Upper respiratory tract infections (URTIs), including sinusitis and otitis media, continue to be a major concern in clinical practice. Although these infections are not typically life-threatening, chronic and recurrent URTIs are common, may be refractory to treatment and account for two-thirds of antibiotic prescriptions.1 In addition chronic infections may be associated with a shift in microflora, which, together with antimicrobial misuse, can encourage the emergence of resistant organisms.2 Understanding how normal host defenses are overcome by pathogenic organisms and how treatment is affected by the emergence of resistance on a local and national basis are critical to effective URTI management.
PATHOGENESIS OF BACTERIAL INFECTIONS OF THE RESPIRATORY TRACT
Local host defense mechanisms. The respiratory mucosa is continuously exposed to harmful substances and organisms inhaled from the environment.3 In addition a variety of potentially pathogenic bacterial genera normally colonize the upper airways.4 Local defense mechanisms in the respiratory tract work together to prevent infection or damage to the respiratory tract. These include the mucociliary transport mechanism, comprised of the epithelial barrier, respiratory mucus and cilia; local production of immunoglobulins; and phagocytosis by macrophages.3
In the respiratory epithelium ciliated columnar cells and goblet cells share responsibility for mucociliary function. The columnar cells have cilia located on the luminal surface that sweep out the bacteria. Goblet cells secrete respiratory mucus, a dense gel-like fluid comprised of mucin. This mucous layer provides passive protection for the epithelium and acts as a trapping agent for particles that enter the respiratory tract. The mucus covers the cilia and is transported by the synchronized wavelike motion of the cilia toward the back of the throat where it can be expectorated or swallowed.3, 5
Plasma cells within the mucous membrane secrete immunoglobulins(predominantly IgA). IgA binds to antigens from bacteria, viruses, toxins and food. When IgA binds to Gram-negative organisms, the complement system is activated, stimulating enzymatic digestion of the mucopolysaccharides found in both Gram-negative and Gram-positive bacteria.3
Bacterial colonization and infection of the respiratory tract. The ability of bacteria to colonize and infect the respiratory tract depends on properties of the respiratory tract epithelium and characteristics of the specific bacterial species. If clearance of bacteria is delayed, this allows time for bacterial-mucosal binding. Bacterial adherence to the epithelial cell surface may lead to colonization, which, in turn, leads to further adherence and increased colonization.6, 7
Bacterial adherence to the epithelium. The density of cilia, the quantity and structure of cell surface mucins and the presence of bacterial antigen receptors all affect the ability of bacteria to adhere to the epithelium. Viral infection and cigarette smoking may also delay mucociliary clearance.3, 5 In addition several microorganisms have been shown to inhibit ciliary beating or alter the respiratory function of ciliated epithelium, including Streptococcus pneumoniae and Haemophilus influenzae.8-10
Disruption of the epithelial surface is associated with a greater potential for bacterial adherence.7 A study by Tsang et al.11 showed that Pseudomonas aeruginosa preferentially adheres to mucus and extruded and damaged epithelial cells. Similarly prolonged exposure to H. influenzae may result in structural and functional damage to the epithelial mucosal surface, an effect that may be related to lipooligosaccharide or to other soluble toxins produced by the bacteria.12 LikeP. aeruginosa, H. influenzae shows little propensity to adhere to structurally normal areas of epithelium but does adhere to damaged cells, whether ciliated or not.13 Thus the microbial factors that cause mucosal damage work in a vicious cycle to promote further colonization.14
Bacterial adherence to the epithelial surface. Bacteria are capable of forming structures on their surface, such as pili, that enhance the ability of the bacterium to adhere to the epithelial surface. H. influenzae expresses pili that are capable of adhering to human nasopharyngeal epithelial cells.6, 14-17S. pneumoniae attaches to human cells through specific bacterial surface molecules that link to carbohydrate-containing protein receptors on the surface of the host cell.14, 18 Some strains of pneumococci secrete proteolytic enzymes that break down immunoglobulins, as well as serine proteases that nonselectively break down immunoglobulins and other host proteins.19, 20
Bacteria that overcome the mucociliary defense mechanism may continue to colonize the respiratory tract.8 The presence of colonizing bacteria stimulates the host to mount an immune and inflammatory response involving the cells of the immune system.
Pathogenesis of bacterial upper respiratory tract infections. If inflammation persists despite the efforts of the host immune defenses to overcome infection, lung damage may result. Damage to the respiratory tissue predispose it to further infection, establishing a vicious cycle (Fig. 1).21 This cycle illustrates the importance of preventing bacterial colonization to avoid tissue damage. Studying the pathogenesis of airway colonization and infection has resulted in a number of therapeutic improvements, including the use of systemic and topical antibiotics in patients with diseases such as bronchiectasis and cystic fibrosis that are characterized by persistent colonization and infection. In addition the current understanding of the infectious process supports the use of antibiotics for acute exacerbations of chronic bronchitis to minimize airway damage. In the future this information may lead to novel strategies for preventing infection, such as the use of receptor or adhesin analogs to competitively inhibit bacterial binding.6
BACTERIAL PATHOGENS IN UPPER RESPIRATORY TRACT INFECTIONS
Common respiratory pathogens.S. pneumoniae, H. influenzae and Moraxella catarrhalis are responsible for a large percentage of URTIs (Fig. 2).4, 22-25 In otitis media S. pneumoniae is the most common single isolate (accounting for ∼28% of cases on average), followed closely by H. influenzae (21% of cases) and M. catarrhalis (20%). The percentage of cases caused by group A streptococci varies with season; in the winter up to 10% of acute otitis media episodes may be caused by this pathogen.22 In children older than 4 years the prevalence of Streptococcus pyogenes increases (causing up to 13% of cases).23 In a 10-year review of the microbiology of otitis media published in 1992, Bluestone et al.24 observed that the most notable changes during the period were a statistically significant increase in the prevalence of S. pneumoniae and a steadily increasing percentage of beta-lactamase-positive strains of H. influenzae and M. catarrhalis. Together these findings underscore the need for therapeutic alternatives to amoxicillin, which is not active against beta-lactamase-producing organisms.
Bacterial resistance to beta-lactam antibiotics is caused mainly by the production of beta-lactamases, enzymes that split the amide bond of the beta-lactam ring. One example is the TEM-1 beta-lactamase, prevalent in Gram-negative bacilli. Many beta-lactamases are determined by plasmids, which nearly always differ in their biochemical properties from chromosomally determined enzymes.26 Another mechanism is the alteration of target enzymes. These lactam-containing antibiotics bind covalently to penicillin-binding proteins in the cytoplasmic membrane. Alteration of these penicillin-binding proteins can lead to resistance to the beta-lactam antibiotic. Bacterial resistance to beta-lactam antibiotics also results from alteration of bacterial outer membrane. Mutations resulting in the loss of specific porins, proteins in the cell membrane that form diffusion channels through which antibiotics may pass, can result in a loss of outer membrane permeability and lead to antibiotic resistance.26
The microbiology of acute sinusitis is nearly identical with that of otitis media.4, 25, 27 The predominant organisms are S. pneumoniae, H. influenzae and M. catarrhalis; organisms isolated infrequently include group A Streptococcus, Streptococcus viridans, Eikenella corrodens, Peptostreptococcus species and Moraxella species. Viruses may cause up to 15% of cases of acute sinusitis, sometimes in combination with bacterial infection. As with otitis media the primary concerns in sinusitis center around the increasing prevalence of beta-lactamase-positive H. influenzae and M. catarrhalis and, more recently, penicillin-resistant S. pneumoniae.27, 28
Although viruses are the primary cause of acute bronchitis, occasionally Mycoplasma pneumoniae, Chlamydia species and Bordetella pertussis can be the causative agents. Secondary invasion by common respiratory pathogens, such as S. pneumoniae and H. influenzae, may play a role in acute bronchitis; however, this is uncertain.29
Chronic bronchitis typically occurs in individuals with contributing factors such as smoking or environmental exposure to dust, which result in decreased mucus production and ciliary function. Although the role of bacterial infection in chronic bronchitis is unclear, bacteria may play a role in complicating the disease and producing characteristic exacerbations known as acute bacterial exacerbations of chronic bronchitis. Patients with chronic bronchitis tend to be colonized by H. influenzae, S. pneumoniae and occasionally M. catarrhalis. Colonization of sputum and airways with pneumococci and unencapsulated strains ofH. influenzae occurs in ≥50% of patients. Many physicians often assume acute bacterial exacerbations of chronic bronchitis to be the result of one or the other of these pathogens and empiric antimicrobial therapy is based on this probability.30
In most cases pharyngitis has a viral etiology; however,S. pyogenes probably accounts for 6 to 20% of pharyngitis cases.31-33S. pyogenes is starting to develop macrolide resistance, according to several reports.34-38 Erythromycin resistance among S. pyogenes has been a problem in Finland, Spain, Italy and Japan. The susceptibility of S. pyogenes to newer macrolides seems to be similar to that of erythromycin.34-36 However, recent findings show that such resistance has declined dramatically over the last decade in Japan, although the reasons for this are unknown.37 In a study conducted in 1997 in Finland, Seppälä et al.38 associated nationwide reductions in outpatient macrolide antibiotic consumption with significant declines in erythromycin resistance among S. pyogenes organisms.
Resistance to erythromycin and other macrolides largely results from an alteration in the ribosomal target site. When the antibiotic fails to bind to its target site on the ribosome, its ability to inhibit protein synthesis and cell growth is disrupted. Enzymatic inhibition is another major mechanism of resistance to macrolides. Recently several substrate-inactivating enzymes, such as erythromycin esterase, which hydrolyzes the lactone ring of the antibiotic, have been characterized. One other mechanism of bacterial resistance to macrolides is active efflux of antibiotic across the cell membrane.26
A closer look atS. pneumoniae, H. influenzaeandM. catarrhalis. S. pneumoniae. S. pneumoniae organisms are a part of the flora of the upper respiratory tract of healthy adults and children14 and cause up to 40% of otitis media. The most common pneumococcal disease in children is acute otitis media,24, 39 whereas in adolescents and adults lobar pneumonia is the most common manifestation of pneumococcal disease. S. pneumoniae easily invades the bloodstream, as demonstrated by the observed rates of bacteremia complicating pneumonia caused by S. pneumoniae and other bacterial species.19, 40
The structure of the bacterial surface is not readily recognized by the host immune system, allowing S. pneumoniae to evade detection. However, with time the cell surface induces pulmonary inflammation by interacting with the host defenses (including both complement- and non-complement-mediated defenses). It has been theorized that the pneumococcal cell surface uses autolysis as a mechanism to facilitate exchange of genetic material (releasing DNA into the surrounding environment). This material promotes inflammation.19, 41 Finally pneumococci release pneumolysin, a toxin that alone is capable of causing all of the symptoms of pneumococcal pneumonia. Pneumolysin, a protein that binds to immunoglobulin and directly activates complement, also has direct cytotoxic effects on lung epithelial tissue.42, 43
Within the past two decades the prevalence of pneumococci resistant to penicillin and other antibiotics has steadily increased.19, 44 Whereas the organism was once susceptible to penicillin, with MICs ≤0.06 μg/ml, increasing numbers of strains now show either intermediate resistance (MICs 0.1 to 1.0 μg/ml) or high resistance (MICs ≥2.0 μg/ml).45 Before 1988 fewer than 5% of the S. pneumoniae strains in the United States demonstrated penicillin resistance.46, 47 In 1991 Mason et al.48 reported that 12.1% of S. pneumoniae isolates from Texas Children's Hospital were penicillin-resistant. Most recently Doern et al.49 found that 23.6% (361) of 1527 clinical isolates were not susceptible to penicillin (14.1% with intermediate resistance and 9.5% with high level resistance).
Because of increasing concerns about penicillin-resistant S. pneumoniae, severalin vitro studies have investigated the susceptibility of clinical isolates to other commonly used oral antibiotics.50-52 In 1993 Thornsberry et al.50 evaluated the in vitro antibiotic susceptibilities of 160 intermediate penicillin-resistant S. pneumoniae isolates obtained between 1990 and 1992. Cefprozil and cefuroxime axetil demonstrated excellent activity against these isolates (>90% of isolates susceptible); lower susceptibility rates were reported with cefaclor and loracarbef, and none of the isolates were susceptible to cefixime. In a study evaluating the activity of antibiotics against intermediate and highly penicillin-resistant S. pneumoniae strains, Pikis et al.51 reported that cefprozil was active against 90% of isolates; 40% were susceptible to cefaclor and loracarbef. In another study susceptibility testing performed on 30 isolates of S. pneumoniae recovered from various body sites (including 24 intermediate penicillin-resistant strains and 2 highly penicillin-resistant strains) showed that all isolates were susceptible to cefprozil, 67% were susceptible to cefaclor and 40% were susceptible to loracarbef.52
Strains of S. pneumoniae may be resistant to multiple classes of antibiotics. In 1996 Thornsberry conducted a second study comparing the in vitro activity of antibiotics (penicillin, vancomycin, cefprozil, cefaclor, erythromycin, azithromycin, clarithromycin and clindamycin) against 750 isolates of S. pneumoniae.45 The results showed that all penicillin-susceptible isolates were susceptible to vancomycin, cefprozil and cefaclor; >93% were susceptible to the macrolide antibiotics and clindamycin. However, susceptibility patterns in strains with reduced penicillin susceptibility were quite different (Fig. 3). In measurements of activity of selected antimicrobials against intermediate resistant isolates of S. pneumoniae, only vancomycin and cefprozil resulted in >90% susceptibility. All isolates ofS. pneumoniae proved susceptible to vancomycin, whereas 96.2% were susceptible to cefprozil. Against clindamycin 88.7% of S. pneumoniae strains were susceptible, whereas 74.4% of strains were susceptible to each of the 3 macrolides.45
In a study of S. pneumoniae antibiotic susceptibility in the United States between 1996 and 1997, Mason et al.53 tested commonly prescribed antibiotics against 4000 isolates of S. pneumoniae. Amoxicillin, amoxicillin-clavulanate, cefixime, cefpodoxime, cefprozil, cefuroxime, cefaclor, loracarbef, azithromycin, clarithromycin and erythromycin were tested. Overall 65% of isolates were penicillin-susceptible, 23% were penicillin-intermediate and 12% were penicillin-resistant. Among penicillin-susceptible isolates only cefaclor and loracarbef had MICs ≥2.0 μg/ml; all others were≤1.0 μg/ml. Among strains with intermediate resistance, only amoxicillin, amoxicillin-clavulanate and cefpodoxime had MICs <2.0 μg/ml. MICs for penicillin-resistant strains varied widely depending on the agent but were all >4.0 μg/ml.
Although the National Committee for Clinical Laboratory Standards (NCCLS) 1995 guidelines consider penicillin-susceptible S. pneumoniae isolates to be susceptible to cefaclor, cefixime, cefpodoxime and cefprozil, in this study 25% of penicillin-susceptible isolates were found to have cefaclor MICs >2.0 μg/ml and 14% to have loracarbef MICs >2.0 μg/ml. These findings suggest that some strains may be erroneously reported as susceptible, which may explain a lack of clinical response in patients treated with these antibiotics.53, 54
H. influenzae. Nontypable H. influenzae is also commonly found in the respiratory tract of healthy adults (present in up to 75% of adults).14H. influenzae is a Gram-negative organism that may occur as coccobacilli or as long filaments. Overall the incidence of infection caused by H. influenzae(type B) is declining; between 1989 and 1993 the rate decreased by ∼95%. However, during this same time period there was also an increase in the incidence of infection caused by nontypable strains (the strains most frequently associated with sinusitis, otitis media, chronic bronchitis and conjunctivitis).55
The incidence of beta-lactamase-producing strains of H. influenzae has steadily increased since the first reports in the early 1970s.56-58 Beta-lactamases are widely distributed in nature, with similar enzymes organized in families. The TEM family includes a group of beta-lactamase enzymes that differ from one another by only one, or at most, a few alterations in their primary amino acid sequence.59 TEM enzymes have long been present in Escherichia coli, where they account for the majority of ampicillin resistance.60-62
Significant resistance to H. influenzae has been observed throughout the United States.56 Thornsberry et al.56 evaluated 1240 clinical isolates and found an overall rate of ampicillin resistance of 36.1%. All isolates that produced beta-lactamase were resistant to ampicillin; however, only 6.6% of these isolates were resistant to cefprozil. In addition this study showed that the national rate of beta-lactamase production among H. influenzae was 35.7%, with rates as high as 48.6% in some areas of the country. Because oral cephalosporins are relatively resistant to the TEM-1 beta-lactamase enzyme, these agents remain a viable option for treatment of infections due to H. influenzae when oral therapy is appropriate. In a 1997 report Doern et al.63 found that overall 36.4% of 1537 clinical isolates of H. influenzae produced beta-lactamase. Again in this study the prevalence of beta-lactamase production varied geographically across the US (Fig. 4).63 The 6 cephalosporins examined in the study fell roughly into 3 categories of susceptibility. Cefprozil, loracarbef and cefaclor had MICs between 16 and 64 μg/ml, and combined percentages of intermediate and resistant strains to these agents ranged from 16.3 to 29.8. Cefuroxime had an MIC of 4 μg/ml; 1.5% of strains were resistant and 4.9% were intermediate. The most active cephalosporins were cefixime and cefpodoxime with MICs of 0.06 to 0.25 μg/ml. The percentage of strains with resistance to these agents ranged from 0.1 to 0.3%, with no beta-lactamase effect detected.63 In addition the study identified 39 strains of H. influenzae that were beta-lactamase-negative but demonstrated intermediate or high level resistance to ampicillin; an additional 17 beta-lactamase-positive strains were resistant to amoxicillin-clavulanate.63
M. catarrhalis. M. catarrhalis is the third major bacterium in respiratory tract infections. The first report of a beta-lactamase-producing strain of M. catarrhalis occurred in 1976. Today virtually all strains are beta-lactamase positive.14, 64, 65 This was confirmed by the results of a study of the prevalence of antimicrobial resistance among clinical isolates of M. catarrhalis in the US between 1994 and 1995. The overall rate of beta-lactamase production among 723 isolates was 95.3%. Based on NCCLS MIC interpretive breakpoints for H. influenzae, the percentage of strains found susceptible to cefprozil was 94.3%. Rates of susceptibility to 5 other cephalosporins were as follows: cefaclor, 99.4%; cefixime, 99.3%; cefpodoxime, 99.0%; loracarbef, 99.0%; and cefuroxime, 98.5%.66
The upper respiratory tract has numerous defense mechanisms that protect against bacterial infection. Local defense mechanisms include mucociliary transport, local production of immunoglobulins and phagocytosis. Infections of the upper respiratory tract occur when these mechanisms are compromised by viral infection or by exposure to environmental stressors such as dust or tobacco smoke. S. pneumoniae, H. influenzae and M. catarrhalis are the most common bacterial pathogens in upper and lower respiratory tract infections.S. pyogenes is the predominant bacterial pathogen in pharyngitis and tonsillitis. In recent years the widespread use of antibiotics has led to increasing resistance among each of these respiratory pathogens. An understanding of the patterns of resistance, as well as the mechanisms of resistance, among common respiratory pathogens can help in the choice of antimicrobial therapy for URTIs.
In vitro studies suggest that a number of antibiotics, including cefprozil, still retain good activity against the major disease-causing organisms.
1. Bartlett G. Management of respiratory tract infections. Baltimore: Williams & Wilkins, 1997.
2. Nord CE. The role of anaerobic bacteria in recurrent episodes of sinusitis and tonsillitis. Clin Infect Dis 1995;20:1512-24.
3. Johnson JA. Pathogenesis of bacterial infections of the respiratory tract. Br J Biomed Sci 1995;52:157-61.
4. Gwaltney JM Jr, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992;90:457-62.
5. Wanner A. Clinical aspects of mucociliary transport. Am Rev Respir Dis 1977;116:73-125.
6. Niederman MS. The pathogenesis of airway colonization: lessons learned from the study of bacterial adherence. Eur Respir J 1994;7:1737-40.
7. Niederman MS. Gram-negative colonization of the respiratory tract: pathogenesis and clinical consequences. Semin Respir Infect 1990;5:173-84.
8. Cole P, Wilson R. Host-microbial interrelationships in respiratory infection. Chest 1989;95(Suppl):217S-221S.
9. Wilson R, Pitt T, Taylor G, et al. Pyocyanin and 1-hydroxyphenazine produced by Pseudomonas aeruginosa
inhibit the beating of human respiratory cilia in vitro.
J Clin Invest 1987;79:221-9.
10. Denny FW. Effect of a toxin produced by Haemophilus influenzae
on ciliated respiratory epithelium. J Infect Dis 1974;129:93-100.
11. Tsang KWT, Rutman A, Tanaka E, et al. Interaction of Pseudomonas aeruginosa
with human respiratory mucosa in vitro.
Eur Respir J 1994;7:1746-53.
12. Johnson AP, Inzana TJ. Loss of ciliary activity in organ cultures of rat trachea treated with lipo-oligosaccharide from Haemophilus influenzae.
J Med Microbiol 1986;22:265-8.
13. Read RC, Wilson R, Rutman A, et al. Interaction of nontypable Haemophilus influenzae
with human respiratory mucosa in vitro.
J Infect Dis 1991;163:549-58.
14. Murphy TF, Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;146:1067-83.
15.Apicella MA, Shero M, Dudas KC, et al. Fimbriation of Haemophilus
species isolated from the respiratory tract of adults. J Infect Dis 1984;150:40-3.
16. Loek van Alphen L, van den Berghe N, Geelen-van den Broek L. Interaction of Haemophilus influenzae
with human erythrocytes and oropharyngeal epithelial cells is mediated by a common fimbrial epitope. Infect Immun 1988;56:1800-6.
17. Bakaletz LO, Tallan BM, Hoepf T, Demaria TF, Birck HG, Lim DJ. Frequency of fimbriation of nontypable Haemophilus influenzae
and its ability to adhere to chinchilla and human respiratory epithelium. Infect Immun 1988;56:331-5.
18. Andersson B, Beachey EH, Tomasz A, Tuomanen E, Svanborg-Edén C. A sandwich adhesin on Streptococcus pneumoniae
attaching to human oropharyngeal epithelial cells in vitro.
Microb Pathog 1988;4:267-78.
19. Watson DA, Musher DM, Verhoef J. Pneumococcal virulence factors and host immune responses to them. Eur J Clin Microbiol Infect Dis 1995;14:479-90.
20. Male CJ. Immunoglobulin A1 protease production by Haemophilus influenzae
and Streptococcus pneumoniae.
Infect Immun 1979;26:254-61.
21. Wilson R. The pathogenesis and management of bronchial infections: the vicious circle of respiratory decline. Rev Contemp Pharmacother 1992;3:103-12.
22. Pichichero ME. Therapeutic considerations for management of otitis media, sinusitis, and tonsillopharyngitis. Pediatr Asthma Allergy Immunol 1992;6:167-74.
23. Block SL. Causative pathogens, antibiotic resistance and therapeutic considerations in acute otitis media. Pediatr Infect Dis J 1997;16:449-56.
24. Bluestone CD, Stephenson JS, Martin LM. Ten-year review of otitis media pathogens. Pediatr Infect Dis J 1992;11(Suppl):S7-11.
25.Wald ER. Microbiology of acute and chronic sinusitis. Immunol Allergy Clin North Am 1994;14:31-45.
26. Mayer KH, Opal SM, Medeiros AA. Mechanisms of antibiotic resistance. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 4th ed. chap 13. New York: Churchill Livingstone, 1995.
27. Newton DA. Sinusitis in children and adolescents. Prim Care 1996;23:701-17.
28. Siegel JD. Diagnosis and management of acute sinusitis in children. Pediatr Infect Dis J 1987;6:95-9.
29. Gwaltney JM Jr. Acute bronchitis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 4th ed. chap 47. New York: Churchill Livingstone, 1995.
30. Reynolds HY. Chronic bronchitis and acute infectious exacerbations. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 4th ed. chap 48. New York: Churchill Livingstone, 1995.
31. Cherry JD. Pharyngitis(pharyngitis, tonsillitis, tonsillopharyngitis, and nasopharyngitis). In: Feigin RD, Cherry JD, eds. Pediatric infectious diseases. 3rd ed. Philadelphia: Saunders, 1992:159-66.
32. Middleton DB. Pharyngitis. Prim Care 1996;23:719-39.
33. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH. Diagnosis and management of group A streptococcal pharyngitis: a practice guideline. Clin Infect Dis 1997;25:574-83.
34.Gerber MA. Antibiotic resistance in group A streptococci. Antimicrob Resist Pediatr 1995;42:539-51.
35. Betriu C, Casado MC, Gomez M, Sanchez A, Palau ML, Picazo JJ. Incidence of erythromycin resistance in group A streptococci (GAS): a 10-year study [Abstract E-115]. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 28 to October 1, 1997.
36. Mantero E, Bottaro L, Cruciani M, et al. Erythromyc-inresistant Streptococcus pyogenes
associated with pharyngitis in Genoa, Italy [Abstract C-72]. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 28 to October 1, 1997.
37. Bass JW, Weisse ME, Plymyer MR, Murphy S, Eberly BJ. Decline of erythromycin resistance of group A beta-hemolytic streptococci in Japan: comparison with worldwide reports. Arch Pediatr Adolesc Med 1994;148:67-71.
38. Seppälä H, Klaukka T, Vuopio-Varkila J, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 1997;337:441-6.
39. Karma P, Palva T, Kouvalainen K, et al. Finnish approach to the treatment of acute otitis media: report of the Finnish Consensus Conference. Ann Otol Rhinol Laryngol Suppl 1987;96:1-19.
40. Fang GD, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases. Medicine 1990;69:307-16.
41. Tuomanen E, Liu H, Hengstler B, Zak O, Tomasz A. The introduction of meningeal inflammation by components of the pneumococcal cell wall. J Infect Dis 1985;151:859-68.
42. Rubins JB, Duane PG, Charboneau D, Janoff EN. Toxicity of pneumolysin to pulmonary endothelial cells in vitro.
Infect Immun 1992;60:1740-6.
43. Paton JC, Rowan-Kelly B, Ferrante A. Activation of human complement by the pneumococcal toxin pneumolysin. Infect Immun 1984;43:1085-7.
44. Appelbaum PC. Antimicrobial resistance in Streptococcus pneumoniae:
an overview. Clin Infect Dis 1992;15:77-83.
45.Thornsberry C. Activity of selected antimicrobials against penicillin-resistantS. pneumoniae
isolates. Infect Med 1997;14(Suppl A):13-9.
46. Jacobs MR. Increasing importance of antibiotic-resistant Streptococcus pneumoniae
in acute otitis media. Pediatr Infect Dis J 1996;15:940-3.
47. Spika JS, Facklam RR, Plikaytis BD, et al. Antimicrobial resistance of Streptococcus pneumoniae
in the United States, 1979-1987. J Infect Dis 1991;163:1273-8.
48. Mason EO Jr, Kaplan SL, Lamberth LB, Tillman J. Increased rate of isolation of penicillin-resistant Streptococcus pneumoniae
in a children's hospital and in vitro
susceptibilities to antibiotics of potential therapeutic use. Antimicrob Agents Chemother 1992;36:1703-7.
49. Doern GV, Brueggemann A, Holley HP Jr, Rauch AM. Antimicrobial resistance of Streptococcus pneumoniae
recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996;40:1208-13.
50. Thornsberry C, Brown SD, Yee YC, Bouchillon SK, Marler JK, Rich T. Increasing penicillin resistance in Streptococcus pneumoniae
in the US: effect on susceptibility to oral cephalosporins. Infect Med 1993;10(Suppl D):15-24.
51. Pikis A, Akram S, Donkersloot JA, Campos JM, Rodriguez WJ. Penicillin-resistant pneumococci from pediatric patients in the Washington, DC, area. Arch Pediatr Adolesc Med 1995;149:30-5.
52. Rodriguez WJ, Schwartz RH, Akram S, Khan WN. Streptococcus pneumoniae
resistant to penicillin: incidence and potential therapeutic options. Laryngoscope 1995;105:300-4.
53.Mason EO Jr, Lamberth LB, Kershaw NL, Prosser BT. S. pneumoniae
antibiotic susceptibility in the United States: 1996-97 [Abstract E-48]. Presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 28 to October 1, 1997.
54. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. 4th ed. M7-A4. Villanova, PA: National Committee for Clinical Laboratory Standards, 1995.
55. Urwin G, Krohn JA, Deaver-Robinson K, et al. Invasive disease due to Haemophilus influenzae
serotype f: clinical and epidemiologic characteristics in the H. influenzae
serotype b vaccine era. Clin Infect Dis 1996;22:1069-76.
56. Thornsberry C, Burton P, Vanderhoof B, Ogilvie P. Regional differences in beta-lactamase and ampicillin and cefprozil resistance in Haemophilus influenzae
in the United States. Adv Ther 1996;13:301-11.
57.Thornsberry C. Antimicrobial resistance in Haemophilus influenzae:
a global perspective. Clin Ther 1988;11(Suppl A):20-31.
58.Needham CA. Haemophilus influenzae:
antibiotic susceptibility. Clin Microbiol Rev 1988;1:218-27.
59. Fekete T. Bacterial genetics, antibiotic usage, and public policy: the crucial interplay in emerging resistance. Perspect Biol Med 1995;38:363-82.
60. Sanders CC, Sanders WE Jr. Beta-lactam resistance in Gram-negative bacteria: global trends and clinical impact. Clin Infect Dis 1992;15:824-39.
61.Young H-K, Nandivada LS, Amyes SGB. Antibiotic resistance in the tropics: 1. The genetics of bacterial ampicillin resistance in tropical areas. Trans R Soc Trop Med Hyg 1989;83:38-41.
62. Medeiros AA. Plasmid-determined beta-lactamases. In: Bryan LE, ed. Microbial resistance to drugs. Berlin: Springer-Verlag, 1989:101-27.
63. Doern GV, Brueggemann AB, Pierce G, Holley HP Jr, Rauch A. Antibiotic resistance among clinical isolates of Haemophilus influenzae
in the United States in 1994 and 1995 and detection of beta-lactamase-positive strains resistant to amoxicillin-clavulanate: results of a national multicenter surveillance study. Antimicrob Agents Chemother 1997;41:292-7.
64. Steele RW. Cefprozil: an answer to emerging antimicrobial resistance. Infect Med 1997;14(Suppl A):9-11.
65. Berman S. Otitis media in children. N Engl J Med 1995;332:1560-5.
66. Doern GV, Brueggemann AB, Pierce G, Hogan T, Holley HP Jr, Rauch A. Prevalence of antimicrobial resistance among 723 outpatient clinical isolates of Moraxella catarrhalis
in the United States in 1994 and 1995: results of a 30-center national surveillance study. Antimicrob Agents Chemother 1996;40:2884-6.
Support for the roundtable conference and publication of these proceedings was provided by Bristol-Myers Squibb.