In a noontime session on Thursday, November 2nd 3 speakers discussed issues related to respiratory tract infections, bacterial resistance, and antimicrobial therapy.
This program was supported by an unrestricted educational grant from Aventis Pharmaceuticals.
Options for the Treatment of Community-Acquired Respiratory-Tract Infections
"Community-acquired respiratory tract infections continue to be among the most common and important infections seen by practicing physicians," said Charles W. Stratton, MD, director, Clinical Microbiology Laboratory, The Vanderbilt Clinic, Nashville, TN. These infections involve the sinuses, the airways, and/or the lungs, and can be caused by a wide variety of microorganisms, including viruses. Community-acquired respiratory tract infections caused by bacterial pathogens are usually defined as acute exacerbations of chronic bronchitis, community-acquired pneumonia (CAP) or acute bacterial sinusitis (ABS).
Acute exacerbations of chronic bronchitis are important because the incidence of chronic bronchitis is rising. Chronic bronchitis comprises 90% of all cases of chronic obstructive pulmonary disease (COPD). Risk factors for COPD include smoking, a family history of obstructive lung disease, exposure to tobacco smoke and pollutants, and recurrent respiratory tract infections, particularly during infancy. Chronic obstructive pulmonary disease accounts for more than 14 million office visits to family physicians and 500,000 hospital admissions annually. It is the fourth leading cause of death in the United States and the second most important cause of work disability. Acute exacerbations of chronic bronchitis are frequently caused by bacterial pathogens, among which the most common are Haemophilus influenzae and Strepto-coccus pneumoniae.
CAP remains an important therapeutic problem. In the United States, approximately 4 million cases of pneumonia are reported annually. The mortality rate for CAP is 14%, and pneumonia is the sixth leading cause of death in the United States. The annual direct and indirect costs of CAP total $23 billion. Although the influenza virus can cause CAP, S pneumoniae, H influenzae and the atypical pathogens Mycoplasma pneumoniae, Legionella spp and Chlamydia pneumoniae cause the majority of these infections.
"Acute bacterial sinusitis is a major problem, with approximately 31 million cases of acute and chronic sinusitis reported annually in the United States," said Dr. Stratton. The annual direct and indirect costs of ABS in the United States are more than $3.4 billion. The diagnosis of acute bacterial sinusitis can be difficult, and involves localized maxillary facial pain, poor response to decongestants, history of purulent nasal secretions or discharge, and abnormal transillumination.
Antimicrobial therapy of ABS is important, because the complications of these sinus infections include chronic sinusitis, orbital complications, and intracranial complications such as meningitis, epidural abscess, subdural empyema, venous sinus thrombosis and cerebral abscess. ABS is the fifth most common diagnosis for which antimicrobial agents are prescribed. The dominant bacterial pathogen in ABS is S pneumoniae.
The pathogenesis of these respiratory tract infections is similar and most often involves impairment of the mucociliary defense mechanism due to damage/death of the ciliated epithelial cells lining the sinuses and airways. Such impairment often arises acutely due to viral infections, but is also a chronic problem in people who smoke or are exposed to second-hand smoke.
The dominant respiratory tract pathogens seen in bacterial infections are S pneumoniae, H influenzae, and atypical pathogens such as M pneumoniae, Legionella spp and C pneumoniae. Some of these pathogens, such as S pneumoniae and H influenzae, are present in the normal flora of the respiratory tract. Others, such as C pneumoniae, are initially acquired in droplet nuclei from an infected person, and cause a low-grade chronic infection that can be exacerbated by viral infections. Legionella spp are acquired from a source such as dust, air conditioner mist, drinking water or showers.
"There are important problems associated with choosing therapeutic options for bacterial respiratory tract infections," said Dr. Stratton. When purulent nasal discharge or expectorated sputum specimens are available, a Gram stain is often quite useful in guiding the initial choice of antimicrobial agents; however, a precise microbiological diagnosis is often difficult because of the specialized and invasive procedures needed to obtain a specimen, and treatment is often empirical. Even when specimens can be collected, the differentiation of infection from colonization or contamination is a problem, and mixed infections occur frequently. A number of newly identified respiratory tract pathogens, such as C pneumoniae and Simkania, are difficult to detect, and are still being assessed in terms of their pathogenic potential. Finally, resistance of the most common bacterial pathogens has emerged and is increasing.
"Given the broad spectrum of respiratory tract pathogens and the problem of resistance, it is clear that there are currently few, if any, ideal antimicrobial agents for respiratory tract infections," said Dr. Stratton. The ideal agent should have excellent activity against the broad spectrum of respiratory tract pathogens, and low potential for the development of resistance. It should have a high clinical success rate with empirical therapy. It should have a favorable safety profile, convenient dosing with both oral and intravenous formulations, and a short required treatment course.
Older classes of antimicrobial agents, such as the beta-lactams, macrolides, azalides, and fluoroquinolones, all have members that have been useful in treating respiratory tract infections. Unfortunately, the emergence of newer pathogens and resistant organisms has lowered the clinical efficacy of these drugs. Newer classes of antimicrobial agents, including the streptogramin class (quinupristin/dalfopristin), the oxazolidinone class (linezolid), and the ketolide class (telithromycin), may prove useful for respiratory tract infections. The streptogramins and oxazolidinones are directed primarily against resistant Gram-positive bacteria, and should prove useful for infections caused by multidrug resistant S pneumoniae. The ketolides have the broadest spectrum of the newer classes of agents, and are active against important pathogens, including multi-
drug-resistant pneumococci.
Emerging Antimicrobial Resistance Patterns
"Respiratory tract infections are the most common reason for a physician office visit, more than for hypertension and gastrointestinal disturbances combined," said Richard L. Mabry, MD, professor, department of otolaryngology, University of Texas Southwestern Medical Center, Dallas. Patients often seek medical assistance following self-medication with over-the-counter agents as well as leftover antibiotics prescribed for others.
Current treatment options for respiratory tract infections include the penicillins, augmented penicillin, cephaloporins, macrolides, azalides, fluoroquinolines, trimetheprim/sulfa, and tetracyclines. Factors to be considered in choosing an antibiotic include the possible pathogens, the possibility of resistance, the severity of the infection, and patient characteristics such as age, allergies, and concomitant disease states. Characteristics of the specific antimicrobial that should be considered are the spectrum of activity, penetration of the site of infection, side effects, toxicity profile, drug and food interactions, cost, and convenience.
The most likely causative organisms for sinusitis, bronchitis, and pneumonia are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Approximately 95% of M catarrhalis is now beta-lactam resistant; this has been the case for approximately the past 10 years. With H influenzae, resistance is present in approximately 20% to 30% of strains. While at one time all pneumococci were penicillin-sensitive, resistant strains accounted for 5% to 10% of strains by 1991, and 25% to 40% by 1999. The percentage of resistant strains is lower in New England than in the South Central and South Atlantic regions. Highly penicillin-resistant S pneumoniae strains are resistant not only to penicillin, but most are resistant to amoxicillin/clavulanate and cephalosporins. Approximately 18% of these strains are resistant to macrolides, and 13% to tetracyclines. Quinolones remain effective at this time.
S pneumoniae develops macrolide resistance primarily by mutations that affect methylation of 23SrRNA, or via the efflux pump mechanism. While quinolones are generally very effective, with multiple passages in vitro in culture, resistance can begin to develop. Sporadic isolated cases of S pneumoniae that are resistant to quinolones have been reported. "Bacteria are becoming resistant at an alarming rate," said Dr. Mabry.
Antibiotics may be time dependent or concentration dependent in their antibacterial action. Minimum inhibitory concentration (MIC) is the concentration of an antimicrobial that inhibits 90% of bacterial growth; the most potent antibiotic is the one with the lowest MIC. Pharmacodynamic parameters to be considered are the peak concentration divided by the MIC, the area under the curve (AUC) divided by the MIC, and the time above the MIC.
Physicians contribute to the development of antimicrobial resistance by underdosing or giving an inadequate course of therapy for an infection. Avoiding prescribing antibiotics for trivial indications, encouraging proper dosing and duration of therapy, and employing cultures freely, especially after an initial treatment failure, are important measures in slowing the development of resistance.
Meeting the Antimicrobial Needs in the Current Age of Resistance
"For decades, most dosing of antibiotics has been more a matter of style or habit than science," said Richard Quintiliani, MD, professor of medicine, University of Connecticut School of Medicine and director, anti-infective research, Hartford Hospital, Hartford, Connecticut. New evidence has supported a marked change in dosing of antibiotics over the last few years that maximizes bacterial killing.
Principles to keep in mind to achieve a good outcome while minimizing cost include using monotherapy to decrease need for labor and reduce compliance issues, employing low and infrequent doses, preferably once daily, and abbreviating the duration of therapy. Older regimens of 10 to 14 day of antibiotic therapy have given way to newer 3- to 5-day regimens with newer antibiotics.
Rapid conversion from intravenous to oral administration of antibiotics is important in maximizing therapeutic outcome and minimizing cost. The cost of an oral formulation of an antibiotic is considerably less than its intravenous formulation. In addition, the chance of a patient experiencing sepsis from an intravenous line increases precipitously after 4 days. For every episode of line sepsis, the cost of a hospital stay increases by $4,000 to $6,000.
Rapid, proactive conversion from intravenous to oral antibiotic formulations will become a marker in evaluation of hospitals for accreditation. Criteria for conversion include clinical improvement on intravenous formulation, hemodynamic stability, and ability to ingest medication. "Unfortunately, this conversion seldom takes place within 2 days if left to a physician," said Dr. Quintiliani. This is due to the perception that intravenous drugs are more effective than oral formulations, which is not the case with drugs that are highly bioavailable. Another reason is that insurers have in the past required that a patient be discharged from the hospital once converted to oral antibiotics, although this ruling has been changed in recent years. "In the treatment of respiratory tract infection, we are very interested in oral agents that can be used to replace parenterally administered drugs," said Dr. Quintiliani.
Blood levels of antibiotics and other drugs decline from peak or maximum concentration at a rate that depends on the half-life of the drug. In general, concentrations reach minimum at approximately 6 times their half-life. Many older antibiotics have short half-lives, and must therefore be dosed every 4 hours. Many new agents have long half-lives that permit once-daily dosing.
"Antibiotics do no harm to bacteria until they make their way through the outer membrane and attach themselves to those binding sites that mediate metabolic processes of the organism," said Dr. Quintiliani. These binding sites vary with antibiotic class. In order to be effective, enough of these binding sites need to be blocked to interfere with metabolic processes, and the drug must remain at the site for a sufficient period of time to eradicate the organism; therefore, both the concentration at binding sites and the duration of residence at the binding sites are correlated with bacterial killing. Time and concentration are measured by the AUC, or the area under plasma concentration time curves obtained after a given dose of an antibiotic.
With some antimicrobials, the importance of 1 of these 2 variables (time at the binding site or concentration at the binding site) may far outweigh the other. Thus, antibiotic killing of bacteria may be referred to as either "time-dependent" or "concentration-dependent." Penicillins, cephalosporins, beta-lactams, clindamycin, vancomycin, erythromycin, and clarithromycin are time-dependent; they are equally effective whether their concentrations are just above MIC or much higher. For this reason, current recommendations to give larger doses for more severe infections with time-dependent agents are not useful. On the other hand, with concentration-dependent agents, maximum bacterial killing occurs at approximately 10 times the MIC. Compared with time-dependent drugs, concentration-dependent agents are more rapid killers of bacteria, resulting in a more rapid clinical response that allows for a shorter course of therapy. Currently available concentration-dependent drugs include the quinolones, aminoglycosides, amphotericin-B, and metronidazole.
For time-dependent antibiotics, the concentration of the antibiotic should be above its minimum inhibitory concentration against the target organism(s) for at least 50% of the dosing interval to obtain maximum response. Constant infusion achieves this 100% of the time, and achieves considerable cost savings related to less supply and labor costs.
To obtain the best clinical outcome in the treatment of community-acquired pneumonia, the initial regimen should have activity against both the intracellular atypical pathogens and the extracellular bacteria. Currently, approximately 30% of CAP is due to the atypical pathogens, Chlamydia spp, Legionella spp, and Mycoplasma spp. Because it is often difficult to differentiate CAP due to these organisms from those due to the typical bacteria (e.g., H influenzae, M catarrhalis, S pneumoniae), therapy for CAP is often empirical and directed at all of these organisms.
Because penicillins and cephalo-sporins do not penetrate inside cells, they exhibit minimal to no activity against the atypical pathogens. To obtain coverage against the atypical organisms, another antibiotic that penetrates inside cells and has activity against these atypical organisms has to be added. This is usually a macrolide. Unfortunately, resistance to macrolides occurs in approximately 20% of cases of infections with
S pneumoniae.
In patients with co-morbid conditions and in whom a rapid response is particularly important, the respiratory fluoroquinolones, which includes levofloxacin, gatifloxacin, and moxifloxiacin, are often recommended. At the present time, there is little resistance of S pneumoniae to these agents. They are currently not approved for use in the United States in children age 18 or younger because of concerns about arthropathy, although they have been used in many children with cystic fibrosis without this problem. "While clinical pressure exists to make respiratory fluoroquinolones available for pediatric use as resistance to other agents increases, using these powerful agents in children may cause the development of resistance to these agents as well," said Dr. Quintiliani.
The newest family of antimicrobials developed for the treatment of CAP is the ketolides. Chemically, they are similar to the macrolides; however,one of the sugar moieties has been replaced by a ketone. The first of this class is telithromycin, which has a wide spectrum of activity, including efficacy against S pneumoniae, H influenzae, M catarrhalis, S pyogenes, and the atypical pathogens C pnuemoniae, L pnuemophila, and Mycoplasma spp. "Telithromycin is incredibly active against penicillin- and macrolide-resistant S pneumoniae, and also against macrolide-resistant Staphylococcus aureus," said Dr. Quintiliani. Telithromycin will initially be introduced in an oral formulation, and subsequently will become available in an intravenous formulation. Telithromycin is a concentration-dependent drug, as are the quinolones.
Guidelines for selection of antibacterial therapy for CAP were recently put forth by the Infectious Disease Society of America (IDSA) and the Community Disease Center (CDC). The CDC recommends reserving quinolones for critically ill patients, while the IDSA encourages the use of respiratory quinolones for oral outpatient therapy if the patient has comorbid disease. "Future recommendations for therapy will most likely include the use of ketolide antibiotics," said Dr. Quintilia
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