 1018).

69. Goldsmith CE, Moore JE, Murphy PG, Ambler JE. Increased incidence of ciprofloxacin resistance in penicillin-resistant pneumococci in Northern Ireland. J Antimicrob Chemother 1998;41:420-421 (letter).

70. Descheemaeker P, Chapeele S, Lammens C, Hauchecorne M, Wijdooghe M, Vandamme P, et al. Macrolide resistance and erythromycin resistance determinants among Belgian Streptococcus pyogenes and Streptococcus pneumoniae isolates. J Antimicrob Chemother 2000;45:167-173.

71. Hoban D, Brown S, Harding I. Telithromycin is highly active against erythromycin-susceptible and -resistant isolates of Streptococcus pyogenes collected in the United States during the winter of 2000-2001. Presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, December 16-19, 2001 (abstract 1017).

72. Larsen EL. APIC guidelines for hand washing and hand antisepsis in health-care settings. Am J Infect Control 1995;23:251-269.

73. Garner JS, Favero MS. CDC guidelines for handwashing and hospital environmental control, 1985. Infect Control 1986;7:231-235.

74. U.S. Food and Drug Administration. Topical antimicrobial drug products for over-the-counter human use. 21 CFR ch 1, pt 333 (Rev. April 1, 2002). Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=333. Accessed April 2, 2003.

75. Burns IT, Zimmerman RK. Haemophilus influenzae type B disease, vaccines, and care of exposed individuals. J Fam Pract 2000;49(9 Suppl):S7-S14.

76. Ortqvist A. Pneumococcal vaccination: Current and future issues. Eur Respir J 2001;18:184-195.

RELATED ARTICLE: Key Points

* Respiratory tract pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, are becoming increasingly resistant to standard antibiotics.

* Factors such as an overuse of broad-spectrum antibiotics, a lack of knowledge of local resistance patterns, and failure of patients to adhere to their antibiotic regimen can contribute to antibacterial resistance in the primary care setting.

* The increase in resistance to available antibiotics is associated with an increase in morbidity, mortality, and treatment cost.

* To curb development of antibacterial resistance, physicians have a variety of options, including restricting antibiotic use, cycling antibiotics with a low potential to develop resistance, becoming aware of and using local resistance patterns, and using or adapting available treatment guidelines.

* Although the potential for development of resistance remains an ongoing challenge for clinicians, new antibacterial agents such as oxazolidones, fluoroquinolones, quinupristin/dalfopristin, and the soon-to-be-available ketolides offer promise as additions to the therapeutic armamentarium.

Paul Iannini, MD