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Meeting the Challenge Of Bacterial Resistance In Primary Care

Learning Objectives:
Upon completion of this course, you should be able to: Recognize the emergence of antimicrobial resistance and its significance in the management of lower respiratory tract infections Discuss the causative pathogens associated with LRTIs and their susceptibility to common antibiotics Describe the methodology of selecting the most effective antimicrobial agent for various resistant infections

ue to the development of resistance in many of the bacterial pathogens that commonly cause lower respiratory tract infections (LRTIs) (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) treatment of these types of infections has become increasingly difficult over the past decade. Community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB) are two LRTIs that are becoming increasingly difficult to manage due to bacterial resistance.1

For information on how to earn CME credit, see inside front cover. To view disclosure information, see page 5. Course ID: AB0188

Sanjay Sethi, MD
Associate Professor, Division of Pulmonary Critical Care, School of Medicine and Biomedical Sciences, SUNY at Buffalo; Staff Physician, VA Western NY Healthcare System, Buffalo, NY

Annually, in the United States, it is estimated that there are up to 5.6 million cases of CAP, requiring approximately 10 million primary care visits, an estimated 500,000 to 1.1 million hospitalizations, and approximately 45,000 deaths. This significant morbidity and mortality attributed to CAP make it the sixth leading cause of death overall and the number one cause of death from infectious disease in the United States. The high rates of CAP morbidity and mortality within the U.S. population necessitate early recognition, diagnosis, and treatment to prevent serious disease progression.2

Each year in the United States, acute bronchitis is responsible for about 12 million physician visits, with a healthcare cost of $200 million to $300 million. The clinical and economic consequences of this disease largely depend on host factors and the severity of the specific episode; elderly patients and those with significant comorbidities are at risk for poor outcomes. The likely pathogens and their susceptibility to various antimicrobial drugs differ among patient populations and geographic areas.3
Treatment of LRTIs Chronic bronchitis has a complex

ABBREVIATIONS
AECB ATS CAP DRSP IDSA LRTIs PBP TRUST Acute exacerbation of chronic bronchitis American Thoracic Society Community-acquired pneumonia Drug-resistant S. pneumoniae Infectious Disease Society of America Lower respiratory tract infections Penicillin-binding protein Tracking Resistance in the United States Today

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Meeting the Challenge of Bacterial Resistance in Primary Care

disease process, attributed to a number of toxic stimuli, including inhalation of tobacco smoke, bacterial infection, viral infection, allergy, and numerous other causes that culminate in inflammation of the bronchial tree. Bacterial pathogens account for the majority of CAP cases and are a contributing factor in over half of all cases of AECB. Historically, bacterial infections in CAP have been broken down into two categories: the typical pathogens and the atypical pathogens. The typical pathogens are defined as those that were thought to cause classic symptoms and include the common bacterial pathogens for CAP . Organisms that fall in this category include, but are not limited to, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa, and opportunistic Gramnegative pathogens. Atypical pathogens have fewer classic symptoms and are defined as infections involving one or more of the following: Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. It was originally thought that the clinical presentation in a patient would be different between the pathogens designated typical and atypical. However, there is substantial overlap in the presentations and this classification is not proven to be clinically diagnostic for determining etiology.4
Exercise 1
Which of the following statements concerning typical and atypical pathogens is true? a. Typical pathogens for CAP include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila b. Atypical pathogens are defined by the symptoms they cause c. The classification of pneumonia into typical and atypical categories is not clinically diagnostic d. The classification of pathogens into typical and atypical categories is a significant recent development Answer on page 25.

A review of CAP studies over the last two decades revealed the most common pathogens of CAP. They include, in order of frequency of incidence, Streptococcus pneumoniae, Haemophilus influenzae, Legionella species, and Chlamydia pneumoniae. However, it is important to note that prospective studies of CAP have failed to identify the etiology of 40% to 60% of cases. Of the above common pathogens, S. pneumoniae is by far the most identifiable and accounts for almost two thirds of bacteremic CAP. Other pathogens identified, but less frequently implicated in CAP, include Mycoplasma pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitidis, Moraxella catarrhalis, Klebsiella pneumoniae, other Gram-negative rods, anaerobes, mycobacteria, fungi, and viruses.5 An important caveat is that the incidence of the atypicals is frequently determined serologically rather than by microbial culture. A positive single serology only indicates immune response to microbe exposure at some point within the patients life and does not necessarily indicate infection coincident to the pneumonia. Paired sera showing a four-fold rise in titer are more definitive, but are often not done. A review reported in 2000 concluded that 80% of AECB episodes were induced by infectious agents, and 40% to 50% were caused by typical bacteria, predominantly nontypeable H. influenzae, M. catarrhalis, and S. pneumoniae. Other bacterial pathogens reported with less frequency included S. aureus, P. aeruginosa, and opportunistic Gram-negative organisms. Five to 10% of AECBs were caused by atypical bacteria (Chlamydia pneumoniae and Mycoplasma pneumoniae), 30% were caused by viruses, and concomitant infection existed in 10% to 20% of patients. Conclusions drawn from this study and others suggest that bacterial pathogens play an important role in

shifting a patient with chronic bronchitis from the stable state to an exacerbation.6 Although studies reveal that bacterial pathogens account for the majority of CAP and AECB cases, it is often impossible to determine the etiologic bacterial agent for an individual patient. Due to the limitations in determining the etiological agents, most of these infections are treated empirically rather than based on culture data. Empirical treatment relies on a firm knowledge of a patients case history, including, but not limited to, patient age, patient history, severity of illness, epidemiology, and host risk factors. Certain epidemiological clues can be used to narrow down the possible etiology of infection. However, this empirical approach is increasingly challenged due to the expanding number of bacterial pathogens implicated in CAP infections and the changing susceptibility of the bacterial pathogens to antibiotic therapy.7
Exercise 2
The most common pathogen responsible for CAP is: a. Chlamydia pneumoniae b. Haemophilus influenzae c. Legionella species d. Streptococcus pneumoniae Answer on page 25.

Overview of Antibiotic Resistance Over the last 15 years, antimicrobial resistance among respiratory pathogens has become an increasing problem worldwide. The genes and mutations that confer antibiotic resistance pose an increasing challenge to physicians involved in the treatment of LRTIs. Understanding the mechanisms of specific bacterial resistance to antibiotics in LRTIs is important for optimizing existing antibiotic therapies, and developing future therapies. To understand the changing susceptibility of the bacterial pathogens to antibiotic therapy and the current problem of antibiotic resistance, it is essential to first review the target sites of antibacterial drugs.8

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Meeting the Challenge of Bacterial Resistance in Primary Care

Antibiotics are natural or synthetic substances that either inhibit the growth of or directly destroy bacteria. To be effective, all antibiotics must display selective or targeted toxicity (i.e., the drug must be toxic to bacterial cells but cause minimal to no toxicity to human cells). Based on cellular targets in the bacteria, antibiotics are classified as cell-wall synthesis inhibitors, protein synthesis inhibitors, nucleic acid synthesis inhibitors, cell-membrane disrupters, and metabolic antagonists. The most important classes with respect to lower RTIs include the cell-wall, protein synthesis, and nucleic acid synthesis inhibitors (Figure 1).9 Historically, the most frequently prescribed classes of antibiotics used in the empirical treatment of LRTIs involved in CAP and AECB included -lactams (penicillins and cephalosporins) and macrolides. More recently, fluoroquinolones have been added to the treatment list. Since these classes of antibacterials have been the most widely prescribed, they also represent the classes to which there is the most antibiotic resistance. Antibiotic resistance is attributable to many factors. One factor that is responsible for the surge of antibiotic-resistant bacteria is the misuse or overuse of antibiotics for the treatment of infections. Human treatment accounts for roughly half the antibiotics consumed every year in the United States. Perhaps only half of that use is appropriate, meant to cure bacterial infections, and administered correctly in ways that do not strongly encourage resistance. Researchers at the Centers for Disease Control have estimated that some 50 million of the 150 million outpatient prescriptions for antibiotics every year are unnecessary.11 In the industrial world, most antibiotics are available only by prescription, but this restriction does not ensure proper use. Individuals, for a variety of reasons, often fail to finish the full course of treatment. Leftover doses are then stockpiled and used to self-medicate in less-than-therapeutic amounts. In both circumstances,

FIGURE 1. CELLULAR TARGETS IN LRTIs INCLUDE CELL-WALL SYNTHESIS INHIBITORS, PROTEIN SYNTHESIS INHIBITORS, AND NUCLEIC ACID SYNTHESIS INHIBITORS9
CELL-WALL BIOSYNTHESIS: -LACTAMS GLYCOPEPTIDES CEPHALOSPORINS

PROTEIN BIOSYNTHESIS: MACROLIDES TETRACYCLINES AMINOGLYCOSIDES OXAZOLIDINONES

DNA REPLICATION AND REPAIR: FLUOROQUINOLONES

improper dosing fails to eliminate the disease agent completely and encourages the growth of resistant strains. Furthermore, antibiotic resistance that emerges in one location can often spread far and wide. With the everincreasing volume of international travel, another factor that may contribute to the rise in antibiotic-resistant bacteria is the wide use of antibiotics in animal husbandry and agriculture. More than 40% of the antibiotics manufactured in the United States are given to animals. Some of that amount goes to treating or preventing infection, but the majority is mixed into feed to promote growth. In agriculture, antibiotics are applied as aerosols to acres of fruit trees for controlling or preventing bacterial infections. High concentrations may kill all the bacteria on the trees at the time of spraying, but lingering antibiotic residues can encourage the growth of resistant bacteria that later colonize the fruit during processing and shipping. According to the CDC, there are multiple factors that influence physicians decisions to prescribe antibiotics for acute respiratory infections when they are unlikely to benefit patients. Patient demands for antibiotics have been singled out in numerous studies as having

a strong association with excess antibiotic use. Additional studies show that rates of antibiotic prescription for upper respiratory tract infections increase as patient volume increases, which suggests that time limitations are a factor in busy practices when it comes to discussion of nonantibiotic treatment alternatives.12,13 Therefore, the decision to prescribe antibiotics for acute respiratory infections appears to be a combination of multifaceted interactions among patients, physicians, and the healthcare system. To develop effective strategies for improvement of antibiotic-prescribing behavior, clinicians need to address each of these areas.
Epidemiology and Mechanisms of Resistance Among Respiratory-Tract Pathogens Bacteria become resistant to antibiotics by a number of different mechanisms (Figure 2), and genes for resistance can occur either by spontaneous mutation or by the acquisition of a resistant plasmid. The three general mechanisms by which bacteria can become drug-resistant are (a) reduction of the intracellular concentration of drug (through efflux or reduced permeability); (b) drug inactivation or modification through enzymatic actions; and (c) elimination

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Meeting the Challenge of Bacterial Resistance in Primary Care

or modification of the antibacterial target with the bacterial cell.14 The first general mechanism of antibiotic resistance involves a reduction in the intracellular concentration of the drug within the bacteria. This can be accomplished by decreasing the permeability of the membrane barrier (a mechanism for Gram-negative resistance), reducing the uptake of the drug across the plasma membrane, or pumping the drug out of the cell cytoplasm after the antibiotic has entered (a mechanism for Gram-positive and Gram-negative resistance). This last phenomenon, performed by efflux pumps, maintains the intracellular drug concentrations at subtherapeutic levels. Additionally, these pumps are seldom drug-specific and can pump out many different drugs, leading to multiple drug resistance. Resistance to many different antibiotics, including macrolides, quinolones, -lactams, and chloramphenicol, have all been attributed to efflux pumps. Bacteria that possess such pumps include S. pneumoniae, Escherichia coli, P . aeruginosa, Mycobacterium smegmatis, and S. aureus. For example, S. pneumoniae contains an efflux mechanism for macrolides encoded by the mefE genes.9,15,16 A second mechanism of resistance is the ability of some bacteria to inactivate drugs. This is done through chemical modification by possessing inactivating enzymes. The best known of these mechanisms includes the -lactamases. -lactamases, also called penicillinases, are unique enzymes that are secreted into the periplasmic space between the inner (plasma) membrane and the cell wall of Gram-negative bacteria. The -lactamases/penicillinases hydrolyze the -lactam ring of penicillins and cephalosporins before they can bind to the penicillin-binding protein (PBP) target. Over 200 different types of lactamases have been described in the literature. These enzymes are found in a wide variety of Gram-positive and Gram-negative bacteria.15,16 Other examples of antibiotic classes susceptible to inactivating enzymes within bacteria include aminoglycosides and
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chloramphenicol. Aminoglycosides have been found to be modified by bacteria possessing phosphorylation, acylation, or adenylation enzymes. Similarly, chloramphenicol can be modified by acylation. The modification of either aminoglycosides or chloramphenicol with these enzymes prevents their targeting of the bacterial ribosome and therefore their actions as protein synthesis inhibitors.17 The last general mechanism of antibiotic resistance arises when the drug target inside the bacterial cell is modified or eliminated. Modification of a single nucleotide or amino acid can change the bacterial targets ability to bind the antibiotic. For example, the change of an adenine nucleotide within the

bacterial ribosome, carried out by the methyl transferase enzyme (encoded by the erm genes), can dramatically reduce the binding affinity of macrolides as well as lincosamides and streptogramin type B to the bacterial ribosome (MLSB resistant phenotype). Similarly, the modification of transpeptidase enzymes (called Penicillin Binding Protein (PBP) mutants) renders many bacteria resistant to penicillins. S. pneumoniae is one particular bacteria that can modify many intracellular targets to acquire resistance to three different classes of antibiotics, including penicillins, macrolides, and fluoroquinolones. PBP mutants cause low, intermediate, and high levels of penicillin-resistance. Ribosomal changes (through the erm genes) confer the MLSB phenotype in S.

FIGURE 2. THE THREE GENERAL MECHANISMS BY WHICH BACTERIA CAN BECOME DRUG-RESISTANT: A) REDUCTION OF THE INTRACELLULAR CONCENTRATION OF DRUG; B) DRUG INACTIVATION OR MODIFICATION; AND C) ELIMINATION OR MODIFICATION OF THE ANTIBACTERIAL TARGET11

Source: Levy, 1998.

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Meeting the Challenge of Bacterial Resistance in Primary Care

pneumoniae. Additionally, mutations in the gyrA gene (DNA gyrase) or the parC steroid (topoisomerase IV) in S. pneumoniae strains alter the intracellular targets of the fluoroquinolones, leading to resistance to this class of drugs.15,18,19 Lastly, bacteria also may be able to use an alternative pathway and completely bypass the drug target. This phenomenon, known as target elimination, has been reported in vancomycin-resistant strains of enterococci that possess the vanHAX genes that change the D-Ala-DAla substrate to a D-Ala-D-Lac substrate, lowering the binding affinity to vancomycin a thousand-fold. Recent evidence of vancomycin resistance in S. aureus suggests a novel mutation involving changes in cell-wall content and composition, another example of target elimination. Target elimination is also used in multiple bacteria exhibiting sulfonamide resistance.17,20 Regardless of the mechanism of resistance, bacterias ability to overcome antibiotic treatment resides in its genetic information. Mechanisms of resistance can occur through the spontaneous mutation of the bacterial chromosome or through the acquisition of antibioticresistance genes. Spontaneous mutations occur within any species but arise in greater frequency in bacteria that find themselves in an unfavorable environment. The selective pressure placed on a bacterial population by frequent antibiotic exposure will result in the maintenance of pressure for the emergence of this advantageous mutation within the bacteria. Vertical transmission of this mutation will allow for all bacterial offspring to have the same beneficial mutation.9 Finally, antibiotic-resistance genes can also be acquired through the horizontal transmission of plasmid or transposonborne antibiotic-resistance genes. Both plasmids and transposons are found extrachromosomally and can be transferred between bacterial cells and even different bacterial species. The acquisition of plasmids or transposons can occur through the processes of bacterial conjugation (direct cell-cell transfer), transduction (transfer using a viral

TABLE 1. RATES OF RESISTANCE OF S. pneumoniae IN THE U.S., 19942000 2123


ANTIBIOTIC RESISTANT BACTERIA: S. pneumoniae
ANTIBACTERIAL RESISTANCE (%) ANTIBIOTIC Intermediate-, high-level penicillin Trimethoprim/sulfamethoxazole (TMP/SMX) Macrolides Tetracycline Chloramphenicol Clindamycin Ciprofloxacin Vancomycin Multidrug resistance 19941995 23.6 26.8 10.3 7.6 4.3 Not tested 1.2 0 9.1 19971998 29.5 31.0 19.2 13.2 7.2 5.7 1.6 0 16.0 19992000 34.2 35.9 26.2 16.6 8.3 19.2 1.4 0 22.4

Sources: Doern GV et al., 1996; Doern GV et al., 1999; and Doern GV et al., 2001.

intermediate), and/ or transformation (uptake directly from the environment).17


Exercise 3
Which of the following concerning the development of bacterial resistance is not true? a. A favorable environment for bacteria will encourage antibiotic resistance b. Bacteria can acquire resistant genes from other bacteria extrachromosomally c. One mechanism of resistance is to eliminate the target of the antibiotic drug within the bacteria d. Bacterias ability to overcome antibiotic treatment resides in its genetic information Answer on page 25.

The isolates exhibiting high levels of penicillin resistance are of particular concern since these strains many times display similar resistance patterns to other -lactam antibiotics. Furthermore, this study collected S. pneumoniae specimens from five sources: lower respiratory tract, upper respiratory tract, blood, cerebrospinal fluid, and other. Of the penicillin-nonsusceptible isolates found, 44.5% were from the lower respiratory tract, far surpassing the percentages isolated from any of the other sites (21.3%, 29.9%, 2.2%, and 2.2%, respectively). These data reaffirm the clinical relevance of resistant isolates in LRTIs.2124 It has been estimated by the CDC that over the past 5 years, the rate of resistance to penicillin in S. pneumoniae has increased by more than 300% (Table 1). Indeed, this increase in penicillin resistance has been associated with a crossresistance to other -lactams and other classes of antibiotics. Currently, we are seeing overall prevalence of approximately 35.9% in trimethoprim/sulfamethoxazole resistance and 26.2% in erythromycin (macrolide) resistance. Additionally, 16.6% of clinical isolates are tetracycline resistant, 19.2% are clindamycin resistant, 8.3% are chloramphenicol resistant, and 1.4% display ciprofloxacin resistance. Furthermore, data accumulated through these surveillance studies

Clinical Impact of Antibiotic Resistance The resistance to antibiotics and the spread of drug-resistant pathogens over the past decade is a serious threat to the successful treatment of LRTIs and is a national health concern.

Current rates of resistance in pneumococcus within the United States are quite high and increasing for many antibiotics. Studies in 19992000 of 1,531 clinical isolates demonstrated that 34.2% were not susceptible to penicillin. Of these nonsusceptible isolates, 12.7% demonstrated intermediate resistance (MIC = 0.12 to 1 g/mL) whereas 21.5% were found to possess high-level resistance (MIC *2 g/mL).

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indicate that 22.4% of pneumococci in the United States are multidrug resistant. Multidrug resistance is defined as intermediate- or high-level penicillin resistance plus intermediate- or highlevel resistance to at least two other classes of antibiotics.24 S. pneumoniae has many mechanisms by which it becomes resistant. Genes essential for DNA uptake and recombination are found ubiquitously within pneumococcus, allowing for these bacteria to readily accept antibiotic-resistance genes. The mechanism by which pneumococci become resistant to penicillin involves genetic changes that alter the target site. Mutations in five transpeptidases or penicillin-binding proteins have been found and highly resistant strains contain a greater number of genetically altered penicillin-binding proteins than do strains that exhibit intermediate resistance. Erythromycin resistance was first reported in the 1950s shortly after its introduction into clinical use. Since then, many bacteria have acquired resistance, including S. pneumoniae. Ribosome modification and alterations in antibiotic transport have been found to be mechanisms by which S. pneumoniae displays eyrthromycin resistance. Of particular clinical concern is the resistance to erythromycin mediated by the ermAM gene. This gene not only confers cross-resistance to other 14-, 15-, and 16-membered ring macrolides (such as clarithromycin and azithromycin) but also provides resistance to lincosamides and streptogramin-B drugs, resulting in the MLSB phenotype.25,26 As mentioned previously, mutations in the gyrA gene (DNA gyrase) or the parC gene (topoisomerase IV) in S. pneumoniae strains alter the intracellular targets of the fluoroquinolones leading to resistance to this class of drugs. The emergence of high-level resistance to the fluoroquinolone class of drugs is of utmost relevance to clinical management of lower respiratory infections and will be monitored very closely.27
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TABLE 2. ANTIBIOTIC RESISTANCE: H. influenzae AND M. catarrhalis

ANTIBACTERIAL RESISTANCE (%) H. influenzae -lactamase positive Ampicillin Trimethoprim/sulfamethoxazole (TMP/SMX) Cefuroxime Cefriaxone Azithromycin Clarithromycin Levofloxacin Amoxicillinclavulanate M. catarrhalis -lactamase positive
Source: Thornsberry, 2002.

1998-1999 34.5 33.9 11.7 0.1 0 0.3 0.3 0 0.1 93.4

1999-2000 31.3 30.7 14.0 0.1 0 0.3 0.8 0 0.2 94.9

Haemophilus influenzae, another common lower respiratory-tract pathogen, also displays antibiotic resistance. Recently published results from the TRUST (Tracking Resistance in the United States Today) surveillance program indicate that resistance in H. influenzae is leveling off in comparison to the increases seen over the past decade (Table 2).28 The number of clinical isolates found to be producing -lactamase decreased slightly from 34.5% in 19981999 to 31.3% in 19992000. As shown in the table, susceptibility to specific antibiotics demonstrated a slight decrease in resistance to ampicillin from 33.9% in 19981999 to 30.7% in 19992000. An increase in resistance during this twoyear time frame was seen in TMP-SMX, increasing from 11.7% in 19981999 to 14.0% in 19992000. All other antibiotics examined did not demonstrate a change in bacterial resistance between 1998 and 2000. Like H. influenzae, M. catarrhalis displays very high antibiotic resistance to penicillin due to the presence of BRO1 and BRO2 -lactamases. Studies suggest that the bro2 gene was acquired by M. catarrhalis through gene transfer and then evolved into the bro1 gene by random mutation events. Results from the TRUST surveillance program indicate that the number of clinical isolates producing -lactamase increased

slightly from 93.4% in 19981999 to 94.9% in 19992000. All other antibiotics tested on clinical isolates of M. catarrhalis did not demonstrate significant resistance or significant changes in resistance over the 2-year period.28 Atypicals The atypical bacteria Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila have not demonstrated the acquisition of specific antibiotic-resistant genes or selective mutations. However, members of the atypical group do not respond to lactam antibiotics because of natural resistance. Natural resistance is the nonresponsiveness to an antibiotic based on the inherent structure of the bacteria. For example, M. pneumoniae and C. pneumoniae both lack a peptidoglycan cell wall and therefore are lacking the cell target for penicillins and cephalosporins. Similarly, C. pneumoniae and L. pneumophila replicate intracellularly, which directly affects the efficacy of -lactams because they work extracellularly.29
Strategies to Minimize Antimicrobial Resistance The emergence and spread of antimicrobial resistance increasingly threatens the success of infectious disease treatment and prevention in the 21st century. World Health Organization30

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Meeting the Challenge of Bacterial Resistance in Primary Care

Acquired antibiotic resistance develops and is maintained in bacterial populations by the recurring pressure of antibiotics in the microbial environment. The emergence of antibioticresistant strains is an inevitable response to nondiscriminant and widespread use. To extend the usefulness of current and future antibiotics, we must rethink our current therapeutic strategies.30 Guidelines for decreasing antibacterial resistance include the following.9,17,31 When possible, culture before treating. Positive identification of the infectious agent will result in more efficacious and narrow spectrum treatment. Resist patients requests for unneeded antibiotics and respond proactively by providing education and alternative therapies. Isolate patients who have multidrug-resistant bacterial infections to prevent dissemination of the infection. Consult your local heath department for surveillance data on antimicrobial resistance rates in your area and report atypical infections. Use antibiotics judiciously and after careful consideration. Sometimes the use of the narrowest spectrum antibiotic will be enough. Sometimes combination therapy, targeting multiple bacterial sites to prevent the emergence of resistance, will be more appropriate. Whatever the prescription, patient adherence is an important link in breaking the resistance cycle since selective pressure on a microbial population is optimal at subtherapeutic doses.
Guidelines Clinical guidelines are now readily available, particularly in the case of common infections, such as CAP. These guidelines may improve appropriate antibiotic use, especially if results are audited and feedback is provided to prescribers. The use of antibiotic order forms and concurrent feedback to physicians or next-

day review of antibiotic correctness also can improve prescriptions. Guidelines for the treatment of CAP have been developed by the American Thoracic Society, British Thoracic Society, Canadian Infectious Disease Society, and the Infectious Disease Society of America.
ATS In 2001, the ATS released its most recent set of guidelines based on a review of the current literature and evidence-based recommendations to provide a framework for CAP evaluation and therapy.7 Included in these

and who are not at risk for DRSP or Gram-negative infections. The most common etiologies within this category are S. pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, and respiratory viruses. Less commonly, infection can also be caused by other pathogens, including Legionella spp., and H. influenzae. In appropriate epidemiologic settings, one may also consider M. tuberculosis and endemic fungi. The therapeutic recommendation given by the ATS for patients falling within this class includes advanced-

Rates of antibiotic prescription for upper respiratory tract infections increase as patient volume increases, which suggests that time limitations are a factor in busy practices when it comes to discussion of nonantibiotic treatment alternatives.
guidelines are the current patient stratifications for etiologic diagnosis of the most likely pathogens, as well as the current guidelines for empiric antibiotic therapy. Patient stratification was determined by four criteria: Severity of illness (mild, moderate, or severe). Place of therapy (outpatient, hospital ward, or intensive care unit). Presence of coexisting cardiopulmonary disease. Presence of risk factors for drugresistant S. pneumoniae (DRSP) and/or Gram-negative infection (termed modifying factors). The patient stratification scheme was then used to define the common pathogenic etiologies within a given stratification, and to recommend therapy. Four subsets of patients were defined by the ATS using these four criteria: Group 1: Outpatients without any history of cardiopulmonary disease generation macrolides (azithromycin or clarithromycin) or doxycycline for patients who are allergic or intolerant of macrolides. Azithromycin and clarithromycin are recommended over erythromycin because their lower frequency of administration and fewer gastrointestinal side effects improve patient compliance with these antibiotics. Group 2: Outpatients with a history of cardiopulmonary disease and/ or modifying factors. Modifying factors are conditions that increase the risk of certain bacterial etiologies. The most commonly seen etiologies within this category are S. pneumoniae (including DRSP), M. pneumoniae, C. pneumoniae, mixed infections (bacteria plus atypical pathogen or virus), H. influenzae, M. catarrhalis, enteric Gram-negatives (including Escherichia coli, Klebsiella spp., etc.), and respiratory viruses. As in Group 1, one may also consider M. tuberculosis and

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endemic fungi under certain epidemiologic circumstances. The therapeutic recommendation given in the ATS guidelines for patients falling within this class includes two options. The first option is the use of a -lactam drug with either a macrolide (azithromycin or clarithromycin) or doxycycline. Suggested -lactams include oral cefpodoxime, cefuroxime, high-dose amoxicillin, and amoxicillin/clavulanate, or parenteral ceftriaxone followed by oral cefpodoxime. The addition of doxycycline or an advanced-stage macrolide is necessary to provide coverage for cases with atypical bacterial infection. The second option includes the use of monotherapy with an antipneumococcal fluoroquinolone (e.g., levefloxacin or moxifloxacin). Group 3: Patients hospitalized due to a more severe infection but who do not require intensive care. This third stratification is further broken into two subcategories: (a) patients with a history of cardiopulmonary disease and/or modifying factors and (b) patients with no cardiopulmonary disease and/or modifying factors. The etiology of CAP in Group 3a is similar to Group 2 and Group 3b is similar to Group 1. However, these patients require hospitalization because of increased severity of illness. Patients in the first subcategory (3a) are frequently infected S. pneumoniae (including DRSP), H. influenzae, M. pneumoniae, C. pneumoniae, mixed infections (bacteria plus atypical or virus), enteric Gramnegatives, oral anaerobes (if an aspiration risk factor is present), respiratory viruses, or Legionella species. Additionally, infection can also be caused by less common pathogens including M. tuberculosis, Pneumocystic carinii, and endemic fungi. The treatment recommendations for a patient in the Group 3a category include intravenous -lactams plus another drug (intravenous or oral
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macrolide/doxycycline) or monotherapy with an intravenous antipneumococcal fluoroquinolone. Patients in the second subcategory (3b) are commonly infected with similar infectious agents as those in the first subcategory. However, these patients usually have infections with S. pneumoniae that are not drugresistant and are not usually infected with enteric Gram-negatives or anaerobes. Group 3b treatment recommendations call for intravenous advanced macrolide alone. However, with the increasing resistance to macrolides in S. pneumoniae, it may be more prudent to treat all Group 3 patients as Group 3a. Group 4: Patients who suffer from severe CAP and therefore require immediate recognition and treatment within an intensive care unit to prevent mortality. The pathogens most frequently associated with Group 4 include S. pneumoniae (including DRSP), Legionella species, H. influenzae, enteric Gramnegatives, Staphylococcus aureus, M. pneumoniae, and respiratory viruses. In appropriate epidemiologic settings, M. tuberculosis and dendemic fungi should also be considered. Pseudomonas aeruginosa infection is considered a possibility in this group when the patient has risk factors such as bronchiectasis, malnutrition, or diseases/treatments associated with neutrophil dysfunction, or has been on chronic/prolonged broad-spectrum antibiotic therapy (greater than seven days within the past month). The treatment recommendations for patients without the risk of P. aeruginosa include IV -lactam (cefotaxime or ceftriaxone) plus either IV macrolide (azithromycin) or IV fluoroquinolone. Patients with a risk of P. aeruginosa are recommended to receive combination antipseudomonal therapy, along with coverage for other pathogens, including DRSP and atypical pathogens.

Exercise 4
A patient presents with symptoms of CAP. You determine that he can safely be treated as an outpatient, and that he has little risk for DRSP or Gram-negative infections. What treatment do the ATS Guidelines suggest? a. Advanced-generation macrolides (azithromycin or clarithromycin) b. A -lactam drug with either a macrolide or doxycycline c. Intravenous -lactams plus another drug (intravenous or oral macrolide/doxycycline) d. Monotherapy with an intravenous antipneumococcal fluoroquinolone Answer on page 25.

IDSA In 2000, the IDSA released its set of guidelines for CAP management and therapy.10 Similar to the ATS guidelines, the IDSA based its guidelines on a review of the most recent literature and clinical studies for immunocompetent adult patients. The admission decision for CAP patients, according to the IDSA recommendations, relies on a prediction rule scoring system (PORT) with points being given for epidemiological risk of mortality. The sum of the points allows for the breakdown into five patient stratifications or risk classes for death. The scoring system is based on demographics, preexisting conditions, physical exam findings, and laboratory findings.32

Once the decision is made to treat the CAP patient on an inpatient or outpatient basis, management of the patient should involve the use of appropriate antibiotic therapy. Sputum samples can be helpful in identifying the etiologic pathogen and are recommended for both outpatients and inpatients. Initiation of antibiotic therapy within eight hours of presentation has been shown to improve outcome in inpatients with CAP. Therefore, diagnostic samples should be obtained expeditiously and therapy initiated within this time period.

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TABLE 3. PATHOGEN-DIRECTED ANTIMICROBIAL THERAPY FOR CAP


ORGANISM Streptococcus pneumoniae Penicillin-susceptiblea Penicillin G., amoxicillin Cephalosporins (cefazolin, cefuroxime, cefotaxime, ceftriaxone, or cefepime); oral cephalosporins (cefpodoxime, cefprozil, or cefuroxime); imipenem or meropenem; macrolidesb; clindamycin; fluoroquinolonec; doxycycline; ampicillin sulbactam or piperacillin tazobactam PREFERRED ANTIMICROBIAL ALTERNATIVE ANTIMICROBIAL

Penicillin-resistantd Haemophilus influenzae

Agents based on in vitro susceptibility test results, including cefotaxime and ceftriaxone; fluoroquinolonec; vancomycin Cephalosporin (2d or 3d generation); doxycycline; -lactam/-lactamase inhibitor; azithromycin; TMP-SMZ Fluoroquinolonec; clarithromycin

Moraxella catarrhalis Anaerobe Staphylococcus aureus


e

Cephalosporin (2d or 3d generation); TMP-SMZ; macrolide; -lactam/-lactamase inhibitor -lactam/-lactamase inhibitor; clindamycin

Fluoroquinolonec Imipenem

Methicillin-susceptible Methicillin-resistant Enterobacteriaceaef Pseudomonas aeruginosae

Nafcillin/oxacillin rifampin or gentamicine Vancomycin rifampin or gentamicin Cephalosporin (3d generation) aminoglycoside; carbapenem Aminoglycoside antipseudomonal -lactam; ticarcillin, piperacillin, mezlocillin, ceftazidime, cefepime, aztreonam, or carbapenem Macrolideb rifampin; fluoroquinalonec (including ciprofloxacin) Doxycycline; macrolideb Doxycycline; macrolideb Doxycycline TMP-SMZ; sulfonamide minocycline or amikacin Tetracycline Amantadine or rimantadine (influenza A); zanamavir or oseltamivir (influenza A or B) Supportive care
d

Cefazolin or cefuroxime; vancomycin; clindamycin; TMP-SMZ Linezolid Aztreonam; -lactam/-lactamase inhibitor; fluoroquinolonec Aminoglycoside + ciprofloxacin; cyprofloxacin + antipseudomonal -lactam Doxycycline rifampin Fluoroquinolonec Fluoroquinolonec Erythromycin; chloramphenicol Imipenem amikacin; doxycycline or minocycline Chloramphenicol

Legionella Mycoplasma pneumoniae Chlamydia pneumoniae Chlamydia psittaci Nocardia Coxiella burnetii (Q fever) Influenza virus Hantavirus

Note: TMP-SMZ, trimethoprim-sulfamethoxazole; , with or without.


a

MIC, >2 g/mL. In vitro susceptibility tests are required for optimal treatment; against

MIC, <2 g/mL. Erythromycin, clarithromycin, azithromycin or dirithromycin; S. pneumo-

Enterobacter species, the preferred antibiotics are fluoroquinolones and carbapenems.


f

niae, especially strains with reduced susceptibility to penicillin, should have verified in vitro susceptibility.
c

Coliforms: Escherichia coli, Klebsiella, Proteus, and Enterobacter.

Levofloxacin, gatifloxacin, moxifloxacin, trovafloxacin, or other fluoro-

Source: Bartlett, et al, 2000.

quinolone with enhanced activity against S. pneumoniae; ciprofloxacin is appropriate for Legionella, C. pneumoniae, fluoroquinolone-susceptible S. aureus, and most gram-negative bacilli; ciprofloxacin may not be as effective as other quinolones against S. pneumoniae.

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Meeting the Challenge of Bacterial Resistance in Primary Care

Sputum samples are not always obtainable, or diagnostic, and physicians must often treat patients empirically. The empirical treatment recommendations by the IDSA depend upon the management setting (outpatient or inpatient) as well as epidemiological risk factors. Empirical treatment recommendations for outpatients include doxycycline, a macrolide, or a fluoro- quinolone since these drugs cover the most likely etiologic pathogens. Inpatient empirical treatment recommendations for patients not in an intensive care unit (ICU) are extended spectrum cephalosporin combined with a macrolide or a -lactam/-lactamase inhibitor combined with a macrolide, or monotherapy with a fluoroquinolone. ICU patient therapy recommendations generally include an extended spectrum cephalosporin or a -lactam/lactamase inhibitor combined with either a macrolide or fluoroquinolone. If a sputum sample can be obtained and the pathogenic etiology identified, the IDSA guidelines suggest the following pathogen-specific therapies as summarized in Table 3.10 The ATS and IDSA guidelines have been established to provide physicians with an outline of how to best manage patients who exhibit initial signs and symptoms of CAP. Both sets of guidelines strive to create a management rubric with a two-fold purpose. First, these guidelines provide a way to empirically treat the CAP patient quickly. Since timely use of antibiotic therapy has been proven to decrease CAP morbidity and mortality, these guidelines will hopefully lead to better patient outcomes. Secondly, the defining of possible etiological agents for each patient/risk category results in the selection of the most efficacious antibiotic regimen, potentially lowering the
24

incidence of bacterial resistance to antimicrobials.7,10


Exercise 5
Which statement regarding the IDSA patient risk scoring system is false? a. The scoring system is based on demographics, preexisting conditions, physical exam findings, and laboratory results b. The prediction rule scoring system is based on points for epidemiological risk of mortality c. The sum of points allows for the breakdown into five patient stratifications or risk classes d. None of the above Answer on page 25.

affinity than erythromycin).33 This high affinity makes ketolides much more potent against macrolideresistance bacteria (both efflux [M-type resistance, mefA gene] and MLSB phenotypes [macrolidelincosamide-streptogramin resistance, ermB gene]).34 Additionally, this increased potency seen in the ketolides has been associated with the inability to induce MLSB resistance in vitro in S. pneumoniae, S. aureus and S. pyogenes.35 Telithromycin is the first ketolide drug to undergo clinical development. There have been several Phase III clinical trials of telithromycin with patients diagnosed with CAP or AECB that have shown that telithromycin was generally welltolerated, with the most frequently reported side effects being diarrhea and nausea. The majority of cases of diarrhea and nausea were mild or moderate in intensity, and only rarely led to discontinuation of therapy.36
Conclusions CAP and AECB remain important causes of lower respiratory tract morbidity and mortality. Many patients are diagnosed based on case history and presentation and are treated empirically. Since bacterial infection is the most common underlying cause of these infections, antibiotics are indicated. Unfortunately, the injudicious use of antibiotics over the last century has resulted in the selection of antibiotic-resistant strains of bacteria. Since this increase in antibiotic resistance among bacterial species can directly affect patient outcomes, it is a driving force behind the development of new treatment strategies. These strategies include using our current armamentarium of antibiotics more wisely and the development of new classes of antibiotics for the treatment of CAP and AECB patients. Newly developed guidelines for antibiotic use may also help achieve these goals.

Introduction of Newer Drugs The current challenges of antibiotic resistance have driven the development of new pharmacological agents. Novel antibiotics in the treatment of RTIs are called to provide for a wide range of etiological organisms, including strains that exhibit antibiotic resistance to other drugs. Additionally, novel antibiotics should minimize the further development of resistance.

The newest class of antibiotics that have demonstrated potent activity against bacteria associated with RTIs are the ketolides. Ketolides are a new class of semisynthetic, 14-membered macrolides that have been developed for use against respiratory pathogens. Structurally, ketolides have the basic macrolactone structure shared by all macrolides but have a 3-ketone group in place of the L-cladinose moiety at the C3 position.25 Ketolides, like all macrolides, are bacteriostatic antibiotics that have the ability to bind to the 23S rRNA component of the 50S ribosomal subunit (domains II and V) and inhibit protein synthesis. However, unlike other macrolides, the affinity by which a ketolide binds to a bacterial ribosome is much greater (e.g., ten-fold to a thousand-fold greater

CME-TODAY

Meeting the Challenge of Bacterial Resistance in Primary Care

Answers
Exercise 1 Which of the following statements concerning typical and atypical pathogens is true? a. Typical pathogens for CAP include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila b. Atypical pathogens are defined by the symptoms they cause c. The classification of pneumonia into typical and atypical categories is not clinically diagnostic d. The classification of pathogens into typical and atypical categories is a significant recent development Answer: c. The classifications of typical and atypical are not clinically diagnostic, therefore, these terms are now falling out of favor to classify pneumonia. Exercise 2 The most common pathogen responsible for CAP is: a. Chlamydia pneumoniae b. Haemophilus influenzae c. Legionella species d. Streptococcus pneumoniae Answer: d. A review of CAP studies over the last two decades has revealed the most common pathogens of CAP. They include, in order of frequency of incidence: Streptococcus pneumoniae, Haemophilus influenzae, Legionella species, and Chlamydia pneumoniae. S. pneumoniae is by far the most identifiable and accounts for almost two thirds of bacteremic CAP. Exercise 3 Which of the following concerning the development of bacterial resistance is not true? a. A favorable environment for bacteria will encourage antibiotic resistance b. Bacteria can acquire resistant genes from other bacteria extrachromosomally c. One mechanism of resistance is to eliminate the target of the antibiotic drug within the bacteria d. Bacterias ability to overcome antibiotic treatment resides in its genetic information Answer: a. Spontaneous mutations occur within any species but arise in greater frequency in bacteria that find themselves in an unfavorable environment. Exercise 4 A patient presents with symptoms of CAP. You determine that he can safely be treated as an outpatient and that he has little risk for DRSP or Gram-negative infections. What treatment do the ATS Guidelines suggest? a. Advanced-generation macrolides (azithromycin or clarithromycin) b. A -lactam drug with either a macrolide or doxycycline c. Intravenous -lactams plus another drug (intravenous or oral macrolide/ doxycycline) d. Monotherapy with an intravenous antipneumococcal fluoroquinolone Answer: a. This patient falls into Group 1. Recommendations include advancedgeneration macrolides (azithromycin or clarithromycin) or doxycycline. Exercise 5 Which statement regarding the IDSA patient risk scoring system is false? a. The scoring system is based on demographics, preexisting conditions, physical exam findings, and laboratory results b. The prediction rule scoring system is based on points for epidemiological risk of mortality c. The sum of points allows for the breakdown into five patient stratifications or risk classes d. None of the above Answer: d. Patient stratification within the IDSA guidelines is based on a scoring system with points being given for mortality risk. The sum of the points allows for the breakdown into five patient stratifications or risk classes. The scoring system is based on demographics, preexisting conditions, physical exam findings, and laboratory findings.

Creative Approaches to Managing Antibiotic Resistance Presented by Mona M. Counts, PhD, CRNP, FNAP, FAANP This interactive, Web-based course will help clinicians address the growing problem of antibiotic resistance by:
Exploring

various approaches of presenting the consequences of antibiotic overuse communicating effective therapeutic alternatives to patients

Proactively

Examining factors contributing to antibiotic overuse and patterns of resistance

Recorded live Tuesday, March 18, 2003 To view this program visit www.ce-today.com

CME-TODAY

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Meeting the Challenge of Bacterial Resistance in Primary Care

Bibliography
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