Background: Clarithromycin is a new acid-stable, 14-membered macrolide active against many of the organisms responsible for lower respiratory tract infections. It has been administered to over 5,000 patients worldwide and has been shown to be a safe and effective treatment for acute bacterial exacerbations of chronic bronchitis and bacterial pneumonia when given twice daily (250 to 500 mg). Cefixime is an amino-thiazolyl cephalosporin with an extended spectrum of antibacterial activity inhibiting [beta]-lactamase-producing respiratory pathogens. It has a long half-life, allowing once-daily administration.
Methods: This randomized, double-blind multicenter study compared clarithromycin and cefixime as treatment for patients with community-acquired lower respiratory tract infections (n = 213). Patients had bacterial pneumonia (clarithromycin, 19 percent; cefixime, 21 percent) or acute bacterial exacerbation of chronic bronchitis or asthmatic bronchitis (clarithromycin, 81 percent; cefixime, 79 percent). Patients received 500 mg of clarithromycin twice daily (n = 103) or 400 mg of cefixime once daily (n = 110) for 7 to 14 days.
Results: Clinical cure or improvement occurred in 86 percent of the clarithromycin-treated patients and 88 percent of the cefixime-treated patients. When only patients with identified infections with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae were considered, clinical success rates were 97 percent for clarithromycin and 96 percent for cefixime; the rate of bacteriologic eradication was 91 percent for clarithromycin and 90 percent for cefixime. Adverse events occurred in 29 percent of the clarithromycin-treated patients and 23 percent of the cefixime-treated patients.
Conclusions: This study demonstrates that clarithromycin and cefixime are effective treatments for pneumonia and acute bacterial exacerbations of bronchitis of mild to moderate severity caused by the most common infecting organisms.
(Chest 1993; 104:1393-99)
ANOVA = analysis of variance; MIC = minimum inhibitory concentration
In recent years, there has been a need to provide alternative therapy to the [beta]-lactamase-stable penicillins and cephalosporins for the treatment of lower respiratory tract infections in outpatients. The most important causes of respiratory infections are pneumococci and Haemophilus species. Organisms such as Legionella, Chlamydia, and Mycoplasma species are recognized to be important causes of pneumonitis, and [beta]-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis have become more prevalent.[1-6] Macrolides are active against intracellular pathogens such as Legionella, Chlamydia, and Mycoplasma, and inhibit [beta]-lactamase-producing respiratory pathogens while retaining excellent activity against Streptococcus pneumoniae.[7-14]
Clarithromycin is an acid-stable, 14-membered macrolide active against many of the organisms responsible for lower respiratory tract infections. Clarithromycin is metabolized to a 14-hydroxy metabolite that is twice as active as the parent compound against H influenzae; together, the two compounds exert either an additive or a synergistic effect.
Clarithromycin has been administered to over 5,000 patients worldwide in clinical trials and has been shown to be a safe and effective treatment for acute bacterial exacerbations of chronic bronchitis and bacterial pneumonia when give twice daily in doses of 250 to 500 mg.[16-22] The present multicenter study was undertaken to compare the efficacy and safety of clarithromycin with cefixime, an extended-spectrum oral cephalosporin which is [beta]-lactamase stable and inhibits the major respiratory pathogens. Cefixime, because of its long half-life (4 h), is used once daily in the treatment of acute lower respiratory tract infections in both inpatients and outpatients.
Materials and Methods
Design of Study
The study was a double-blind, randomized multicenter trial conducted by 23 investigators throughout the United States (see Acknowledgment for list of investigators).
Eligible patients were those who had community-acquired lower respiratory tract infections diagnosed at the participating centers during the winter of 1990 to 1991 and were suitable candidates for oral therapy. Qualifying diagnoses included acute bacterial exacerbation of chronic bronchitis or asthmatic bronchitis and bacterial pneumonia. Patients were excluded if they had received other antibiotics within 1 week of the study (within 6 weeks if it was a long-acting injectable antibiotic). To participate in the study, patients had to be at least 12 years of age. Women had to be nonpregnant and nonlactating. A total of 213 patients were enrolled in the study, with 103 randomized to receive clarithromycin and 110 to receive cefixime.
Patients could be withdrawn from the study at their own request or that of the investigator, Reasons for withdrawal included insufficient improvement or occurrence of an adverse event.
Patients (and parents when the participant was a minor) signed informed consent forms after the protocol had been fully explained and before participating in the study. The institutional review board of each participating center approved the protocol.
At each site, patients were randomly assigned in equal numbers to receive an oral dose of either 500 mg of clarithromycin every 12 h or 400 mg of cefixime once daily. The recommended duration of therapy was a minimum of 7 days and a maximum of 14 days in both groups.
Clarithromycin was obtained in the form of 500-mg tablets. Cefixime was supplied in the form of 200-mg tablets, each of which was placed in a capsule. Placebo capsules and tablets were used to preserve the double-blind nature of the study. Each patient received 2 capsules and 1 tablet every 12 h; patients assigned to cefixime received only placebos for their second daily dose.
Patients were instructed to refrain from using systemic antibiotics other than the studied medication. Concomitant use of other drugs, including over-the-counter medications, was recorded during the trial.
A complete medical history was obtained from each patient and a physical examination performed before the first dose of medication was administered. A chest roentgenogram was ordered if pneumonia was suspected. The investigator recorded the nature and severity of clinical signs and symptoms and the overall status of each patient at baseline. Routine laboratory tests were also performed.
During the first week of treatment, each patient reported his or her clinical status to the investigator in a telephone consultation. An interim visit was scheduled, if needed, on the basis of this information.
Within 48 h after completion of therapy, the preinvestigational assessments were repeated. The investigator judged the clinical response by comparing the signs and symptoms noted before treatment with those observed afterward. Clinical cure was defined as complete resolution of the pretreatment signs and symptoms or return of signs and symptoms to preinfection baseline. Clinical improvement was defined as improvement in pretreatment signs and symptoms without resolution or return to baseline. Clinical failure was defined as worsening or lack of improvement in pretreatment signs and symptoms; this category applied to all patients who were prematurely withdrawn by the investigator due to insufficient improvement after at least 3 days of therapy.
The follow-up visit occurred 10 to 14 days after the last dose, or earlier if the infection recurred or worsened. if the chest x-ray film obtained immediately after treatment failed to show complete resolution of pneumonia, another roentgenograrn was obtained. Clinical relapse was defined as worsening or reappearance of the signs and symptoms of infection at this visit.
Patients were instructed to contact the investigator if any adverse events occurred. The investigator assessed the severity of adverse events and abnormal laboratory findings and determined whether they were likely to be related to the drug. Adverse events that were related to concurrent conditions and that were only remotely related to the drug were not tallied in the analysis of safety.
A specimen of bronchopulmonary secretions was obtained before treatment by sputum expectoration, bronchoscopy, or transtracheal aspiration. Patients were enrolled in the study before the results of cultures became available if they had clinical and, in the case of pneumonia, radiographic evidence of infection.
In vitro susceptibility to the drugs was determined by disk zone size or minimum inhibitory concentration (MIC). Susceptibilities were determined according to the National Committee for Clinical Laboratory Standards. Organisms other than Haemophilus species were considered susceptible to clarithromycin if the diameter of the inhibition zone was 15 mm or more; they were considered susceptible to cefixime if the zone was 19 mm or more. Susceptibilities for Haemophilus isolates were defined as diameters for the inhibition zone of 23 mm or more for clarithromycin and of 21 mm or more for cefixime. Resistance to clarithromycin was defined as diameter for the inhibition zone of 11 mm or less for all species; for cefixime, it was 15 mm or less. Alternatively, susceptible was defined as MIC break points of 2 [mu]g/ml or less for clarithromycin and of 1 [mu]g/ml or less for cefixime. Organisms were considered resistant if the MIC break point was 8 [mu]g(ml or more for clarithromycin and 4 [mu]g/ml or more for cefixime. The presence of [beta]-lactamase was determined and did not affect susceptibility to clarithromycin.
The response to treatment of all pathogens was considered; however, three pathogens were of primary interest: H influenzae, S pneumoniae, and M catarrhalis. The bacteriologic response of the pathogen could be eradication, persistence, reinfection, (presence of an organism other than the pretreatment isolate 48 h after treatment), or eradication with recurrence (absence of pretreatment pathogen immediately after treatment, but reappearance of the same organism within 2 weeks). The patient's bacteriologic response was categorized as cure (all pretreatment pathogens in a given patient eradicated after treatment), mixed (some eradicated and some persistent after treatment), or failure (all pretreatment pathogens persisted at end of therapy).
The planned sample for this study was 160 patients (80 per treatment). A sample of this size would allow for detection of significant differences of 20 percent using a 2-tailed hypothesis test at a significance level of 0.05 and power of 80 percent, assuming that the better of the 2 treatment groups had a 90 percent response rate. With a 50 percent evaluability rate, a sample of this size would allow for detection of significant differences of 25 percent at a significance level of 0.05 and a power of 70 percent. For each comparison of treatment groups, the level of significance was 0.05.
Statistical differences, if any, between the demographic characteristics and baseline status of the two treatment groups were determined by Fisher's exact test (two-tailed) and one-way analysis of variance (ANOVA). Fisher's exact test (two-tailed) was used for sex, race, infection status, and overall clinical condition; ANOVA was used for age, weight, treatment duration; and number of lower respiratory tract infections in the previous 12 months.
Clinical and bacteriologic efficacies combined across all investigators were assessed by the two-tailed Fisher's exact test. The same statistical method was used to compare the percentage of evaluable patients in the two treatment groups in whom signs and symptoms had resolved or improved 48 h after treatment.
Adverse events were categorized by the COSTART system. A patient reporting more than one adverse event for a particular COSTART term was counted only once. The incidences of adverse events, excluding those related to concurrent conditions and only remotely related to the drug, were summarized by treatment group and compared for each body system and overall by Fisher's exact test combined across investigators.
Comparability of Baseline Data
No significant differences were found between treatment groups with respect to sex, race, age, and weight. The treatment groups were comparable in terms of status of infection and general health (Table 1).
The initial diagnosis was bronchitis in 81 percent of the clarithromycin-treated patients and 79 percent of the cefixime-treated patients. The other patients had pneumonia (19 percent of the clarithromycin-treated group and 21 percent of the cefixime-treated group). The infection was mild or moderate in most cases. Besides the acute infection, 61 percent of the patients had chronic bronchitis, 42 percent had bronchial asthma, 35 percent had COPD, and 22 percent had emphysema. The two treatment groups were similar with respect to these underlying pulmonary conditions.
Duration of Treatment
No statistically significant differences were found in the duration of treatment between the two groups. Approximately 40 percent of all patients were treated for 11 to 14 days.
Overall, investigators rated treatment clinically successful in 86 percent of the patients in the clarithromycin-treated group and 88 percent of the patients in the cefixime-treated group. Because 36 percent of the pretreatment bronchial specimens did not contain 1 of the 3 accepted pathogens (Table 2), we elected to calculate clinical efficacy for patients with the baseline pathogens that are the main causes of acute exacerbations of chronic bronchitis and pneumonia: H influenzae, M catarrhalis, and S pneumoniae. These pathogens were present in pretreatment specimens of 31 clarithromycin-treated and 47 cefixime-treated patients. The 2 antibiotics were equally effective in the treatment of these infections (Table 3). At the end of treatment, 97 percent of the clarithromycin-treated patients and 96 percent of the cefixime-treated patients were considered clinically cured or improved. At the 2-week follow-up evaluation, 3 patients receiving clarithromycin (2 with chronic bronchitis and 1 with pneumonia) and 1 patient receiving cefixime (who had asthmatic bronchitis) showed signs of clinical relapse.
A total of 162 patients had pathogens in their pretreatment specimens. The bacteriologic response was similar in the two treatment groups, with 7 percent failures in both groups.
All isolates of M catarrhalis and S pneumoniae and 13 of 16 H influenzae isolates were eradicated by clarithromycin. Cefixime successfully eradicated all H influenzae but failed to eliminate M catarrhalis in 1 case and S pneumoniae in 4 cases (Table 4). Two of the failures for H influenzae with clarithromycin and one of the failures for S pneumoniae with cefixime occurred in patients with pneumonia. Of the two failures for H influenzae, one patient's condition improved clinically after treatment but was found to have a relapse at follow-up; the other patient's condition improved and was considered clinically cured at follow-up. The patients with the S pneumoniae bacteriologic failure was found to be clinically cured both after treatment and at follow-up.
[TABULAR DATA OMITTED]
One patient in each treatment group had reinfection of S pneumoniae. Moraxella catarrhalis was recultured in one patient treated with clarithromycin, and H influenzae was recultured in one patient treated with cefixime. Since biotyping was not performed, it is not possible to state whether these were the same or new pathogens.
In vitro susceptibility tests revealed that most study pathogens in pretreatment specimens were susceptible to both antibiotics. Only 7 percent of H influenzae pathogens were resistant to clarithromycin, and 5 percent of H influenzae and 4 percent of S pneumoniae pathogens were resistant to cefixime by the disk susceptibility test method. No strains of M catarrhalis were resistant to either drug, and no strains of S pneumoniae showed in vitro resistance to clarithromycin.
All patients who received at least one dose of the study drug were included in the safety analyses. Overall, 30 of the 103 patients in the clarithromycin-treated group and 25 of the 110 in the cefixime-treated group reported 1 or more adverse events. Eighteen patients in each treatment group ended the study early. Adverse events accounted for ten premature withdrawals in the clarithromycin-treated group and eight in the cefixime-treated group. Two clarithromycin-treated patients and seven cefixime-treated patients withdrew prematurely because of insufficient improvement. The most frequent adverse events in both groups were related to the digestive system (Table 5). Nausea was the most common gastrointestinal complaint in the clarithromycin group (11 instances) and the second most common complaint in the cefixime group (6 cases), following diarrhea (8 reports by cefixime-treated patients; 2 by clarithromycin-treated patients). The only statistically significant difference in adverse events was the high incidence of taste perversion, which was reported by 14 clarithromycin-treated patients and two cefixime-treated patients (p=0.001). The taste perversion likely reflects the propensity of clarithromycin to diffuse into the saliva, as well as into other body fluids.
[TABULAR DATA OMITTED]
There was 1 death, a 73-year-old man with a history of COPD, emphysema, congestive heart failure, aortic stenosis, and coronary artery disease. The severe exacerbation of congestive heart failure and COPD after 3 days of clarithromycin therapy was believed to be related to the patient's underlying conditions, rather than to the drug, but clarithromycin therapy was discontinued nevertheless. The patient died of cardiac arrest 3 days later.
The effects of the study drugs on concomitant usage of theophylline and carbamazepine were assayed by analysis of serum levels before and after antibiotic administration. Among the 24 clarithromycin-treated patients and 27 cefixime-treated patients in whom theophylline levels were measured at baseline, 1 in each group showed changes. Transient elevation of the serum theophylline level was detected at the end of clarithromycin therapy in one patient, and a decrease in baseline elevation of theophylline was noted during cefixime therapy in the other case. Two patients received carbamazepine concomitantly with clarithromycin, and neither had changes in serum carbamazepine levels during therapy
Increasingly, oral cephalosporins are being used to treat outpatient respiratory infections because of their limited adverse effects of a serious nature and their activity against [beta]-lactamase-producing organisms. There has been particular interest in macrolide antibiotics in the past decade, primarily due to their activity against Legionella, Mycoplasma, and Chlamydia pneumoniae infections. These pathogens cannot be readily cultured or identified by the physicians likely to see patients with bacterial bronchitis or mild pneumonia. Pneumonia in the outpatient setting is still most often caused by S pneumoniae, and bacterial exacerbations of bronchitis are most often due to H influenzae, S pneumoniae, and M catarrhalis. The contribution of other organisms to bacterial exacerbations of bronchitis and to pneumonia has not been established. Organisms that have been implicated include Legionella species. Haemophilus parainfluenzae, and aerobic Gram-negative bacteria.[28-30] Undoubtedly, many episodes of so-called bacterial bronchitis are due to viruses such as parainfluenza viruses 1, 2, and 3 and even to respiratory syncytial virus. The important bacterial species (S pneumoniae, H influenzae, and M catarrhalis) are inhibited by both cefixime and clarithromycin,[31,32] making it appropriate to compare these agents, especially as they can be taken once and twice daily, respectively, thus enhancing compliance by patients.
Although erythromycin inhibits S pneumoniae and most Moraxella species, it is less active against H influenzae, and a majority of isolates have MICs beyond the usual achievable levels in serum and lung tissue. In general, erythromycin is not used for respiratory infections in adults unless it is prescribed in combination with other agents. Furthermore, erythromycin, due to its conversion to an inactive spirochetal derivative in acidic conditions, produces severe gastrointestinal distress in adults, which generally results in failure to complete therapy and necessitates a return visit to the physician, so that a longer period may be required to achieve cure of the respiratory infection.
Clarithromycin is a new 14-membered macrolide that inhibits most of the important respiratory pathogens. Studies of its in vitro activity have demonstrated that clarithromycin and its 14-hydroxy metabolite inhibit H influenzae, as well as S pneunioniae, Mycoplasma, and Chlamydia.[33-35] (Clarithromycin is metabolized to an active component, 14-hydroxyclarithromycin, which has been shown to potentiate the activity of the parent compound against H influenzae.) The activity of clarithromycin against Haemophilus is unaffected by the presence of [beta]-lactamase, and like erythromycin, clarithromycin achieves high intracellular concentrations. In contrast, [beta]-lactam antibiotics do not enter phagocytic cells. We have shown that clarithromycin produces adequate serum bactericidal activity against H influenzae when taken orally at a dose of 250 mg or 500 mg every 12 h and has serum bactericidal activity against streptococci for more than 12 h.[36-37]
This study has demonstrated that clarithromycin administered twice daily has efficacy similar to that of cefixime, a [beta]-lactamase stable oral cephalosporin with a long serum half-life. As in most studies involving the treatment of respiratory infections, the recovery of pathogens was not complete, although patients had clinical, laboratory, and radiologic signs and symptoms of infection. Analysis of reports of respiratory infections over 2 decades reveals that pathogens such as H influenzae, S pneumoniae, and M catarrhalis are recovered in only 20 to 30 percent of the cases.[28,30,38,39] This is undoubtedly due to poor laboratory technique in processing specimens and to problems in obtaining adequate specimens. Indeed, many authors suggest that sputum cultures in cases of bacterial exacerbation of bronchitis have no value and are not cost-effective in an era of increasing medical costs. Others have argued that sputum cultures in patients with pneumonia are of less value than a well-done Gram stain of expectorated sputum.[38,41-44] Indeed, in this study a number of isolates of H parainfluenzae were listed by our coinvestigators as pathogens in pneumonia or bacterial bronchitis. In accord with the proposed guidelines of the Food and Drug Administration and the Infectious Diseases Society of America, we did not consider H parainfluenzae, Staphylococcus aureus, Escherichia coli, or Klebsiella species as causes of mild pneumonia or exacerbations of bronchitis. Also, in patients with persistent H influenzae, since there was an appropriate clinical response, as there was for the few cefixime-treated patients in whom S pneumoniae persisted, it is probable that such patients with chronic pulmonary disease have chronic colonization with isolates similar to the Pseudomonas aeruginosa colonies observed in patients with cystic fibrosis and patients with bronchiectasis.
In patients included in the intent-to-treat analysis, as well as those with proven pathogens, clarithromycin was as effective as cefixime in achieving clinical cure and improvement: 100 percent of S pneumoniae and M catarrhalis and 81 percent of H influenzae pathogens were eradicated by clarithromycin. In clinical situations where organisms such as Mycoplasma or C pneumoniae are suspected, a macrolide such as clarithromycin would be preferred to a [beta]-lactam, since the macrolide would inhibit not only these pathogens but, as this study shows, S pneumoniae, H influenzae, and Moraxella, as well.
It is important to stress that the patients selected for this study had mild to moderate infection which did not require hospitalization.[38,45] Patients were carefully evaluated to exclude individuals who had disease severe enough to alter blood gas function and who were at risk of death. Bacteremia due to S pneumoniae was not seen in this study; it occurs in only 25 to 30 percent of S pneumoniae pneumonias. Importantly, the blood levels of both agents have been shown by our group to be adequate to inhibit S pneumoniae.[32,37]
In conclusion, this study corroborates the findings of earlier reports on the efficacy of clarithromycin and cefixime as treatment for pneumonia in outpatients and for acute bacterial exacerbations of bronchitis.
 Lafong AC, Crothers E, Bamford KB, Rooney PI. Distribution of serotypes and antibiotic resistance among pneumococci in Northern Ireland. J Infection 1988; 16:235-42  Hager H, Verghese A, Alvarez S, Berk SL. Branhamella catarrhalis respiratory infections. Rev Infect Dis 1987; 9:11.40-49  Pennington JE. Community-acquired pneumonia and acute bronchitis. In: Pennington JE, ed. Respiratory infections: diagnosis and management. New York: Raven Press, 1983; 125-34  McKellar PP. Treatment of community-acquired pneumonias. Am J Med 1985; 79(suppl 21):25-31  MacFarlane JT, Word MJ, Finch RG, MaCrae AD. Hospital study of adult community acquired pneumonia. Lancet 1982; 2:255-58  Ausina V, Coll P, Sambeat M, Puig I, Condon MJ, Luquin M, et al. Prospective study on the etiology of community-acquired pneumonia in children and adults in Spain. Eur J Clin Microbiol Infect Dis 1988; 7:342-47  Malmborg AS. The renaissance of erythromycin. J Antimicrob Chemother 1986; 18:293-96  Ridgway GL, Mumtaz G, Fenlon L. The in vitro activity of clarithromycin and other macrolides against the type strain of Chlamydia pneumoniae (TWAR). J Antimicrob Chemother 1991; 27(suppl A):43-6  Jones RN, Barry AL. The antimicrobial activity of A-56268 (TE-031) and roxithromycin (RU965) against Legionella using broth microdilution method. J Antimicrob Chemother 1987; 19:841-42  Chirgwin K, Roblin PM, Hammerschlag MR. In vitro susceptibilities of Chlamydia pneumoniae (Chlamydia sp strain TWAR). Antimicrob Agents Chemother 1989; 33:1634-35  Barry AL, Jones RN, Thornsberry C. In vitro activities of azithromycin (CP 62,993), clarithromycin (A-56268; TE-031), erythromycin, roxithromycin, and clindamycin. Antimicrob Agents Chemother 1988; 32:752-54  Fernandes PB, Bailer R, Swanson R, Hanson CW, McDonald E, Ramer N, et al. In vitro and in vivo evaluation of A-56268 (TE-031), a new macrolide. Antimicrob Agents Chemother 1986; 30:865-73  Anderson R, Joone G, van Rensburg EJ. An in vitro evaluation of the cellular uptake and intraphagocytic bioactivity of clarithromycin (A-56268, TE-031), a new macrolide antimicrobial agent. J Antimicrob Chemother 1988; 22:923-33  Benson C, Segreti J, Kessler H, Hines D, Goodman L, Kaplan R, et al. Comparative in vitro activity of A-56268 (TE-031) against gram-positive and gram-negative bacteria and Chlamydia trachomatis. Eur J Clin Microbiol 1987; 6:173-78  Jansson L, Kalin M. Comparative in vitro activity of A-56268 against respiratory tract pathogens. Eur J Clin Microbiol 1987; 6:494-96  Peters DH, Clissold SP. Clarithromycin: a review of its antimicrobial activity, pharmacokinetic properties, and therapeutic potential. Drugs 1992: 44:117-64  Bachand RT Jr. Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob Chemother 1991; 27(suppl A):91-100  Aldons P. A comparison of clarithromycin with ampicillin in the treatment of outpatients with acute bacterial exacerbation of chronic bronchitis. J Antimicrob Chemother 1991; 27(suppl A):101-08  Anderson G, Esmonde TS, Macklin J, Coles S, Carnegie C. A comparative safety and efficacy study of clarithromycin and erythromycin stearate in the treatment of community-acquired pneumonia. J Antimicrob Chemother 1991; 27(suppl A):117-24  Fraschini F. Clinical efficacy and tolerance of two new macrolides, clarithromycin and josamycin, in the treatment of patients with acute exacerbations of chronic bronchitis. J Int Med Res 1990; 18:171-76  Poirier R. Comparative study of clarithromycin and roxithromycin in the treatment of community-acquired pneumonia. J Antimicrob Chemother 1991; 27(suppl A):109-16  Straneo G, Scarpazza G. Efficacy and safety of clarithromycin versus josamycin in the treatment of hospitalized patients with bacterial pneumonia. J Int Med Res 1990; 18:164-70  National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests. 3rd ed. Villanova, Pa: National Committee for Laboratory Standards, 1991  Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley and Sons, 1981  COSTART coding symbols for thesaurus of adverse reaction terms. 3rd ed. Rockville, Md: US Department of Health and Human Services, Food and Drug Administration, 1990  Fick RB, Reynolds HY. Changing spectrum of pneumonia: news media creation or clinical reality? Am J Med 1983; 74:1-7  Hass H, Morris J, Samson S, Kilbourn JP, Kim PJ, et al. Bacterial flora of the respiratory tract in chronic bronchitis: comparison of transtracheal, fiberbronchoscopic, and oropharyngeal sampling methods. Am Rev Respir Dis 1977; 116:41-7  Fang G, Fine M, Orloff J, Arisumi D, Yu VL, Kapoor W, et al. New and emerging etiologies for community acquired pneumonia and implications for therapy: a prospective multicenter study of 359 cases. Medicine 1990; 69:307-16  Griffin DE, Mazweh GH. Pneumonia in chronic obstructive lung disease. Infect Dis Clin North Am 1991; 5:467-84  Mannion PT. Sputum microbiology in a district general hospital: the role of Branhamella catarrhalis. Br J Dis Chest 1987; 81:391-96  Neu HC. The development of macrolides: clarithromycin in perspective. J Antimicrob Chemother 1991; 27(suppl A):1-10  Brittain DC, Scully BE, Hirose T, Neu HC. The pharmacokinetic and bactericidal characteristics of oral cefixime. Clin Pharmacol Ther 1985; 38:590-94  Cassell GH, Drnec J, Waites KB, Pate MS, Duffy LB, Watson HL, et al. Efficacy of clarithromycin against Mycoplasma pneumoniae. J Antimicrob Chemother 1991; 27(suppl A):47-59  Ridgway GL, Mumtaz G, Fenelon L. The in-vitro activity of clarithromycin and other macrolides against the type strain of Chlamydia pneumoniae (TWAR). J Antimicrob Chemother 1991; 27(suppl A):43-5  Hardy DJ, Guay DRP, Jones RN. Clarithromycin, a unique macrolide: a pharmacokinetic, microbiological, and clinical overview. Diagn Microbiol Infect Dis 1992; 15:39-53  Dabernat H, Delmas C, Seguy M, Fourtillan JB, Girault J, Lareng MB. The activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae, determined by in vitro and serum bactericidal tests. J Antimicrob Chemother 1991; 27(suppl A):19-30  Gu JW, Scully BE, Neu HC. Bactericidal activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae and streptococcal pathogens. J Clin Pharmacol 1991; 31:1146-50  Murray P, Washington J. Microscopic and bacteriologic analysis of expectorated sputum. Mayo Clin Proc 1975; 50:339-42  Sullivan R, Dowdle WR, Marine WM, Hierholzer JC. Adult pneumonia in a general hospital. Arch Intern Med 1972; 129:935-42  La Force FM. Approach to the patient with pleuropulmonary infection. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious diseases. Philadelphia: WB Saunders, 1992; 460-65  Heineman HS, Chawla JK, Lofton WM. Misinformation from sputum cultures without microscopic examination. J Clin Microbiol 1977; 6:518-27  Fekety FR, Caldwell J, Gump D, Johnson JE, Maxson W, Mulholland J, et al. Bacteria, viruses, and mycoplasmas in acute bacterial pneumonias in adults. Am Rev Respir Dis 1971; 104:499-507  Lentino JR, Lucks DA. Nonvalue of sputum culture in the management of lower respiratory tract infections. J Clin Microbiol 1987; 25:758-62  Jacobson JT, Burke JP, Jacobson JA. Ordering patterns: collection, transportation, and screening of sputum cultures in a community hospital: evaluation of methods to improve results. Infection Control 1981; 2:307-10  Fine MJ, Orloff JJ, Arisumi D, Fang GD, Arena VC, Hanusa BH, et al. Prognosis of patients hospitalized with community acquired pneumonia. Am J Med 1990; 88(5N):1N-8N  Pachon J, Prados D, Capote F, Cuello JA, Garacho J, Vesano A. Severe community-acquired pneumonia. Am Rev Respir Dis 1990; 142:368-73
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