Epidemiology and Treatment of Chronic Bronchitis and Its Exacerbations

Abstract

(CHEST 1995; 108:43S-52S) The term “chronic bronchitis” appears to have been introduced in the United Kingdom in the early 19th century to describe chronic bronchial mucosal inflammation.1Badham C. Observations on the inflammatory affections of the mucous membranes of the bronchiae. London, 1808Google Scholar The British population continues to suffer one of the highest mortality rates from chronic bronchitis in Europe, and in the 1960s, as many as 17% of adult men were thought to be affected.2Report (College of General Practitioners)Chronic bronchitis in Great Britain..BMJ. 1961; 2: 973Crossref PubMed Scopus (44) Google Scholar However, the problem is worldwide in distribution. In the mid-1980s, 6.4 million Americans per year suffered episodes of bronchitis,3Garibaldi RA Epidemiology of community acquired respiratory infections in adults..Am J Med. 1985; 78: 32-37Abstract Full Text PDF PubMed Scopus (376) Google Scholar and in excess of 600,000 Canadians have symptoms of chronic obstructive pulmonary disease.4Balter MS Hyland RH Low DE et al.Recommendations on the management of chronic bronchitis: a practical guide for Canadian physicians..Can Med Assoc J. 1994; 151: 1-23Google Scholar It has been suggested that 25% of adults in their middle years in the United States are affected.5Woolcock AJ Epidemiology of chronic airways disease..Chest. 1989; 96: 302S-306SAbstract Full Text Full Text PDF PubMed Google Scholar The precise relationship of infective exacerbations to the progress of the disease in individuals remains uncertain, but huge sums are expended each year on the antibiotic treatment of exacerbations, indicating a widespread belief in the efficacy of such treatment among the medical profession. However, recent studies of lower respiratory tract infections and acute exacerbations of chronic bronchitis (AECB)6MacFarlane JT Colville A Guion A et al.Prospective study of aetiology and outcome of adult lower respiratory tract infections in the community..Lancet. 1993; 341: 511-514Abstract PubMed Scopus (372) Google Scholar, 7Ball P Harris JM Lowson D et al.Acute infective exacerbations of chronic bronchitis: study of outcome by clinical parameters..Q J Med. 1995; 88: 61-68Google Scholar suggest that, while the majority of patients respond satisfactorily to traditional antibiotics such as the broad spectrum penicillins, others may not. Factors which distinguish this group of less responsive patients have only recently been investigated. This overview will examine the epidemiology of the disease, current chemotherapeutic modalities, and methods of assessing treatment response and will suggest avenues for more discriminatory evaluation of new agents. A classic study of 1,000 adult bronchitic patients from 1951 to 1953 in London indicated that, after onset mainly from the third decade onwards, the prevalence rose steadily in the fifth and sixth decades predominantly in smoking men from the lower social classes.8Oswald NC Harold JT Martin WJ Clinical pattern of chronic bronchitis..Lancet. 1953; 3: 639-643Abstract Scopus (43) Google Scholar This pattern of disease remained unchanged in a survey of 471 patients in the United Kingdom 40 years later,7Ball P Harris JM Lowson D et al.Acute infective exacerbations of chronic bronchitis: study of outcome by clinical parameters..Q J Med. 1995; 88: 61-68Google Scholar the medical history and clinical features of these patients confirming the classic definition of chronic bronchitis.9Medical Research CouncilDefinition and classification of chronic bronchitis for clinical and epidemiological purposes..Lancet. 1965; 1: 775-779PubMed Google Scholar United Kingdom government statistics indicate respiratory illnesses to account for 14% of cash sickness benefits and that 56% of this total was related to chronic obstructive airways disease, in comparison with 9% for asthma. Although the onset phase of this illness takes many years in most patients, once significant respiratory obstruction has developed, the prognosis is poor. The 10-year mortality of a cohort of 60-year-old nonatopic smokers rose to 60% compared with 15% in nonsmoking asthmatic subjects.10Burrows B Bloom JW Traver GA et al.The course and prognosis of different forms of chronic airways obstruction in a sample from the general population..N Engl J Med. 1987; 317: 1309-1314Crossref PubMed Scopus (378) Google Scholar Annual death rates from chronic bronchitis in various countries, taken from the World Health Organization Statistics Annual 1986 are shown in Figure 1. In the United Kingdom in the 1980s, deaths from this disease and its exacerbations among adult men ranked third after myocardial infarction and lung cancer (WHO Statistics Annual, 1983), predominating in the lower social classes. In the 1970s, male death rates ranged from 33/100,000 in social class 1 to 97,115, and 191/100,000, respectively, in classes 3, 4, and 5.11Parliamentary QuestionBronchitis and asthma deaths..BMJ. 1971; 1: 616Google Scholar Epidemiologic surveys, for example in England and Wales,12Barker DJP Osmond C Childhood respiratory infection and adult chronic bronchitis in England and Wales..BMJ. 1986; 293: 1271-1275Crossref PubMed Scopus (130) Google Scholar have suggested that recurrent respiratory tract infections in childhood, consequent upon the poor social conditions of the 1920s, may have predisposed to the development of chronic bronchitis in later life and that such factors may have had a greater influence on the geographic distribution of the disease than cigarette smoking. However, numerous studies have shown a positive correlation between mortality rates from chronic bronchitis and smoking, perhaps the most convincing describing this relationship among British doctors.13Doll R Peto R Mortality in relation to smoking: 10 years observations on British doctors..BMJ. 1976; 2: 1525-1528Crossref PubMed Scopus (1394) Google Scholar Industrial pollution is a further major precipitant, massive increases in mortality accompanying the London and Los Angeles “smogs” of the 1950s and 1960s. Reid and Fairbaim14Reid DD Fairbairn AS The natural history of chronic bronchitis..Lancet. 1958; 2: 1147-1152Abstract PubMed Scopus (30) Google Scholar had previously defined the relationship between fog and work absenteeism due to bronchitis among London postmen during the 1940s. Since the Clean Air legislation in the United Kingdom, mortality from this disease has been dropping among younger people, death rates in the 1970s falling by 40 to 60% compared with those of the 1960s among patients aged 35 to 74 years.15Report (Royal College of Physicians of London)Health and smoking. Pitman, London1983Google Scholar However, the cost to society of this illness remains high. In each of recent years, the total drug costs in the United Kingdom have exceeded £50M and the annual cost to Canadians is in excess of $33M.4Balter MS Hyland RH Low DE et al.Recommendations on the management of chronic bronchitis: a practical guide for Canadian physicians..Can Med Assoc J. 1994; 151: 1-23Google Scholar A variety of microorganisms have been shown to be associated with exacerbations of chronic bronchitis (Table 1). However, the preeminent pathogen is Haemophilus influenzae which has been recognized since the 1950s to cause more than 50% of all bacteriologically defined exacerbations.16Mulder J Goslings WRO Vaan der Plas MC et al.Studies on the treatment with antibacterial drugs of acute and chronic purulent bronchitis caused by Haemophilus influenzae..Acta Med Scand. 1952; 143: 32-49Crossref PubMed Scopus (41) Google Scholar, 17Lees AW McNaught W Bacteriology of lower respiratory tract secretions, sputum and upper respiratory tract secretions in <<normals>> and chronic bronchitics..Lancet. 1959; 2: 1112-1115Abstract PubMed Scopus (75) Google Scholar Initial attempts to confirm the invasive nature of this pathogen by detection of serologic responses after exacerbations originally provided conflicting data but later evidence indicates a positive association and demonstrates the previously negative results to have been methodologic in origin.18Murphy TF Sethi S Bacterial infection in chronic obstructive pulmonary disease..Am Rev Respir Dis. 1992; 146: 1067-1083Crossref PubMed Scopus (435) Google Scholar The frequency of isolation of H influenzae increases as respiratory obstruction worsens,19Smith CB Golden CA Kanner RE et al.Haemophilus influenzae and Haemophilus parainfluenzae in chronic obstructive pulmonary disease..Lancet. 1976; 1: 1253-1255Abstract PubMed Scopus (54) Google Scholar and its role in the initiation and perpetuation of the “vicious circle” hypothesis of bronchial damage appears beyond doubt.20Cole P Wilson R Host-microbial interelationships in respiratory infection..Chest. 1989; 95: 217S-221SAbstract Full Text Full Text PDF Scopus (85) Google Scholar, 21Wilson R Infections of the airways..Curr Opin Infect Dis. 1991; 4: 166-167Crossref Scopus (11) Google Scholar The role of Haemophilus parainfluenzae is less certain: Smith and colleagues19Smith CB Golden CA Kanner RE et al.Haemophilus influenzae and Haemophilus parainfluenzae in chronic obstructive pulmonary disease..Lancet. 1976; 1: 1253-1255Abstract PubMed Scopus (54) Google Scholar identified the organism frequently but found no correlation with symptoms or decreasing pulmonary function. Another study of 214 patients found this organism in almost 30% of sputum cultures.22Chodosh S Bronchitis and asthma.in: Gorbach SL Bartlett JG Blacklow NR Infectious diseases. WB Saunders, Philadelphia1992: 476-485Google ScholarTable 1Pathogens Associated With Exacerbations of Chronic BronchitisBacteriaH influenzae Accounting for 70% of all exacerbations and 85-95% of bacterial exacerbationsS pneumoniae VM catarrhalisStaphylococcus aureusPseudomonas aeruginosaOpportunist Gram-negativesMycoplasma pneumoniaeVirusesInfluenza/parainfluenza viruses Accounting for 30% of all acute infective exacerbationsRespiratory syncytial virusRhinovirusesCoronaviruses Open table in a new tab The proportions of major bacterial respiratory pathogens isolated from patients in recent clinical trials are indicated in Table 2. Moraxella catarrhalis and Streptococcus pneumoniae account for approximately a further third of isolates from AECB. Although persistently present in respiratory secretions of established chronic bronchitic patients, H influenzae and pneumococci are isolated significantly more frequently during infective exacerbations.23Fisher M Akhtar AJ Calder MA et al.Pilot study of factors associated with exacerbations in chronic bronchitis..BMJ. 1969; 4: 187-192Crossref PubMed Scopus (52) Google Scholar Further evidence suggests that they may persist in low numbers in sputum after apparently effective therapy of AECB and that the same phenotypic isolates are responsible for subsequent relapses.24Calder MA Schonell ME Pneumococcal typing and the problem of endogenous or exogenous reinfection in chronic bronchitis..Lancet. 1971; 1: 1156-1159Abstract PubMed Scopus (20) Google Scholar, 25Groeneveld K van Alphen L Eijk PP et al.Endogenous and exogenous re-infections by Haemophilus influenzae in patients with chronic obstructive airways disease: the effect of antibiotic treatment on persistence..J Infect Dis. 1990; 161: 512-571Crossref PubMed Scopus (90) Google ScholarTable 2Prevalence of Major Respiratory Pathogens in AECBPercentage of Total Isolates Accounted for byStudyNo. of isolatesH influenzaeM catarrhalisPneumococciDavies et al, 198678Davies BI Maesen FPV Teengs JP et al.The quinolones in chronic bronchitis..Pharm Weekbl Sci. 1986; 8: 53-59Crossref PubMed Scopus (34) Google Scholar12758,51516,5Basran et al, 199059Basran GS Joseph J Abbas AMA et al.Treatment of acute exacerbations of chronic obstructive airways disease: a comparison of amoxycillin and ciprofloxacin..J Antimicrob Chemother. 1990; 26: 19-24Crossref PubMed Scopus (36) Google Scholar6043.33.325Chodosh, 199222Chodosh S Bronchitis and asthma.in: Gorbach SL Bartlett JG Blacklow NR Infectious diseases. WB Saunders, Philadelphia1992: 476-485Google Scholar21437.922.422.4Aidons, 199155Aldons PM A comparison of clarithromycin with ampieillin in the treatment of outpatients with acute bacterial exacerbation of chronic bronchitis..J Antimicrob Chemother. 1991; 27: 101-108Crossref PubMed Google Scholar53701315Bachand, 199176Bachand RT Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis..J Antimicrob Chemother. 1991; 27: 91-100Crossref PubMed Google Scholar843010.721.4Lindsay et al, 199283Lindsay G Scorer HJN Carnegie CMD Safety and efficacy of temafloxacin versus ciprofloxacin in lower respiratory tract infections: a randomised, double-blind trial..J Antimicrob Chemother. 1992; 30: 89-100Crossref PubMed Scopus (24) Google Scholar39849.71917Ball, 199462Ball P Efficacy and safety of cefprozil versus other beta-lactam antibiotics in the treatment of lower respiratory tract infections..Eur J Clin Microbiol Infect Dis. 1994; 13: 851-856Crossref PubMed Scopus (24) Google Scholar85521316,5 Open table in a new tab Viruses and mycoplasmas are probably responsible for a third of all exacerbations.26Gump DW Phillips CA Forsyth BR et al.Role of infection in chronic bronchitis..Am Rev Respir Dis. 1976; 113: 465-473PubMed Google Scholar Chlamydiae, important precipitants of acute bronchitis, play a minor role, if any, in the causation of AECB.27Beaty CD Grayston JT Wang SP et al.Chlamydia pneumoniae, Strain TWAR, infection in patients with chronic obstructive pulmonary disease..Am Rev Respir Dis. 1991; 144: 1408-1410Crossref PubMed Scopus (142) Google Scholar The majority of patients with AECB presenting to primary care physicians receive antibiotic therapy. In the United Kingdom, this accounts for a substantial proportion of the 17.2 million antibiotic prescriptions issued per year (Intercontinental Medical Statistics, MDI Dec 1993, MAT). However, between 13 and 25% of such patients with lower respiratory tract infections treated on a domiciliary basis return within a matter of a few weeks because of persisting symptoms.6MacFarlane JT Colville A Guion A et al.Prospective study of aetiology and outcome of adult lower respiratory tract infections in the community..Lancet. 1993; 341: 511-514Abstract PubMed Scopus (372) Google Scholar, 7Ball P Harris JM Lowson D et al.Acute infective exacerbations of chronic bronchitis: study of outcome by clinical parameters..Q J Med. 1995; 88: 61-68Google Scholar, 28Davey P Rutherford D Graham B et al.Repeat consultations after antibiotic prescribing for respiratory infection: a study in one general practice..Br J Gen Pract. 1994; 44: 509-513PubMed Google Scholar It is thus necessary to question whether antibiotic therapy per se is effective in AECB, and if so, whether certain of the newer antibiotics, which have improved in vitro activity and pharmacokinetics, are likely to prove more effective than traditional agents such as the broad spectrum penicillins. It is perhaps even more important to assess the evidence for the efficacy of rapid, effective therapy of acute exacerbations in preventing the inexorable decline in respiratory function which characterises this disease. Anthonisen and colleagues29Anthonisen NR Manfreda J Warren CPW et al.Antibiotic therapy in acute exacerbations of chronic obstructive pulmonary disease..Ann Intern Med. 1987; 106: 196-204Crossref PubMed Scopus (2089) Google Scholar found that the acute reduction in FEV1 associated with AECB improved more rapidly with antibiotic therapy than with placebo. However, a comprehensive literature review18Murphy TF Sethi S Bacterial infection in chronic obstructive pulmonary disease..Am Rev Respir Dis. 1992; 146: 1067-1083Crossref PubMed Scopus (435) Google Scholar found only one study which indicated recurrent infective exacerbations to have any long-term detrimental effect on pulmonary function in chronic bronchitics. As depicted in Table 3, the efficacy or otherwise of antimicrobial chemotherapy has remained for many years a controversial issue, with various placebo-controlled studies in relatively small numbers of patients having provided conflicting evidence for and against the benefit of antibiotics.18Murphy TF Sethi S Bacterial infection in chronic obstructive pulmonary disease..Am Rev Respir Dis. 1992; 146: 1067-1083Crossref PubMed Scopus (435) Google Scholar, 30Tager I Speizer FE Role of infection in chronic bronchitis..N Engl J Med. 1975; 292: 563-571Crossref PubMed Scopus (184) Google Scholar, 31Nicotra MB Rivera M Awe RJ Antibiotic therapy of acute exacerbations of chronic bronchitis: a controlled study using tetracycline..Ann Intern Med. 1982; 97: 18-21Crossref PubMed Google Scholar In the late 1980s, Anthonisen and coworkers29Anthonisen NR Manfreda J Warren CPW et al.Antibiotic therapy in acute exacerbations of chronic obstructive pulmonary disease..Ann Intern Med. 1987; 106: 196-204Crossref PubMed Scopus (2089) Google Scholar published a further, large scale, placebo-controlled study in over 350 patients which, in defined exacerbations, indicated significant benefit from antibiotic therapy. Patients allocated antibiotic therapy received either amoxycillin (40%), co-trimoxazole (40%), or doxycycline (20%). Although the results overall indicated a significant difference in favor of antibiotic treatment, optimal benefits were observed in patients who had exacerbations characterized by increases in dyspnea, sputum production, and sputum purulence (often termed the “Winnipeg criteria”). Subsequently, an Italian group31Allegra L Grassi C Grossi E et al.Ruolo degli antibiotici nel trattamento delle riacutizza della bronchite cronica..Ital J Chest Dis. 1991; 45: 138-148Google Scholar studying a similarly sized population, showed a highly significant difference in favor of co-amoxyclav (Augmentin) compared with placebo in patients with standardized disease severity. This group based their assessment on an empiric scoring system which incorporated the Winnipeg criteria together with additional factors, including the presence and degree of pyrexia, severity of cough, and presence of coexistent cardiopulmonary disease. The results of these and earlier studies are shown in Table 3.Table 3Results of Placebo-Controlled Trials of Efficacy of Antibiotic Therapy in AECBComparatorsNo. of patientsOutcome of TherapyReferencePlacebo vs17950.3% vsAllegra et al, 199131Allegra L Grassi C Grossi E et al.Ruolo degli antibiotici nel trattamento delle riacutizza della bronchite cronica..Ital J Chest Dis. 1991; 45: 138-148Google Scholarco-amoxyclav19086.4% clinical successp<0.0lPlacebo vs18055% vsAnthonisen et al, 198729Anthonisen NR Manfreda J Warren CPW et al.Antibiotic therapy in acute exacerbations of chronic obstructive pulmonary disease..Ann Intern Med. 1987; 106: 196-204Crossref PubMed Scopus (2089) Google Scholareither TMP-SMX,*Trimethoprim-sulfamethoxazole.18268% clinical successamoxycillin or doxycyclinep<0.0lPlacebo vs20100% vsNicotra et al, 198284Nicotra MB Rivera M Awe RJ Antibiotic therapy of acute exacerbations of chronic bronchitis: a controlled study using tetracycline..Ann Intern Med. 1982; 97: 18-21Crossref PubMed Scopus (114) Google Scholartetracycline20100% clinical response†Significant trends to more rapid response in oxygenation with tetracycline.Placebo vs1520% vsPines et al, 196885Pines A Raafat H Plucinski K et al.Antibiotic requirements in severe and acute purulent exacerbations of chronic bronchitis..BMJ. 1968; 2: 735-738Crossref PubMed Scopus (68) Google Scholarpenicillin/1566% improvement‡Nine patients deteriorated (three deaths) on placebo compared with two (one death) on active therapy.streptomycinPlacebo vs10No significant differences in eitherPetersen et al, 196786Petersen ES Esmann V Honcke P et al.A continuing study of the effect of treatment on chronic bronchitis..Acta Med Scand. 1967; 182: 293-305Crossref PubMed Scopus (55) Google Scholarphysiotherapy,10groupchloramphenicol9Placebo vs28No significant difference in clinicalElmes et al, 196550Elmes PC King TC Langlands JHM et al.Value of ampicillin in the hospital treatment of exacerbations of chronic bronchitis..BMJ. 1965; 2: 904-908Crossref PubMed Scopus (70) Google Scholarampicillin28response§The frequency of relapse of H influenzae infections was reduced by ampicillin.* Trimethoprim-sulfamethoxazole.† Significant trends to more rapid response in oxygenation with tetracycline.‡ Nine patients deteriorated (three deaths) on placebo compared with two (one death) on active therapy.§ The frequency of relapse of H influenzae infections was reduced by ampicillin. Open table in a new tab The varying results of the historic and contemporary studies of chemotherapy in AECB may have a number of explanations, not least the nonhomogeneity of the patient populations studied and the improvements in chemotherapy over the 30 years in question. The increasing prevalence of bacterial resistance has also had a major influence on choices between traditional agents and novel antibiotics which are either insusceptible to or are capable of bypassing the common resistance mechanisms. However, insistence by many registration authorities that new drugs must be compared to traditional agents such as amoxycillin and that for standard evaluation, all isolates should be sensitive to both the investigational and comparator agents often results in failure to prove what should be clear advantages. As frequently shown in pneumonia trials,32Anderson G Esmonde TS Coles A et al.A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community acquired pneumonia..J Antimicrob Chemother. 1991; 27: 117-124Crossref PubMed Google Scholar intention to treat analyses may be far more indicative of the subsequent clinical role of the new agent. A further problem follows the use of such criteria as those proposed by the Winnipeg group,29Anthonisen NR Manfreda J Warren CPW et al.Antibiotic therapy in acute exacerbations of chronic obstructive pulmonary disease..Ann Intern Med. 1987; 106: 196-204Crossref PubMed Scopus (2089) Google Scholar in that although these criteria define an exacerbation, they do not define its etiology. Thus noninfective or viral exacerbations may be being compared with bacterial exacerbations, with inevitably confusing results. Sensitivity of respiratory tract pathogens to traditional antibiotics may no longer be assumed. Nationwide studies in the United States and Canada in the 1980s indicated beta-lactamase-mediated amoxycillin resistance among nonencapsulated strains of H influenzae to have risen to approximately 15 to 16%.33Jorgensen JH Doern GV Maher LA et al.Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae in the United States..Antimicrob Agents Chemother. 1990; 34: 2075-2080Crossref PubMed Scopus (310) Google Scholar, 34Tremblay LD L’ecuyer J Provencher P et al.Canadian study group: susceptibility of Haemophilus influenzae to antimicrobial agents used in Canada..Can Med Assoc J. 1990; 143: 895-901Google Scholar These figures were mirrored by rates of up to 20% in Poland in the 1990s35Hryniewicz W Bacterial resistance in Eastern Europe: selected problems..Scand J Infect Dis. 1993; 93: 33-39Google Scholar and 8.3% in the United Kingdom36Powell M Fah YS Seymour A et al.Antimicrobial resistance in Haemophilus influenzae from England and Scotland in 1991..J Antimicrob Chemother. 1992; 29: 547-554Crossref PubMed Scopus (49) Google Scholar where there was an associated increase in non-beta-lactamase-mediated beta-lactam resistance (5.8%), implying resistance to co-amoxyclav, and in resistance to sulphamethoxazole (16.9%), trimethoprim (8%), and cefaclor (5.2%). Resistance rates in Europe vary widely, but in mainland Spain, 31% of isolates were resistant to ampicillin, 16.7% to chloramphenicol, 15% to erythromycin (27.9% in France), 17.2% to tetracycline, and 41.3% to co-trimoxazole.37Kayser FH Morenzoni G Santanam P The second European collaborative study on the frequency of antimicrobial resistance in Haemophilus influenzae..Eur J Clin Microbiol Infect Dis. 1990; 9: 810-817Crossref PubMed Scopus (119) Google Scholar Methodologic differences may influence erythromycin sensitivity testing but in the United Kingdom, Powell et al38Powell M McVey D Kassim MH et al.Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella (Branhamella) catarrhalis isolated in the UK from sputa..J Antimicrob Chemother. 1991; 28: 249-259Crossref PubMed Scopus (60) Google Scholar found 86.6% to have minimum inhibitory concentrations (MICs) equal to or greater than 1 mg/L. Most isolates of M catarrhalis produce beta-lactamase, 79% of UK isolates being considered resistant38Powell M McVey D Kassim MH et al.Antimicrobial susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella (Branhamella) catarrhalis isolated in the UK from sputa..J Antimicrob Chemother. 1991; 28: 249-259Crossref PubMed Scopus (60) Google Scholar and penicillin resistance among S pneumoniae is burgeoning worldwide, reaching approximately one third of all isolates in Spain, 26% in some areas of France, and 15 to 20% in the United States.39Goldstein FW Garau J Resistant pneumococci: a renewed threat in respiratory infections..Scand J Infect Dis. 1994; 93: 55-62Google Scholar, 40Jacoby GA Prevalence and resistance mechanisms of common bacterial respiratory pathogens..Clin Infect Dis. 1994; 18: 951-957Crossref PubMed Scopus (61) Google Scholar Choice among appropriate agents for the management of AECB is now clearly constrained by local resistance rates, and broad recommendations for the use of standard beta-lactams, co-trimoxazole, tetracyclines, and erythromycin can no longer be justified. There are profound differences in the penetration of different antibiotic classes into the tissues and secretions of the respiratory tract, and the implications of these factors for the treatment of acute exacerbations of chronic bronchitis merit initial consideration. Although precise relationships have not been clearly established, both sputum and bronchial mucosal concentrations of antibiotics are considered potentially predictive of the outcome of therapy in lower respiratory infections.41Walstad RA Concentrations of antibiotics in sputum..Res Clin Forums. 1990; 12: 87-100Google Scholar, 42Baldwin DR Andrews JM Wise R et al.Bronchoalveolar distribution of cefuroxime axetil and in vitro efficacy of observed concentrations against respiratory pathogens..J Antimicrob Chemother. 1992; 30: 377-385Crossref PubMed Scopus (29) Google Scholar In general, beta-lactams attain only 5 to 25% of simultaneous serum concentrations in sputum and bronchial secretions, whereas erythromycin, chloramphenicol, and tetracyclines often achieve ratios of 50% or more, and quinolones produce concentrations in bronchial secretions which are 80 to 200% of those in serum.41Walstad RA Concentrations of antibiotics in sputum..Res Clin Forums. 1990; 12: 87-100Google Scholar, 42Baldwin DR Andrews JM Wise R et al.Bronchoalveolar distribution of cefuroxime axetil and in vitro efficacy of observed concentrations against respiratory pathogens..J Antimicrob Chemother. 1992; 30: 377-385Crossref PubMed Scopus (29) Google Scholar, 43Bergogne-Berezin E Penetration of antibiotics into the respiratory tree..J Antimicrob Chemother. 1981; 8: 171-174Crossref PubMed Scopus (54) Google Scholar Azithromycin is highly concentrated in sputum and bronchial secretions.44Baldwin DR Wise R Andrews JM et al.Azithromycin concentrations at the sites of pulmonary infection..Eur Respir J. 1990; 3: 886-890PubMed Google Scholar Levels of beta-lactams in bronchial mucosa are higher, perhaps 35 to 55% of those in serum, while concentrations of quinolones range up to 200% and those of azithromycin may be 50- to 100-fold greater.42Baldwin DR Andrews JM Wise R et al.Bronchoalveolar distribution of cefuroxime axetil and in vitro efficacy of observed concentrations against respiratory pathogens..J Antimicrob Chemother. 1992; 30: 377-385Crossref PubMed Scopus (29) Google Scholar The ratios of the concentrations obtained in respiratory tissues and fluids to those in serum are shown in Table 4.Table 4Ratios of Sputum/Bronchial Secretion to Serum Concentrations for Selected Antibiotics at Dosages ShownAgent, dose, mg*Data taken from references 43, 49, 87, 88, 89, 90, 91 (co-amoxiclav 67, 68) and various other references in the text.Concentration (mg/L) in SerumRatio of Sputum or B. Secretion/SerumRatio of Bronchial Mucosa/SerumAmoxycillin, 1,0006.90.06Amoxycillin, 5004.130.65Amoxycillin, 5005.11.41*Data taken from references 43, 49, 87, 88, 89, 90, 91 (co-amoxiclav 67, 68) and various other references in the text.Clavulanate, 1252.31.04*Data taken from references 43, 49, 87, 88, 89, 90, 91 (co-amoxiclav 67, 68) and various other references in the text.Amoxycillin, 5006.60.40†See text.Clavulanate, 2505.150.36†See text.Cefaclor, 5006.230.067Cefaclor, 5007.20.14Cefaclor, 5009.60.45Cefuroxime, 1,00012.80.14Cefuroxime, 5003.50.51Cefixime, 4006.60.36Doxycycline, 2003.80.18Doxycycline, 1002.00.17Ciprofloxacin, 5003.40.38Ciprofloxacin, 5003.11.29Ofloxacin, 4004.030.77Temafloxacin, 4006.91.77Clindamycin, 3002.60.61Erythromycin, 5004.30.051.67Clarithromycin, 5002.34.43Azithromycin, 5000.49.75(single dose)* Data taken from references 43, 49, 87, 88, 89, 90, 91 (co-amoxiclav 67, 68) and various other references in the text.† See text. Open table in a new tab The ratios of the attainable sputum, bronchial secretion, and bronchial