From Macrolides to Ketolides: Meeting the Antimicrobial Needs in the Current Age of Resistance

Options for the Treatment of Community-Acquired Respiratory Tract Infections in the Elderly

“In 1992, three-quarters of all the antimicrobials prescribed in the United States were for upper respiratory tract infections (RTIs), and, mainly in the pediatric population, for otitis media,” began Chesley Richards, Jr, MD, MPH, Medical Epidemiologist, Centers for Disease Control and Prevention (CDC), Division of Geriatric Medicine, Emory University, Atlanta, GA. He indicated that there has been an emergence of antibiotic resistance in community organisms and that Streptococcus pneumoniae is what physicians are most concerned with. In about two to three million cases of community-acquired pneumonia, the most common cause is S. pneumoniae, and the highest incidence in case fatality rates (15-20%) for pneumonia occurs in the elderly. Data from the CDC Active Bacterial Surveillance Network show a high level of penicillin resistance in the early 1990s, which has increased dramatically and is a clinically important issue, according to Dr. Richards. “S. pneumoniae is also resistant to sulfas, erythromycin, amoxicillin, and cephalosporin,” he continued, adding that, although at present there is little resistance to levofloxacin, that resistance is doubling every year in the United States. Resistance differs throughout geographic regions of the country. “In 1996, penicillin resistance was 10-20% in the Northeast and on the West Coast, about 35% in the south, and about 20% in Texas,” noted Dr. Richards.

The speaker then discussed two practice guidelines: Principles for Appropriate Antibiotic Use for Treatment of Acute Respiratory Tract Infections in Adults, published in The Annals of Internal Medicine in March 2001, and the Practice Guideline for the Management of Community-Acquired Pneumonia, published in the Clinical Infectious Disease Journal in 2000 and sponsored by the Infectious Disease Society of America. Within these guidelines, he spoke about various upper RTIs: colds, acute pharyngitis, acute sinusitis, acute bronchitis, and pneumonia. “Upper RTIs do not have prominent sinus, pharyngeal, or lower airway symptoms,” Dr. Richards explained. “They are usually viral and account for 10% of antibiotic prescriptions given in ambulatory practice.”

Recommendations from the guidelines are to provide symptomatic treatment, giving patients instructions on how to relieve symptoms, and not to prescribe antibiotic therapy. Symptomatic treatment should include analgesics, antipyretics, and gargles. “Do use an antibiotic in upper RTI patients who have a history of acute rheumatic fever, valvular heart disease, immunosuppression, or recurrent or chronic pharyngitis,” Dr. Richards counseled. The criteria for antibiotic use in otherwise healthy persons with upper RTI are fever, tonsillar exudate, tender anterior cervical adenopathy, and the absence of cough. If patients do have cough, the physician must make sure that they do not have pneumonia. If they do not have cough but have these other symptoms, the physician is dealing with pharyngitis. Empiric antibiotic therapy with penicillin or erythromycin should be used in those who have all four criteria or two to three and a positive rapid antigen test. Acute sinusitis infections are frequently due to viruses.

When not caused by viruses, S. pneumoniae or Haemophilus influenzae are usually to blame. “If symptoms are mild, no antibiotic therapy is recommended,” Dr. Richards continued. “If symptoms are severe, or the patient has persistence of moderate symptoms such as nasal discharge or facial pain for more than one week, amoxicillin would be the first choice, followed by doxycycline, and distantly by trimethoprim sulfamethoxazole.” In acute bronchitis—an RTI that is associated with cough and mucus production—a viral or bacterial pathogen is identified 17-40% of the time. “Of the nonviral causes, chlamydia and mycoplasma are the most important,” the speaker added. Adults do not develop whooping cough because of the immunity they had as children, but they do have a clinical syndrome associated with chronic cough. “It is important, even in the outpatient setting, to obtain a sputum sample,” Dr. Richards said. If a microbiologic diagnosis can be obtained, therapy can be tailored to target that organism.

Outpatients with S. pneumoniae, mycoplasma, or chlamydia should be treated with doxycyline, macrolides, and fluoroquinolones, according to Dr. Richards. Hospitalized patients in the non–intensive care unit (ICU) should be treated with a cephalosporin plus a macrolide, a beta-lactamase inhibitor plus a macrolide, or a fluoroquinolone, which must have enhanced activity against S. pneumoniae such as lev?o?floxacin. Those in the ICU should receive an extended-spectrum cephalosporin or a beta-lactamase inhibitor in addition to a macrolide or a fluoroquinolone. “Influenza is a leading cause of outbreaks of RTIs in the community and in nursing homes,” explained the presenter. “Current guidelines state persons over 65 should have an annual influenza vaccination and a pneumococcal vaccination at least once after the age of 65, as well as those at high risk under that age. Influenza and pneumococcal vaccination coverage is approximately 60-70% and 30-40%, respectively; it should be 80% in persons over 65.” Much work is needed to increase coverage, added Dr. Richards. Unnecessary antibiotic use and the spread of resistance need to be reduced. Clinicians can aid in doing so by reading up on the guidelines, talking to their colleagues in the community, being an opinion leader in the community, displaying patient education materials in the office, promoting open dialogue with patients, and conducting patient follow-up phone calls.

-----

Emerging Antimicrobial Resistance Patterns

“The most common sites of nosocomial infection in long-term care [LTC] settings are the urinary tract, respiratory tract, skin and soft tissue, and gastrointestinal tract,” began Dan Osterweil, MD, CMD, Professor of Medicine and Geriatrics and Research Associate, Borun Center, University of California at Los Angeles School of Medicine. “One of six [patients] will acquire infection each month in a nursing home. The more disabled and dysfunctional individuals are, the higher the infection rate.”¹ Antibiotic-resistant infections in LTC facilities have been increasing in complexity, stated Dr. Osterweil. The infections include penicillin-resistant pneumococci, vancomycin-resistant enterococci (increased from 0.3 to 7.9 per 100 infections), gram-negative bacteria, and extended beta-lactamase–producing bacteria (making common antibiotics and cephalosporins obsolete), and quinolone-resistant, gram-positive, and gram-negative bacteria (emerging quickly in nursing homes). “Some of the mechanisms of antibiotic resistance are molecular rearrangement of penicillin-binding protein genes, acquisition of a mobile genetic element, and point mutations that alter active sites,” continued Dr. Osterweil. “Additional problems include vancomycin-intermediate S. aureus, not a big problem but something to be aware of, and multidrug efflux pumps in gram-negative bacteria.” The speaker noted that 28% of bacteria most frequently causing hospitalization are resistant to standard therapy.

Dr. Osterweil turned his focus to a study by Weiner and colleagues,² which was conducted on patients infected or colonized with cefazidine-resistant Klebsiella pneumoniae and Escherichia coli in a 400-bed hospital and a community nursing home setting from July 1992 to November 1999. Fifty-five hospital patients were infected; 35 were admitted from eight nursing homes; and all strains were resistant to ceftazidine, gentamycin, and tobramycin (98% were resistant to trimethoprim-sulfamethoxazole, and 41% were resistant to ciprofloxacin). “The [researchers’] conclusions were that nursing home resistance may be an important reservoir of extended beta-lactamase containing multiple antibiotic-resistant E. coli and K. pneumoniae.” He added, “Widespread dissemination of a predominant antibiotic plasmid had occurred, and use of broad-spectrum oral antibiotics and poor infection control practices may facilitate spread of this plasmid-mediated resistance.”

Risk factors for colonization, according to Dr. Osterweil, include poor functional status, presence of gastrostomy tube or decubitus ulcers, and prior receipt of ciprofloxacin and/or trimethoprim-sulfamethoxazole. “The consequences of MRSA (multidrug-resistant S. aureus) carriage in a nursing home residents study³ showed that the relative risk for dying within six months was almost twice in carriers versus noncarriers,” he noted. “After one year, the risk was only 1.3-fold.” The speaker also stated that Mulhausen and associates⁴ conducted a comparison of hospital-based VA and community nursing home patients, and found that only three of 27 patients colonized at baseline developed any MRSA infection. “Strict adherence to infection control practices essentially eliminated patient-to-patient transfer,” he added. The cultural and economic factors that negatively influence antibiotic use include:

• Patient motivation to get a tangible product
• Incorrect perceptions of the effectiveness of antibiotics
• Lack of information among physicians
• Desire to satisfy patient demand
• Pressure from managed care organizations
• Marketing campaigns

Dr. Osterweil concluded by stating, “Rapid spread of resistance demands immediate and aggressive response; preliminary data suggest antibiotic-prescribing practices can be improved, particularly in nursing homes; and acceleration of the development of new tests and antimicrobial agents should be encouraged.”

References

1. Nosocomial infection rates for five long-term care facilities in western New York State. SUNY Buffalo School of Medicine and Biomedical Sciences. Available at: https://www.smbs.buffalo.edu. Accessed June 13, 2001.

2. Weiner J, et al. Klebsiella and Escherichia coli in the nursing home setting. JAMA 1999;281:563-564.

3. Niclaes L, Buntinx F, Banuro F, et al. Consequences of MRSA carriage in nursing home residents. Epidemiol Infect 1999;122:235-239.

4. Mulhausen PL, Harrell LJ, Weinberger M, et al. Contrasting methicillin-resistant Staphylococcus aureus colonization in Veterans Affairs and community nursing homes. Am J Med 1996;100:24-31.

-----

Meeting the Antimicrobial Needs in the Current Age of Resistance 

Charles W. Stratton, MD, Associate Professor of Medicine and Director, Clinical Microbiology Laboratory Center, Vanderbilt University Medical Center, Nashville, TN, spoke about the goals of antimicrobial-resistance control that should be sought by physicians and pharmaceutical companies. “We need to define new targets for antimicrobial agents, develop new antimicrobial agents for resistant microbes, and develop ‘resistance inhibitors,’” he began. “Efflux pumps are a major form of resistance. They pump the antibiotics from various families out of the bacteria cell as fast as they get into it.” Other goals Dr. Stratton mentioned were:

• Understand the epidemiology of antimicrobial resistance
• Monitor resistance rates with feedback to physicians
• Adhere to infection control measures
• Improve education for practitioners and the public about resistance and infection control
• Reduce inappropriate use of antimicrobial agents in patients and in the animals used for food
• Develop and use vaccines to reduce the need for antimicrobial agents

“Antimicrobial-resistance mechanisms must be understood,” Dr. Stratton continued. “Decreased penetration is an important mechanism. One reason that macrolides do not work well against gram-negative E. coli is they do not get into the organism. Macrolides, which work against gram-positives, can also be pumped out by active efflux. This fact is becoming increasingly recognized.” Important resistance mechanisms mentioned by the speaker were the destruction of antimicrobial agents, seen with beta-lactamase (which destroys penicillin), inactivation of the agent, and alteration of the agent. Dr. Stratton discussed the epidemiology of antimicrobial resistance, noting that it develops due to antimicrobial pressure.

“If you expose patients to antibiotics, one of two things will happen,” he noted. “The organism will be completely eliminated, but then be replaced, or the bacteria will select out strains that are resistant. The selection mechanisms have been around for eons.” The source of the pressure may be unknown or unappreciated. “There is a tendency to put antiseptic or antibacterial agents in such products as mouthwash, toothpaste, and soaps to cut down on bacteria,” he continued. “It was recently published that the use of these agents actually promotes resistance.” Resistance is often spread from patient to patient by busy health care workers who do not wash their hands, and more convenient ways are needed to wash hands. “There are only seven different types of multidrug-resistant strains throughout the world, and they also have a high level of resistance to penicillin,” explained Dr. Stratton. “If it is known what those strains are when vaccines are made, the vaccines could include those strains.”

The speaker concluded by presenting information on telithromycin’s activity against S. pneumoniae, erythromycin-resistant S. pneumoniae, H. influenzae, Moracella catarrhalis, Legionella species, Mycoplasma pneumoniae, and Chlamydia pneumoniae. “Telith?romycin possesses potent in vitro activity against the common respiratory pathogens S. pneumoniae and M. catarrhalis,” he stated. “It shows similar activity to that of azithromycin against H. influenzae, being four to eight times more potent than erythromycin and clarithromycin. It also demonstrates potent activity against atypical respiratory tract pathogens including L. pneumophila, M. pneumoniae, and C. pneumoniae.” He noted that it should not be used for all patients because of risk factors and resistance rate fluctuations throughout the community, but he stated that “there is light at the end of the tunnel.”