Latest Evidence-Based Medicine on the Emergence of Antimicrobial Resistance to Streptococcus pneumoniae: Key Determinants
This report was reviewed for medical and scientific accuracy by Gary V. Doern, PhD, Professor, Section Director, Clinical Microbiology, University of Iowa, Iowa City
Streptococcus pneumoniae (S. pneumoniae) is among the leading causes of infection and death worldwide for young children, persons who have underlying chronic diseases, and the elderly. This important respiratory tract pathogen is the leading cause of community-acquired pneumonia (CAP) and acute otitis media in the United States (US).1 The pneumococcus is now also recognized as the most common bacterial cause of meningitis in the US.1
Until recently in the US, S. pneumoniae was nearly uniformly susceptible to penicillin and other Я-lactam antimicrobial agents. This allowed clinicians to treat patients, even those with severe pneumococcal infections, with Я-lactam agents alone. In vitro susceptibility testing was largely unnecessary. Since the early 1990's, however, the prevalence of Я-lactam resistance in S. pneumoniae has risen steadily each year.
Results from a multicenter US national surveillance study2 conducted between November 1999 and April 2000 indicate that ~35% of pneumococci are now non-susceptible to penicillin (minimum inhibitory concentration (MIC) ≥ 0.12 µg/mL) with circa 60% of these isolates expressing high-level penicillin resistance (MIC ≥ 2 µg/mL). Overall, antimicrobial resistance was highest among middle ear fluid and sinus isolates of S. pneumoniae; lowest resistance rates were noted with isolates from cerebrospinal fluid and blood. Resistant isolates were most often recovered from children 0 to 5 years of age.2
Mechanism of Resistance
The principal mechanism of resistance to penicillin and other Я-lactam antibiotics with S. pneumoniae is alterations in penicillin-binding proteins (PBPs) as a consequence of a mosaic of genetic changes at the level of the bacterium's chromosome.3 Я-lactam resistant pneumococci are characterized by PBPs with diminished antibiotic affinity, leading in turn to decreased antibiotic effect (i.e. increased Я-lactam MICs). Resistance to numerous other non-Я-lactam antibiotic classes (e.g. macrolides, clindamycin, tetracyclines, chloramphenicol, trimethoprim/sulfamethoxazole (TMP/SMX) and the fluoroquinolones) has also become manifest with S. pneumoniae in the US.4-6 Resistance to these agents is the result of alternative mechanisms, each specific to a particular antibiotic class. Interestingly, despite different mechanisms of resistance, defined both phenotypically and genotypically, resistance to multiple antibiotic classes often occurs within the same strain of S. pneumoniae. Such strains are referred to as multi-drug resistant.
There are two mechanisms of macrolide resistance with S. pneumoniae: an efflux pump (encoded for by the mefA gene)7-10 and altered ribosomes as a result of ribosomal methylation (encoded by the ermB gene).11 Strains with efflux as their resistant determinant express modest levels of resistance to macrolides (MIC 0.5-32 µg/mL), but remain susceptible to clindamycin and streptogramin B antimicrobials; such strains are referred to as having the M phenotype. Strains with altered ribosomes typically express high levels of macrolide resistance (MIC > 256 µg/mL) and are also resistant to clindamycin and streptogramin B agents; they are referred to as having the MLSB phenotype. The M phenotype is most prevalent in the US with 70-75% of macrolide-resistant strains having efflux as their resistance determinant. Despite high rates of macrolide resistance with S. pneumoniae in the US as determined in the laboratory, it is not clear what macrolide resistance, especially efflux-mediated resistance, means from a clinical perspective.12,13
The most important mechanisms of fluoroquinolone resistance are chromosomal mutations in the genes encoding the polypeptide subunits of topoisomerase IV and DNA gyrase, two enzymes necessary for DNA replication in S. pneumoniae, and overexpression of endogenous multi-drug transporters (i.e. efflux pumps). The first mechanism results in diminished binding of fluoroquinolones to their enzyme targets of action. The presence and enhanced expression of endogenous efflux pumps leads to active extrusion of fluoroquinolones from within the bacterial cytoplasm resulting in reduced levels of intracellular accumulation.
Currently in the US, the following approximate overall resistance rates apply to S. pneumoniae and non-Я-lactam antimicrobial agents: macrolides, 25.9%; tetracyclines, 16.4%; chloramphenicol, 8.4%; trimethoprim/sulfamethoxazole, 30.3%; and clindamycin, 8.8%.2 [see Figure 1] Furthermore, approximately 22.5% of S. pneumoniae clinical isolates are multi-drug resistant. Although an emerging problem in certain other countries, fluoroquinolone resistance has not yet emerged as a problem with S. pneumoniae in the US.4,14-18
Causes of Resistance
The question arises: "What are the factors that have influenced the emergence of drug resistant S. pneumoniae in the US during the past decade?" One important consideration relates to the observation that the emergence of resistance to antibiotics is often a direct result of antibiotic use. Specifically, the rising prevalence of antibiotic resistance is a consequence of the selective pressure exerted by use of antibiotics.19-22 The correlation between increasing antibiotic use and increasing prevalence of resistance has been shown most clearly in the hospital23,24 but has also been demonstrated in the community setting.25,26
A major contributing factor to increasing antibiotic resistance is inappropriate use of antibiotics. It has been estimated that 20 to 50% of antibiotic prescriptions issued in the community setting are unnecessary.27,28 One recent report29 attributed inappropriate antibiotic prescribing to unreasonable patient expectations or demands, inadequate physician time to explain why antibiotics are unnecessary, and misdiagnosis of nonbacterial infections. Even when physicians know that the use of antibiotics is likely to have marginal, if any, clinical value (e.g., in viral infections), they prescribe antibiotics in an effort to placate and thus maintain good relationships with their patients.30 Furthermore, with the increasing pressures of managed care, physicians may not be accorded the opportunity to spend sufficient time with patients to explain why antibiotics may be unnecessary, indeed, why they may actually be harmful (i.e., side-effects and resistance). It is often the path of least resistance to prescribe an antibiotic. Ironically, this may also be the path to greatest resistance.
The problem of resistance is complicated by the widespread use of antibiotics as growth enhancers in the food animal industry. Although the precise mechanism by which antibiotics promote animal growth is not well understood, more than 40% of antibiotics manufactured in the US are used in animals.31 This type of use creates a circumstance for selecting resistant bacteria in animals that may, in turn, be passed to the human population.32 A panel of World Health Organization consultants has recommended the gradual discontinuation of antibiotics as growth promoters in animals.33
Not all antimicrobial agents have the same potential for selecting for drug resistant S. pneumoniae. Generally speaking, the more potent an antimicrobial agent, the less likely it is to select for resistance.34 This may be explained by the observation that antimicrobial potency is an important determinant not only in achieving a favorable therapeutic outcome, but also in the context of the emergence of antimicrobial resistance. Potency is the product of both antibacterial activity and the ability to deliver an antimicrobial agent in adequate concentrations to the site of infection for bacterial eradication. The most refined in vitro measure of antibacterial effect is determination of MICs. Drug delivery is a product of the pharmacokinetic properties of specific agents. The relationship between in vitro activity (i.e., MICs) and drug delivery (i.e., pharmacokinetics) is referred to as pharmacodynamics.35 Antibiotic potency is best considered from the perspective of the pharmacodynamic properties of given drug versus a specific pathogen. In effect, the emergence of antimicrobial resistance is influenced by the pharmacodynamic potency of antimicrobial agents. One of the best examples of this concept pertains to the macrolide (e.g., erythromycin, clarithromycin, azithromycin) antimicrobial class.
Azithromycin is consistently 3 to 4-fold less active than clarithromycin for S. pneumoniae (i.e., azithromycin MICs are typically 3-4 times higher than clarithromycin MICs for S. pneumoniae).36,37 [see Figure 2] Additionally, peak serum levels of azithromycin are roughly one-tenth those of clarithromycin.38 In other words, azithromycin is inferior to clarithromycin in terms of both in vitro activity and pharmacokinetics. It has been suggested that tissue levels rather than serum levels are most important in pharmacodynamic analyses. In the case of azithromycin and clarithromycin, however, serum levels closely parallel drug levels in lung epithelial lining fluid.39-42 As a result, serum levels with these two macrolides provide a reasonable basis for pharmacodynamic comparisons related to S. pneumoniae vis-а-vis patients with bronchopulmonary infections.
Adapted from Doern GV. CID 2001;33(Suppl 3):S187-S192.
There exists evidence from several studies that usage of azithromycin is much more likely to select for macrolide resistance with S. pneumoniae than is usage of clarithromycin.43-49 If the mechanism of macrolide resistance that is selected for by azithromycin usage happens to be ermB-mediated alterations in ribosomal targets, the resulting strains are now cross-resistant at high levels to all macrolides including the most potent agent in this class--clarithromycin.50,51 In effect, then, use of marginally active agents to select for resistance may lead to a compromise in the utility of more potent agents and ultimately, the erosion of an entire antimicrobial class. This may take on critical importance with the emerging evidence of macrolide-resistant S. pneumoniae exhibiting dual macrolide resistance mechanisms.52 However, the relation between drug resistance and failure of the infection to respond to treatment in patients with pneumococcal pneumonia has not been established.53-56
Addressing Increasing Resistance
The application of pharmacodynamic analyses in assessing the potency of different antimicrobial agents provides an objective basis for optimizing antibiotic therapy in patients with respiratory tract infections. This approach represents one example of the application of evidenced-based medicine in the care of patients with infection in the community. In addition, a number of medical societies have recently developed and published treatment guidelines that, among other things, advocate the judicious use of antimicrobials in the outpatient setting. For example, guidelines for the management of CAP have been issued by the American Thoracic Society57, the Infectious Diseases Society of America58, and the Canadian Infectious Diseases Society/Canadian Thoracic Society.59 Application of pharmacodynamic analyses in optimizing outpatient oral antimicrobial therapy and use of care pathways based on nationally-endorsed management and treatment guidelines have the potential for dramatically impacting on the problem of antibiotic resistance with S. pneumoniae.
Oral antimicrobial usage is a major determinant in the development of antimicrobial resistance with S. pneumoniae. Clearly, judicious use of antimicrobial agents must be emphasized. In patients who truly warrant therapy, consideration must be given to utilization of the most potent agent in a particular antimicrobial class as the most effective means of achieving a favorable therapeutic outcome and preventing the emergence of antimicrobial resistance.
Additional Suggested Reading
Lynch JP, Martinez FJ. Clinical Relevance of Macrolide-Resistant Streptococcus pneumoniae for Community-Acquired Pneumonia. Clin Infect Dis 2002;34(Suppl 1):S27-S46.
File TM. Appropriate Use of Antimicrobials for Drug-Resistant Pneumonia: Focus on the Significance of Я-Lactam-Resistant Streptococcus pneumoniae. Clin Infect Dis 2002;34(Suppl 1):S17-S26.
Hooton T, Levy S. Antimicrobial Resistance: A Plan of Action for Community Practice. Am Fam Physician 2001;63:1087-1096, 1097-1098.
Hellinger W. Confronting the Problem of Increasing Antibiotic Resistance. South Med J 2000;93(9):842-848.
Doern G. Antimicrobial Resistance with Streptococcus pneumoniae in the United States. Sem Resp Crit Care Med 2000;21(4):273-284.
1. Resistance of Streptococcus pneumoniae to Fluoroquinolones-United States, 1995-1999. MMWR Morb Mortal Wkly Rep 2001 Sep 21;50(37):800-804.
2. 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.
3. Laible et al. Interspecies Recombinational Events During the Evolution of Altered PBP 2x Genes in Penicillin-Resistant Clinical Isolates of Streptococcus pneumoniae. Mol Microbiol 1991 Aug;5(8):1993-2002.
4. Doern GV, Pfaller MA, Kugler K, et al. Prevalence of Antimicrobial Resistance Among Respiratory Tract Isolates of Streptococcus pneumoniae in North America: 1997 Results From the SENTRY Antimicrobial Surveillance Program. Clin Infect Dis 1998;27:764-770.
5. Thornsberry et al. Surveillance of Antimicrobial Resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996-1997 Respiratory Season. Laboratory Investigator Group. Diagn Microbiol Infect Dis 1997;29:249-257.
6. Thornsberry et al. In Vitro Activity of Grepafloxacin and 25 Other Antimicrobial Agents Against Streptococcus pneumoniae: Correlation with Penicillin Resistance. Clin Ther 1998 Nov-Dec;20(6):1179-1190.
7. Seppala et al. Three Different Phenotypes of Erythromycin-Resistant Streptococcus pyogenes in Finland. J Antimicrob Chemother 1993;32:885-891.
8. Shortridge et al. Novel Mechanism of Macrolide Resistance in Streptococcus pneumoniae. Diagn Microbiol Infect Dis 1996;26:73-78.
9. Tait-Kamradt et al. mefE is Necessary for the Erythromycin-Resistant M Phenotype in Streptococcus pneumoniae. Antimicrob Agents Chemother 1997;41:2251-2255.
10. Clancy et al. Molecular Cloning and Functional Analysis of a Novel Macrolide-Resistance Determinant, mefA, from Streptococcus pyogenes. Mol Microbial 1996;22:867-879.
11. Arthur et al. Origin and Evolution of Genes Specifying Resistance to Macrolide, Lincosamide and Streptogramin Antibiotics: Data and Hypothesis. J Antimicrob Chemother 1987;20:783-802.
12. Whitney et al. Increasing Prevalence of Multidrug-Resistant Streptococcus pneumoniae in the United States. N Engl J Med 2000;343:1917-1924.
13. Amsden GW. Pneumococcal Macrolide Resistance: Myth or Reality? J Antimicrob Chemother 1999;44:1-6.
14. Thornsberry C, Jones ME, Hickey LM, et al. Resistance Surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis Isolated in the United States., 1997-1998. J Antimicrob Chemother 1999;44:749-759.
15. Doern GV, Brueggemann, AB, Coffman S, et al. Fluoroquinolone Resistance with Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother 2000; (in press).
16. Jones ME, Sahm DF, Martin N, et al. Prevalence of gyrA, gyrB, parC and parE Mutations in Clinical Isolates of Streptococcus pneumoniae with Decreased Susceptibilities to Different Fluoroquinolones and Originating from Worldwide Surveillance Studies During the 1997-1998 Respiratory Season. Antimicrob Agents Chemother 2000;44:462-466.
17. Doern GV, Pfaller MA, Erwin ME, et al. The Prevalence of Fluoroquinolone Resistance Among Clinically Significant Respiratory Tract Isolates of Streptococcus pneumoniae in the United States and Canada: 1997 Results from the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis 1998;32:313-315.
18. Jones RN, Pfaller MA, Doern GV. Comparative Antimicrobial Activity of Trovafloxacin Tested Against 3049 Streptococcus pneumoniae Isolates from the 1997-1998 Respiratory Infection Season. Diagn Microbiol Infect Dis 1998;32:119-126.
19. Waldvogel FA: New Resistance in Staphylococcus aureus. N Engl J Med 1999;340:556-557.
20. Rahal et al. Class Restriction of Cephalosporin Use to Control Total Cephalosporin Resistance in Nosocomial Klebsiella. JAMA 1998;280:1233-1237.
21. Tenover FC, Hughes JM: The Challenges of Emerging Infectious Diseases, Development and Spread of Multiple-Resistant Bacterial Pathogens. JAMA 1996;275:300-304.
22. Duncan RA: Controlling Use of Antimicrobial Agents. Infect Control Hosp Epidemiol 1997;18:260-266.
23. Gaynes R: The Impact of Antimicrobial Use on the Emergence of Antimicrobial-Resistant Bacteria in Hospitals. Infect Dis Clin North Am 1997;11:757-765.
24. Shlaes 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.
25. Arnold KE,Leggiadro RJ, Breiman RF. Risk Factors for Carriage of Drug-Resistant Streptococcus pneumoniae Among Children in Memphis, Tennessee. J Pediatr 1996;128:757-764.
26. Hofmann J, Cecron MS, Furley MM, et al. The Prevalence of Drug-Resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995;333:481-486.
27. Harrison PF, Lederberg J, eds. Antimicrobial Resistance: Issues and Options. Workshop Report. Forum on Emerging Infections, Division of Health Sciences Policy, Institute of Medicine. Washington D.C.: National Academy Press, 1998:1,39-41,46.
28. U.S. Congress, Office of Technology Assessment. Impacts of Antibiotic-Resistant Bacteria, OTA-H-629. Washington, D.C.: U.S. Government Printing Office, September 1995.
29. Schwartz et al. Preventing the Emergence of Antimicrobial Resistance. A Call for Action by Clinicians, Public Health Officials, and Patients [Editorial]. JAMA 1997;278:944-945.
30. Butler et al. Understanding the Culture of Prescribing: Qualitative Study of General Practitioners' and Patients' Perceptions of Antibiotics for Sore Throats. BMJ 1998;317:637-642.
31. Levy SB. The Challenge of Antibiotic Resistance. Sci Am 1998;278:46-53.
32. Fey et al. Ceftriaxone-Resistant Salmonella Infection Acquired by a Child From Cattle. N Engl J Med 2000;342:1242-1249.
33. Levy SB. Multidrug Resistance- A Sign of the Times [Editorial]. N Engl J Med 1998;338:1376-1378.
34. Doern G. Antimicrobial Use and the Emergence of Antimicrobial Resistance with Streptococcus pneumoniae in the United States. Clin Infect Dis 2001;33(Suppl 3):S187-S191.
35. Craig WA. Pharmacokinetic/Pharmacodynamic Parameters: Rationale for Antibacterial Dosing of Mice and Men. Clin Infect Dis 1998;26:1-12.
36. Doern GV, Brueggemann AB, Holley HP, et al. 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.
37. Doern GV, Brueggemann AB, Huynh H, et al. Antimicrobial Resistance with Streptococcus pneumoniae in the United States, 1997-8. Emerg Infect Dis 1999;5(6):757-765.
38. Gilbert DN, Moellering RC, Sande MA. The Sanford Guide to Antimicrobial Therapy. 28th ed. Hyde Park, VT. Antimicrobial Therapy, Inc. 1998.
39. Conte JE, Golden JA, Duncan S, et al. Intrapulmonary Pharmacokinetics of Clarithromycin and of Erythromycin. Antimicrob Agents Chemother 1995;39(2):334-338.
40. Conte JE, Golden J, Duncan S, et al. Single-Dose Intrapulmonary Pharmacokinetics of Azithromycin, Clarithromycin, Ciprofloxacin, and Cefuroxime in Volunteer Subjects. Antimicrob Agents Chemother 1996;40(7):1617-1622.
41. Rodvold KA, Gotfried MH, Donziger LH, et al. Intrapulmonary Steady-State Concentrations of Clarithromycin and Azithromycin in Healthy Adult Volunteers. Antimicrob Agents Chemother 1997;41(6):1399-1402.
42. Patel KD, Xuan D, Tessier PR, et al. Comparison of Bronchopulmonary Pharmacokinetics of Clarithromycin and Azithromycin. Antimicrob Agents Chemother 1996;40(10):2375-2379.
43. Leach AJ, Shelby-James TM, Mayo M, et al. A Prospective Study of the Impact of Community-Based Azithromycin Treatment of Trachoma on Carriage and Resistance of Streptococcus pneumoniae. Clin Infect Dis 1997 Mar;24(3):356-362. Comment in: Clin Infect Dis 1998;26(1):248-249.
44. Ghaffar F, Muniz LS, Katz K et al. Effects of Amoxicillin/Clavulanate or Azithromycin on Nasopharyngeal Carriage of Streptococcus pneumoniae and Haemophilus influenzae in Children with Acute Otitis Media. Clin Infect Dis 2000;31:875-880.
45. Gary GC, Witucki PJ, Gould MT et al. Randomized Placebo-Controlled Clinical Trial of Oral Azithromycin Prophylaxis Against Respiratory Infections in a High-Risk, Young Adult Population. Clin Infect Dis 2001;33:983-989.
46. Hyde TB, Gay K, Stephens DS, et al. Macrolide Resistance Among Invasive Streptococcus pneumoniae Isolates. JAMA 2001;286:1857-1862.
47. Garcia-Rey C, Aguilar L, Baquero F, et al. Importance of Local Variations in Antibiotic Consumption and Differences in Erythromycin and Penicillin Resistance in Streptococcus pneumoniae. J Clin Microbiol 2002;40:159-164.
48. Kastner U, Guggenbichler JP. Influence of Macrolide Antibiotics on Promotion of Resistance in the Oral Flora of Children. Infection 2001;29:251-256.
49. Diekema DI, Brueggemann AB, Doern GV. Antimicrobial Drug Use and Change in Resistance in Streptococcus pneumoniae. Emerg Infect Dis 2000;6:552-556.
50. Shortridge VD, Doern GV, Brueggemann AB, Beyer JM, Flamm RK. Prevalence of Macrolide Resistance Mechanism in Streptococcus pneumoniae Isolates from a Multicenter Antibiotic Resistance Surveillance Study Conducted in the United States in 1994-1995. Clin Infect Dis 1999;29:1186-1188.
51. Sutcliffe J, Tait-Karnredt A, Wondrock L. Streptococcus pneumoniae and Streptococcus pyogenes Resistant to Macrolides But Sensitive to Clindamycin: A Common Resistance Pattern Mediated by an Efflux System. Antimicrob Agents Chemother 1996;40:1817-1824.
52. Farrell JD, Morrissey I, Bakker S, Felmingham D. Determination of Macrolide Resistance Mechanisms in Streptococcus pneumoniae Isolated in the PROTEKT 2000 Study. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001, Chicago, IL. Abstract 1316.
53. Pallares R, Linares J, Vadillo M, et al. Resistance to Penicillin and Cephalosporin and Mortality from Severe Pneumococcal Pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474-480.
54. Ewig S, Ruiz M, Torres A, et al. Pneumonia Acquired in the Community Through Drug-Resistant Streptococcus pneumoniae. Am J Respir Crit Care Med 1999;159:1835-1842.
55. Raz R, Ejhanan G, Shimoni Z, et al. Pneumococcal Bacteremia in Hospitalized Israeli Adults: Epidemiology and Resistance to Penicillin. Clin Infect Dis 1997;24:1164-1168.
56. Watanabe H, Sato S, Kawakami K, et al. A Comparative Clinical Study of Pneumoniae by Penicillin-Resistant and -Sensitive Streptococcus pneumoniae in a Community Hospital. Respirology 2000;5:59-64.
57. 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.
58. Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ. Practice Guidelines for the Management of Community-Acquired Pneumonia in Adults. Guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2000;31:347-382.
59. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH, and the Canadian Community-Acquired Pneumonia Working Group. Canadian Guidelines for the Initial Management of Community-Acquired Pneumonia: An Evidence-Based Update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 2000;31:383-421.
Jointly sponsored by:
UMDNJ - Center for Continuing and Outreach Education
P.O. Box 573 . Newark . NJ . 07101-0573
973.972.4267 or 1.800.227.4852 . Fax 973.972.7128
6 Merrill Drive . Hampton . NH . 03842 . USA
603.929.5078 . Fax 603.926.3942
Susan E. Boruchoff, MD
Has no significant relationships to disclose.
Gary V. Doern, PhD: Grant/Research Support-Abbott Laboratories, GlaxoSmithKline, Pfizer, Ortho McNeil, Bayer; Consultant-Abbott Laboratories, GlaxoSmithKline, Pfizer, Ortho McNeil, Bayer; Speakers' Bureau-Abbott Laboratories, GlaxoSmithKline, Pfizer, Ortho McNeil, Bayer
David C. Howard
Has no significant relationships to disclose.
This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.
This report is supported by an educational grant from Abbott Laboratories.
David C. Howard, BS Pharmacy, Director of Research, Millennium Medical Communications, Inc., Hampton, NH
UMDNJ Medical Reviewer
Susan E. Boruchoff, MD, Associate Professor of Medicine, Division of Allergy, Immunology and Infectious Diseases, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey
The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Respiratory Infectious Disease Express Report includes discussion of treatment and indications outside of current approved labeling. This Respiratory Infectious Disease Express Report was made possible through an unrestricted educational grant from Abbott Laboratories.
© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education