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Methacycline Compared with Ampicillin in Acute Bacterial Exacerbations of Chronic Bronchitis
Methacycline Compared with Ampicillin in Acute Bacterial Exacerbations of Chronic Bronchitis* A Double-Blind Crossover Study Sanford Chodosh, M.D., F.C.C.P.;•• Walter Baigelman, M.D.;t and Tullio C. Medici, M.D.t
In order to objectively document the accepted clinical efficacy of ampicillin in treating bacterial exacerbations of chronic bronchitis, as weD as to evaluate the efficacy of methacycline, a double-blind crossover study was designed. Twenty patients with chronic bronchial disease were treated for two separate acute bacterial exacerbations. once with l gm of ampicillin daily, and once with 600 mg of metbacycline daDy, for 14 days. There were a few significant ditlerences when comparing the efficacy of the antimicrobials. For example, the daily volume of sputum significantly went from 35.6 ml initially to 20.5
ml at the end of treatment with metbacycline, and from 37.4 to 18.0 ml with ampicUiin. Sputum neutrophlls ucreted per day went from 446 to 147 million with metbacycline and from 433 to 94 million with ampicUiin. Gram-positive diplococci and cocci on gram stains of sputum significantly decreased from 10.6 to 3.3 with methacycline and from 16.8 to 2.1 with ampicUiin. This investigation objectively documents the accepted cUnlcal efficacy of ampicUiin and proves metbacycline to be an equally effective agent.
antibiotics are of proven efficacy in the Several treatment of acute exacerbations of chronic
pulmonary disease and evidence of acute bacterial infection were entered in this study. The criteria used to make the diagnosis of chronic bronchitis, chronic bronchial asthma, and emphysema included at least the minimal standards of the American Thoracic Society.l To arrive at a diagnosis of bacterial infection, clinical manifestations, including increase of cough, increase of sputum production, purulent change of the sputum, and increase of chest congestion, were evaluated with gram-stain evidence of an increase of bacteria and with cellular evidence in the sputum of an increase in the inflammatory reaction. Individuals sufficiently ill to require hospitalization, having an infiltrate on their chest roentgenogram, or with a previous history of adverse effects from administration of penicillin, tetracycline, and their analogues were excluded from this study. Gram stained preparations showing a predominance of organisms suggestive of Staphylococcus species or large gram-negative rods also eliminated the patient from the study group. Written consent to participate in the study was obtained from each patient. After meeting the previously mentioned criteri.a the patient was randomly assigned to one of two treatment regimens. The dosage schedule for methacycline was 300 mg for the initial dose followed by 150 mg four times a day for two weeks. Ampicillin was given at a level of 1 gm for the initial dose and then 500 mg four times a day for two weeks. The randomization code was unknown to the investigators, patients, and technicians. After the initial visit, patients returned for follow-up observations at days 3 ± 1, 7 ± 1, 10 ± 1, and 14 ± 1, and after antibiotic therapy had been discontinued for 7 to 14 days. Of the 31 patients who were assigned a first treatment program, 20 had a second exacerbation and were crossed over to receive the other antibiotic. The data were analyzed
bronchitis; however, objective documentation of observed clinical impressions has been limited to pulmonary function tests, bacterial cultures, volumes of sputum, and changes in purulence of the sputum. Methacycline, a tetracycline analogue, has been reported to be of comparable efficacy to ampicillin and tetracycline. Previous comparisons with methacycline have employed only 1 gm of ampicillin per day as the control. This double-blind and crossover investigation was undertaken to compare methacycline with a larger dose of ampicillin, utilizing additional objective factors, such as gram stains of sputum and the cellular content of the sputum. MATERIALS AND METHODS
Thirty-one patients with established chronic obstructive °From the Thorndike Memorial Laboratories (Pulmonary Section), Department of Medicine, Boston City Hospital and Boston University School of Medicine, Boston. Supported by a grant-in-aid from Wallace Pharmaceuticals, Cranbury, NJ. 0 • Associate Professor of Medicine. tFellow. !Privatdozent. Dr. Medici is currently with the Department of Internal Medicine, Kantonsspital ZUrich, Zurich, Switzerland. Manuscript received November 17; revision accepted January 16. Reprint requests: Dr. Chodosh, Pulmonary Section, Boston City Hospital, Boston 02118
CHEST, 69: 5, MAY, 1976
METHACYCUNE COMPARED WITH AMPICILUN .IN CHRONIC BRONCHinS 587
Table !-Laboratory MecuuremenU Durin« Metlaaeyelineand Ampieillin Therapy*
Measurement and Antibiotic
Day from Onset of Therapy 0
2-3
6-7
9-10
13-14
21-28**
SVC, literst Methacycline Ampicillin
2.38±0.84 2.43±1 .02
2.42±0.85 2.44±0.95
2.35±0.92 2.62±0.86t
2.46±0.84t 2.48±0.87
2.61 ±0.89t 2.60±0.91t
2.58±0.87t 2.52±0.80
24-hr sputum volume, mit Methacycline Ampicillin
35.6±38.5 37.4±37.0
26.6±22.5t 27.2±17.7
28.5±32.8t 21.6±12.9t
21.0±20.0t 18.5±12.0t
20.5±25.8t 18.0±11.9t
22.6±33.4t 18.8±13.4t
Cells per milliliter X 10•t Methacycline Ampicillin
15.45±8.25 15.19±9.59
12.54 ±6.61 10.02 ±4.76t
9.57±5.19t 8.69±4.64t
8.42±4.24t 7.91 ±3.38t
8.84±5.99t 7.51 ±4.9It
9.57±9.49t 10.41 ±5.85
446±513 443±432
269±238t 231 ±278t
194 ±223t 140±105t
127±129t 103±74t
147±218t 94±110t
82±67t 197±187t
Histiocytes per day x to• Methacycline Ampicillin
9.53±14.34 16.31 ± 17.27
14.69 ± 18.20 17.78±20.10
19.00 ±26.50t 18.21 ± 16.37
16.00±22.40 16.00 ± 19.54
14.00 ± 18.88 13.84 ± 14.23
10.87 ± 13.75 8.38±7.21
Monocytes per day X 101 Methacycline Ampicillin
3.36±5.38 4.36±8.40
1.66 ±2.60 2.30±3.15
0.63±0.79t 1.01 ± l.05t
0.84±1.41t§ 1.94 ±2.26
0.88±1 .87t 0.71 ±0.80t
0.46±0.77U 1.44 ± 1.57
Bronchial epithelial cells per day X 10•t Methacycline Ampicillin
71.3±72.6 96.3±101.3
50.8±48.0 50.5 ±51.9t
41.6±78.0t 31.4±24.3t
31.9±37.6t 33.8±37.2t
33.2±46.6t 24.6±24.6t
15.6±13.It 30.6±24.9t
10.63 ± 13.43 16.75 ±28.42
1.90±2.86t 1.49±2.4It
1.17 ± 1.8It 3.04±6.76t
1.93±2.83t 3.08±4.86t
3.26±4.55 2.13±2.97t
1.81 ±2.90 4.38±7.40
Gram-positive diplococci and cocci per oil-immersion field 12.72 ± 10.82 Methacycline Ampicillin 16.54 ± 15.13
4.93±3.26H 2.75±1.69t
4.56±4.66H 2.73±1.44t
3.27±1.86t 2.78±1.3It
4.21 ±3.60t 3.32 ±2.54t
5.25±7.46t 3.31 ±2.00t
Hemoglobin, mg/100 mill Methacycline Ampicillin
14.5±1.7 14.2 ± 1.5
14.2±1.6 14.1 ± 1.5
14.6±1.7§ 13.8±1.6t
14.4 ± 1.6 13.6±1.5t
14.4 ± 1.6§ 13.6 ± I.3t
14.3 ± 1.6 13.7 ± 1.7
Hematocrit, percentll Methacycline Ampicillin
47.6±4.7§ 46.3±4.1
46.9±4.4t 45.8±4.2
48.1 ±5.0§ 45.6±4.6
47.3±4.2 45.6±3.8
47.2±4.4 45.3±3.5
46.8±4.5 45.2±4.5
Blood urea nitrogen, mg/100 mit Methacycline Ampicillin
13.5±6.1 17.3±10.3
15.7±7.8t 16.8±9.8
20.1 ± 10.5t 15.8±7.2
17.1 ±8.0t 16.8±11.2
17.0±6.9t 14.8±6.0
14.3±6.1 16.3 ±7.5
Polymorphonuclear neutrophils per day X 10•t Methacycline Ampicillin
H injluenzae-like organisms per oilimmersion field Methacycline Ampicillin
*Table values are means ± SD. **Represents observation 7 to 14 days after completion of therapy. tAnalysis compared percent changes from baseline.
588 CHODOSH, BAIGELMAN, MEDICI
tP 5 0.05 compared to day 0 for same drug. §P 5 0.05 compared to other drug for same day. IIAnalysis compared changes from baseline.
CHEST, 69: 5, MAY, 1976
only for these 20 individuals. The mean age for the group was 50 years. All ancillary therapy was maintained as constant as clinically feasible. On each visit an interval puhnonary history was obtained, a chest physicial examination was performed, a 24-hour collection of sputum was analyzed, and blood studies and puhnonary function studies were performed. The interval history included questions regarding adherence to the drug schedule, the course of the illness, and possible side effects of the drugs. Cough frequency, cough severity, dyspnea, chest examination, and prolongation of expiration were graded and coded in a method previously reported.2 Oral temperature, pulse, and respiratory rate were also measured. Sputum was collected for 24 hours prior to a visit. All individuals were regular patients of the Puhnonary Section of the Boston City Hospital and were trained to collect material that was coughed up from deep in the chest. After the 24hour volume had been measured, aliquots were chosen for gram stain, cell count, Papanicolaou's stain, and routine bacteriologic culture by a method designed to ensure their origin to be the bronchopuhnonary tree.3 Cell concentrations were determined by counting in a hemacytometer. Cell types were diHerentially counted from the Papanicolaou stained smear. From the gram stain the average numbers of each morphologic bacterial type per oil-immersion field were determined from 20 adequate fields.-' Blood studies included a white blood cell count and differential, hemoglobin level, hematocrit reading, and determinations of the levels of serum glutamic oxaloacetic transaminase, blood urea nitrogen, and allcaline phosphatase. A urinalysis was also performed on each visit. Puhnonary function tests were performed using a puhnonary function recorder (Air-Shields, Inc.). The factors measured included a slow vital capacity ( SVC), forced expiratory volumes at one ( FEV 1 ) and six seconds ( FEV6), and a mean forced expiratory Bow between 200 and 1,200 ml of the forced vital capacity ( FEF200-1200). The means and standard deviations of the values for each observation time were calculated. Comparisons between the observation before therapy and all subsequent observations with each drug were made by use of the Wilcoxon signedrank test.5 These comparisons employed analyses of data without transformation (actual values), or transformations utilizing the difference from baseline or percent change from baseline. Probability values of less than or equal to 0.05 were considered to be statistically significant. fu:sULTS
Subjective symptoms (as manifested by cough frequency, cough severity, wheeze severity, and dyspnea) showed consistent statistically significant improvement during both courses of antibiotic therapy. The mean temperature did not leave the normal range, although it decreased significantly with both forms of therapy. The mean pulse and respiratory rate decreased similarly with both agents. Data from physical examination showed significant improvement during both therapies. Pulmonary function data, including FEF200-1200, FEV1, FEVo, and SVC, had statistically significant improvements, compared to the baseline, scattered in both treatment regimens. Table 1 shows the SVC as an example. The 24-hour sputum volume and sputum puru-
CHEST, 69: 5, MAY, 1976
lence had significant improvement over their baselines for both groups. For all of these variables, no significant differences were statistically detectable between the two antimicrobials. The sputum cytologic data are shown in Table 1. The cell concentration decreased for four comparisons made to the initial day for both ampicillin and methacycline. The number of polymorphonuclear neutrophils excreted per day closely paralleled these findings. The histiocytic response showed a significant increase only for one point of the methacycline group. Monocytes decreased significantly for four of the visits of patients receiving methacycline and two of the visits of patients receiving ampiciUin. The only significant difference between the two regimens with regard to cytologic findings occurred in the decreased number of monocytes per day at two observations ;n patients receiving methacycline. Exfoliated bronchial epithelial cells decreased for four and for five visits of the methacycline group and ampiciUin group, respectively. There were no significant alterations of eosinophils in the sputum. Analysis of the data from gram's stain (Table 1) shows that both antibiotics achieved a significant decrease in the number of Hemophilus influenzaelike organisms for four of the five Visits. Gram-positive diplococci and cocci decreased significantly at aU visits for both groups; however, ampicillin was significantly better than methacycline early in the therapeutic course. At no time during or after therapy were there significant increases of Staphylococcus-like organisms or gram-negative bacilli. The hemoglobin leveL hematocritic reading, and white blood cell count remained within normal limits throughout the study (Table 1); however, for three visits of the ampicillin group, the hemoglobin level decreased significantly, and for one visit of the methacycline group, the hematocrit reading decreased significantly. There were also statisticaUy significant differences when the two agents were compared. The white blood cell count decreased significantly for five of the visits by patients receiving methacycline and for two of the visits by patients receiving ampicillin. Analysis of the differential counts showed most of these changes to be secondary to decreases in the polymorphonuclear neutrophils in the peripheral blood. Patients using methacycline had significant increases in the blood urea nitrogen level for the four visits while receiving therapy, although the mean values were within normal limits. Ampicillin-treated individuals manifested no such occurrence. When the two regimens were compared, there were no statisticaUy significant differences between them. During therapy, no significant changes were noted
METHACYCUNE COMPARED WITH AMPICILLIN IN CHRONIC BRONCHmS 589
Table 2--.4dwer•e Reaction. in Sl PatieiiU Duriq Therapy wirla .4mpieillin and MerlaaeyeUne Adverse Reaction
Ampicillin Methacycline
Upper gastrointestinal Nausea Vomiting Indigestion or heartburn Epigastric pain Anorexia Oropharyngeal soreness
0 0 0
Lower gastrointestinal Diarrhea Soft stools Constipation Borborygmi
5 4 1 2
Postural hypotension
0
DizzineBB
7 2
a•
4* 5 2 1 1** 2** 1 1 1
0
1
Hives
0
1
Total
24
22
No. of individuals at risk
27
24
No. of individuals with reactions
15
9
*Responsible for discontinuation of therapy in one case each. ••Combination responsible for discontinuation of therapy in one case.
for the alkaline phosphatase level, serum glutamic oxaloacetic transaminase level, and urinalysis. Table 2 details the adverse reactions which were noted in the total group of 31 patients entered in the study. Of the 27 patients who were treated with ampicillin, 15 noted a total of 24 adverse reactions. One patient discontinued therapy because of heartburn and borborygmi. Nine of the 24 patients who received methacycline noted a total of 22 adverse reactions. Two of these patients discontinued therapy because of adverse reactions; one had nausea, vomiting, and dizziness, and the other had a sore mouth and throat, diarrhea, epigastric pain, nausea, and vomiting. The vast majority of adverse reactions were mild, and therapy was not altered. There is no statistically significant difference between the two drugs as related to the numbers of patients with adverse reactions or the numbers of adverse reactions. DISCUSSION
Ampicillin is of accepted efficacy in the treatment of acute bacterial exacerbations of chronic bronchitis. In previous investigations, it has been compared with several other antimicrobials. Ayliffe and Pride6 evaluated ampicillin, demethylchlortetracycline, and a combination of streptomycin and penicillin and found them comparably effective. A study comparing ampicillin to erythromycin showed the former to be superior in relieving subjective
590 CHODOSH, BAIGELMAN, MEDICI
symptoms. 7 Pines et al 8 compared ampicillin and pivampicillin, and both groups improved. Aitchison et al9 compared doxycycline with ampicillin and found both equally effective. In one report the trimethoprim-sulfamethoxazole combination was significantly superior to ampicillin in reducing the purulence and volume of the sputum. 10 Another investigation of the two agents was unable to demonstrate any differences.U Chodosh et al2 found the trimethoprim-sulfamethoxazole combination to have more significant decreases of the frequency of cough, pulse rate, rales and rhonchi, 24-hour sputum volume, number of neutrophils and bronchial epithelial cells in the sputum, and numbers of H influenzae on the gram stain. The group receiving ampicillin had statistically significant decreases of cough severity and prolongation of expiration. 2 Methacycline has been evaluated in several previous investigations. Marshall-Clarke 12 compared a regimen of 150 mg of methacycline four times a day for five days with a regimen of 250 mg of tetracycline four times a day for five days in a doubleblind crossover study. On initial bacterial cultures, fewer organisms resistant to methacycline were found. Pulmonary function tests were performed, but the results were not reported. Methacycline was superior in decreasing the purulence of the sputum, but no statistical analysis was presented. By overall clinical assessment, methacycline was better than tetracycline (P < 0.001). Thomson et al 13 did a noncomparative study of methacycline using 300 mg twice a day for at least five days. The purulence and volume of the sputum were decreased, as were the subjective cough, bronchospasm, and dyspnea. No statistical analysis was presented. Malone and associates•• compared two regimens of methacycline, 150 mg and 250 mg four times a day, with 250 mg of tetracycline four times a day and 250 mg of ampicillin four times a day. Drugs were taken in a doubleblind manner for 7 to 14 days. All groups were comparable for changes in sputum purulence, pulmonary function tests, and susceptibility of isolated organisms. Pugh and Page 15 compared the same four regimens as Malone et ai•• and found the regimen of 150 mg of methacycline less effective than the other three in overall clinical assessment. Both methacycline regimens and tetracycline therapy yielded greater improvement than ampicillin therapy with respect to forced vital capacity and FEV1. The FEF200-1200, the midexpiratory How, and the maximum voluntary ventilation did not demonstrate any inter- or intra-regimen changes. There was no statistical analysis. Whelton 16 attempted a study employing the same four regimens, but the report comments mostly on the difficulties
CHEST, 69: 5, MAY, 1976
encountered in defining an exacerbation, developing the protocol, and correlating the results. Subjective symptoms, as related by the patient, are the most difficult factors to quantitate and evaluate statistically; however, patients with chronic bronchitis may have minimal changes in more objective variables, such as the physical examination and pulmonary function tests. The previous studies that have monitored subjective symptoms have usually noted improvement for all of the treated groups without statistically significant inter-group differences.7·8·11•18•18•11 Our system for quantitating subjective symptoms permitted statistical demonstration of what is generally observed, decreasing of cough frequency and severity, wheeze severity, and dyspnea. The auscultatory examination of the chest presents difficulties comparable to the subjective symptoms. Perhaps because of these difficulties in quantitating and analyzing what is qualitatively noted, none of the previous studies monitored physical examination. In this study, we were able to show statistically many areas of improvement in the findings from the physical examination, although the differences between therapy with methacycline and with ampicillin were few. Pulmonary function tests are frequently used to demonstrate the efficacy of agents purported to have an effect on processes involving the lung; however, the possible changes in the lungs of a patient with chronic bronchitis may be of too small a magnitude to be delineated because of the variations manifested in the stable state. Several studies did monitor the peak expiratory flow rate,B.lll-20 and others mention doing pulmonary function tests. 9 •12•14- 16 In this study the improvements manifested by both groups lend objective documentation to the observed clinical impression. The 24-hour sputum volume is an established criterion for monitoring changes in the bronchopulmonary system. Although a decrease of sputum volume may be associated with a problem in mobilizing secretions and, therefore, may be an ominous sign, decreases are usually considered an improvement. Many studies measured sputum volume,1· 10•16•1S.22 and almost all found comparable decreases with all antimicrobials. Our study confirms that both methacycline and ampicillin effectively decrease sputum volume. The degree of purulence of the sputum is considered to be another factor for monitoring the inflammatory reaction in chronic sputum producers. The inference from many investigations is that purulence correlates only with bacterial infection; however, inflammatory reactions of diverse etiologies can result in the same finding. Several antibiotic studies
CHEST, 69: 5, MAY, 1976
have assessed the sputum purulence, 7 •9 •10•12 •14 ·ts.24 with most showing no significant differences in the decrease of purulence between the antibiotics. The present investigation shows comparable efficacy for both antibiotics. One of the difficulties in designing a study to evaluate the role of an antibiotic in acute exacerbations of chronic bronchitis is that one must be sure that the exacerbations are secondary to bacteria and not viruses, allergens, or irritants. Most studies have relied upon bacterial cultures and sensitivities as their only microbiologic confirmation. The most frequently implicated bacteria in exacerbations of bronchitis are H influenzae and Streptococcus pneumoniae, both of which can be found as normal oral flora. In the design of this study, as in a previous similar one,2 supporting gram-stain evidence for bacterial infection was required. Bacterial cultures and sensitivities played no role in our initial diagnosis and a minimal role in the ultimate assessment of efficacy. The de-emphasis of cultures in this study is based on the documented lack of correlation between sputum cultures and the clinical course of proven bacterial pulmonary infections.25 This investigation employed an additional factor in the initial evaluation and follow-up assessment of the patients. The use of nonmalignant cytologic examination of the sputum permitted us to ascertain that an increase of the inflammatory reaction was present and that the etiology was not allergic. Indices of subsiding inflammatory reaction should be a decrease of the total cells, polymorphonuclear neutrophils, and bronchial epithelial cells excreted, associated with a relative increase of histiocytes. The cytologic data confirm the clinical impression; both antibiotics are effective in decreasing the number of polymorphonuclear neutrophils and bronchial epithelial cells in the sputum. The paucity of changes in the numbers of histiocytes may reflect the variability of cellular defense responses by individual patients. The toxicity and side effects of ampicillin therapy are well known. In studies of acute exacerbations of chronic bronchitis that have been treated with ampicillin, nausea, stomach pain, diarrhea, gastrointestinal symptoms, rash, and hallucinations have been reported. 6 •11 •18 •19 In the only study of bronchitis employing methacycline that reported side effects, nausea and pruritis were noted.13 In other than bronchitic patients, the side effects of m.ethacycline have been similar in type to those noted with other tetracyclines. In our study, gastrointestinal side effects constituted the majority of those encountered. Adverse reactions were usually of a mild nature. Although not significantly different, 56 percent ( 15) of the patients receiving ampicillin had adverse re-
METHACYCUNE COMPARED WITH AMPICILUN IN CHRONIC BRONCHITIS 591
actions, as opposed to 38 percent (nine) of the patients receiving methacycline. This diHerence may represent a small factor in choosing one drug over another, since the efficacy of both agents was very similar. We have no hypothesis to explain the changes in the hemoglobin level and the hematocrit reading during ampicillin therapy, but this observation warrants further examination. The significant increase of blood urea nitrogen during methacycline therapy probably reflects the catabolic nature of this tetracycline analogue. Within a week of termination of methacycline therapy, the level of blood urea nitrogen had returned to baseline. Methacycline and ampicillin are effective antibiotics for treating acute bacterial exacerbations of chronic bronchitis. Although methacycline is not more effective than ampicillin, it does represent an alternative for individuals with penicillin sensitivity. The incorporation of objective measurements assists in the documentation of clinical observations and may serve to delineate subtle advantages or disadvantages of seemingly comparable therapies.
1 American Thoracic Society: Chronic bronchitis, asthma and pulmonary emphysema: A statement by the Committee on Diagnostic Standards for Nontuberculous Respiratory Diseases. Am Rev Respir Dis 85:762-768, 1962 2 Chodosh S, Eichel B, Ellis C, et al: Trimethoprim-sulfamethoxazole compared with ampicillin in acute infectious exacerbations of chronic bronchitis. J Infect Dis 128: (suppl) :S710-S718, 1973 3 Chodosh S: Examination of sputum cells. N Engl ] Med 282:854~7 . 1970 4 Chodosh S, Medici TC: The bronchial epithelium in chronic bronchitis: 1. Exfoliative cytology during stable, acute bacterial infection and recovery phases. Am Rev Respir Dis 104:888-898, 1971 5 Wilcoxon F, Wilcox RA : Some Rapid Approximate Statistical Procedures. Pearl River, N.Y., American Cyanamid Co, 1964 6 Ayliffe GAJ, Pride NB : Treatment of exacerbations of chronic bronchitis with ampicillin. Br Med J 2 :1641, 1962 7 Erythromycin in lower respiratory infections. Practitioner 204:315-317, 1970 8 Pines A, Greenfield JSB, Raafat H, et al: Acomparison of pivampicillin and ampicillin in exacerbations of chronic bronchitis. Br] Dis Chest 67:221-226, 1973
592 CHODOSH, BAIGELMAN, MEDICI
9 Aitchison WRC, Grant IWB, Gould JC : Treatment of acute exacerbations of chronic bronchitis. Br J Clin Pract 22:8, 1968 10 Hughes DTD: Single-blind comparative trial of trimethoprim-sulphamethoxazole and ampicillin in the treatment of exacerbations of chronic bronchitis. Br Med J 4:470-473, 1969 11 Trimethoprim-sulphamethoxazole in chronic bronchitis. Practitioner 203:817-819, 1969 12 Marshall-Clarke GB: A clinical trial of methacycline in chronic bronchitis. Presented at the Fourth International Congress of Chemotherapy, Washington, DC, Oct 17-21, 1965 13 Thomson DA, Huckbody ]A, Griffits EV, et al : Treatment of chronic bronchitis in general practice with methacycline. Br] Clin Pract 19:509-513, 1965 14 Malone DN, Gould JC, Grant IWB : Acomparative study of ampicillin, tetracycline hydrochloride and methacycline hydrochloride in acute exacerbations of chronic bronchitis. Lancet 2:594-596, 1968 15 Pugh DL, Page N: Acute exacerbations of chronic bronchitis. Br J Geriatr Pract 89-99, 1969 16 Whelton FJ : Experiences with antibiotic trials in chronic bronchitis. Public Health 84 :95-101, 1970 17 Darke C: Comparison of dimethylchlortetracycline with tetracycline in the treatment of chronic bronchitis. Tubercle 45:384-387, 1964 18 Elmes PC, King TKC, Langlads JHM, et al: Value of ampicillin in the hospital treatment of exacerbations of chronic bronchitis. Br Med J 2 :904-908, 1965 19 Pines A, Raafat H, Pluconski K, et al : Antibiotic regimens in severe and acute purulent exacerbations of chronic bronchitis. Br Med J 2 :735-738, 1968 20 Pines A, Raafat H, Greenfield JSB, et al : The management of purulent exacerbations of chronic bronchitis: A comparison of co-trimoxazole and tetracycline. Practitioner 208:265-267, 1972 21 Pines A, Plucinski K, Greenfield JSB, et al : Controlled comparison of lymecycline with tetracycline hydrochloride in exacerbations of chronic bronchitis. Br Med J 2:1495-1498, 1964 22 Lal S, Bahalla KK : Comparison of tetracycline and trimethoprim-sulphamethoxazole in acute episodes in chronic chest infections. Postgrad Med ] 45 ( suppl) :8688, 1969 23 Francis RS, May JR, Spicer CC: Influence of penicillin and tetracycline administered daily or intermittently for exacerbations of bronchitis. Br Med J 2:979, 1961 24 Gould JC : Treatment of respiratory infections: Cephalexin compared to doxycycline. Presented at the 12th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1972 25 Barret-Connor E : The nonvalue of sputum culture in the diagnosis of pneumococcal pneumonia. Am Rev Respir Dis 103:845-848, 1971
CHEST, 69: 5, MAY, 1976
In order to objectively document the accepted clinical efficacy of ampicillin in treating bacterial exacerbations of chronic bronchitis, as weD as to evaluate the efficacy of methacycline, a double-blind crossover study was designed. Twenty patients with chronic bronchial disease were treated for two separate acute bacterial exacerbations. once with l gm of ampicillin daily, and once with 600 mg of metbacycline daDy, for 14 days. There were a few significant ditlerences when comparing the efficacy of the antimicrobials. For example, the daily volume of sputum significantly went from 35.6 ml initially to 20.5
ml at the end of treatment with metbacycline, and from 37.4 to 18.0 ml with ampicUiin. Sputum neutrophlls ucreted per day went from 446 to 147 million with metbacycline and from 433 to 94 million with ampicUiin. Gram-positive diplococci and cocci on gram stains of sputum significantly decreased from 10.6 to 3.3 with methacycline and from 16.8 to 2.1 with ampicUiin. This investigation objectively documents the accepted cUnlcal efficacy of ampicUiin and proves metbacycline to be an equally effective agent.
antibiotics are of proven efficacy in the Several treatment of acute exacerbations of chronic
pulmonary disease and evidence of acute bacterial infection were entered in this study. The criteria used to make the diagnosis of chronic bronchitis, chronic bronchial asthma, and emphysema included at least the minimal standards of the American Thoracic Society.l To arrive at a diagnosis of bacterial infection, clinical manifestations, including increase of cough, increase of sputum production, purulent change of the sputum, and increase of chest congestion, were evaluated with gram-stain evidence of an increase of bacteria and with cellular evidence in the sputum of an increase in the inflammatory reaction. Individuals sufficiently ill to require hospitalization, having an infiltrate on their chest roentgenogram, or with a previous history of adverse effects from administration of penicillin, tetracycline, and their analogues were excluded from this study. Gram stained preparations showing a predominance of organisms suggestive of Staphylococcus species or large gram-negative rods also eliminated the patient from the study group. Written consent to participate in the study was obtained from each patient. After meeting the previously mentioned criteri.a the patient was randomly assigned to one of two treatment regimens. The dosage schedule for methacycline was 300 mg for the initial dose followed by 150 mg four times a day for two weeks. Ampicillin was given at a level of 1 gm for the initial dose and then 500 mg four times a day for two weeks. The randomization code was unknown to the investigators, patients, and technicians. After the initial visit, patients returned for follow-up observations at days 3 ± 1, 7 ± 1, 10 ± 1, and 14 ± 1, and after antibiotic therapy had been discontinued for 7 to 14 days. Of the 31 patients who were assigned a first treatment program, 20 had a second exacerbation and were crossed over to receive the other antibiotic. The data were analyzed
bronchitis; however, objective documentation of observed clinical impressions has been limited to pulmonary function tests, bacterial cultures, volumes of sputum, and changes in purulence of the sputum. Methacycline, a tetracycline analogue, has been reported to be of comparable efficacy to ampicillin and tetracycline. Previous comparisons with methacycline have employed only 1 gm of ampicillin per day as the control. This double-blind and crossover investigation was undertaken to compare methacycline with a larger dose of ampicillin, utilizing additional objective factors, such as gram stains of sputum and the cellular content of the sputum. MATERIALS AND METHODS
Thirty-one patients with established chronic obstructive °From the Thorndike Memorial Laboratories (Pulmonary Section), Department of Medicine, Boston City Hospital and Boston University School of Medicine, Boston. Supported by a grant-in-aid from Wallace Pharmaceuticals, Cranbury, NJ. 0 • Associate Professor of Medicine. tFellow. !Privatdozent. Dr. Medici is currently with the Department of Internal Medicine, Kantonsspital ZUrich, Zurich, Switzerland. Manuscript received November 17; revision accepted January 16. Reprint requests: Dr. Chodosh, Pulmonary Section, Boston City Hospital, Boston 02118
CHEST, 69: 5, MAY, 1976
METHACYCUNE COMPARED WITH AMPICILUN .IN CHRONIC BRONCHinS 587
Table !-Laboratory MecuuremenU Durin« Metlaaeyelineand Ampieillin Therapy*
Measurement and Antibiotic
Day from Onset of Therapy 0
2-3
6-7
9-10
13-14
21-28**
SVC, literst Methacycline Ampicillin
2.38±0.84 2.43±1 .02
2.42±0.85 2.44±0.95
2.35±0.92 2.62±0.86t
2.46±0.84t 2.48±0.87
2.61 ±0.89t 2.60±0.91t
2.58±0.87t 2.52±0.80
24-hr sputum volume, mit Methacycline Ampicillin
35.6±38.5 37.4±37.0
26.6±22.5t 27.2±17.7
28.5±32.8t 21.6±12.9t
21.0±20.0t 18.5±12.0t
20.5±25.8t 18.0±11.9t
22.6±33.4t 18.8±13.4t
Cells per milliliter X 10•t Methacycline Ampicillin
15.45±8.25 15.19±9.59
12.54 ±6.61 10.02 ±4.76t
9.57±5.19t 8.69±4.64t
8.42±4.24t 7.91 ±3.38t
8.84±5.99t 7.51 ±4.9It
9.57±9.49t 10.41 ±5.85
446±513 443±432
269±238t 231 ±278t
194 ±223t 140±105t
127±129t 103±74t
147±218t 94±110t
82±67t 197±187t
Histiocytes per day x to• Methacycline Ampicillin
9.53±14.34 16.31 ± 17.27
14.69 ± 18.20 17.78±20.10
19.00 ±26.50t 18.21 ± 16.37
16.00±22.40 16.00 ± 19.54
14.00 ± 18.88 13.84 ± 14.23
10.87 ± 13.75 8.38±7.21
Monocytes per day X 101 Methacycline Ampicillin
3.36±5.38 4.36±8.40
1.66 ±2.60 2.30±3.15
0.63±0.79t 1.01 ± l.05t
0.84±1.41t§ 1.94 ±2.26
0.88±1 .87t 0.71 ±0.80t
0.46±0.77U 1.44 ± 1.57
Bronchial epithelial cells per day X 10•t Methacycline Ampicillin
71.3±72.6 96.3±101.3
50.8±48.0 50.5 ±51.9t
41.6±78.0t 31.4±24.3t
31.9±37.6t 33.8±37.2t
33.2±46.6t 24.6±24.6t
15.6±13.It 30.6±24.9t
10.63 ± 13.43 16.75 ±28.42
1.90±2.86t 1.49±2.4It
1.17 ± 1.8It 3.04±6.76t
1.93±2.83t 3.08±4.86t
3.26±4.55 2.13±2.97t
1.81 ±2.90 4.38±7.40
Gram-positive diplococci and cocci per oil-immersion field 12.72 ± 10.82 Methacycline Ampicillin 16.54 ± 15.13
4.93±3.26H 2.75±1.69t
4.56±4.66H 2.73±1.44t
3.27±1.86t 2.78±1.3It
4.21 ±3.60t 3.32 ±2.54t
5.25±7.46t 3.31 ±2.00t
Hemoglobin, mg/100 mill Methacycline Ampicillin
14.5±1.7 14.2 ± 1.5
14.2±1.6 14.1 ± 1.5
14.6±1.7§ 13.8±1.6t
14.4 ± 1.6 13.6±1.5t
14.4 ± 1.6§ 13.6 ± I.3t
14.3 ± 1.6 13.7 ± 1.7
Hematocrit, percentll Methacycline Ampicillin
47.6±4.7§ 46.3±4.1
46.9±4.4t 45.8±4.2
48.1 ±5.0§ 45.6±4.6
47.3±4.2 45.6±3.8
47.2±4.4 45.3±3.5
46.8±4.5 45.2±4.5
Blood urea nitrogen, mg/100 mit Methacycline Ampicillin
13.5±6.1 17.3±10.3
15.7±7.8t 16.8±9.8
20.1 ± 10.5t 15.8±7.2
17.1 ±8.0t 16.8±11.2
17.0±6.9t 14.8±6.0
14.3±6.1 16.3 ±7.5
Polymorphonuclear neutrophils per day X 10•t Methacycline Ampicillin
H injluenzae-like organisms per oilimmersion field Methacycline Ampicillin
*Table values are means ± SD. **Represents observation 7 to 14 days after completion of therapy. tAnalysis compared percent changes from baseline.
588 CHODOSH, BAIGELMAN, MEDICI
tP 5 0.05 compared to day 0 for same drug. §P 5 0.05 compared to other drug for same day. IIAnalysis compared changes from baseline.
CHEST, 69: 5, MAY, 1976
only for these 20 individuals. The mean age for the group was 50 years. All ancillary therapy was maintained as constant as clinically feasible. On each visit an interval puhnonary history was obtained, a chest physicial examination was performed, a 24-hour collection of sputum was analyzed, and blood studies and puhnonary function studies were performed. The interval history included questions regarding adherence to the drug schedule, the course of the illness, and possible side effects of the drugs. Cough frequency, cough severity, dyspnea, chest examination, and prolongation of expiration were graded and coded in a method previously reported.2 Oral temperature, pulse, and respiratory rate were also measured. Sputum was collected for 24 hours prior to a visit. All individuals were regular patients of the Puhnonary Section of the Boston City Hospital and were trained to collect material that was coughed up from deep in the chest. After the 24hour volume had been measured, aliquots were chosen for gram stain, cell count, Papanicolaou's stain, and routine bacteriologic culture by a method designed to ensure their origin to be the bronchopuhnonary tree.3 Cell concentrations were determined by counting in a hemacytometer. Cell types were diHerentially counted from the Papanicolaou stained smear. From the gram stain the average numbers of each morphologic bacterial type per oil-immersion field were determined from 20 adequate fields.-' Blood studies included a white blood cell count and differential, hemoglobin level, hematocrit reading, and determinations of the levels of serum glutamic oxaloacetic transaminase, blood urea nitrogen, and allcaline phosphatase. A urinalysis was also performed on each visit. Puhnonary function tests were performed using a puhnonary function recorder (Air-Shields, Inc.). The factors measured included a slow vital capacity ( SVC), forced expiratory volumes at one ( FEV 1 ) and six seconds ( FEV6), and a mean forced expiratory Bow between 200 and 1,200 ml of the forced vital capacity ( FEF200-1200). The means and standard deviations of the values for each observation time were calculated. Comparisons between the observation before therapy and all subsequent observations with each drug were made by use of the Wilcoxon signedrank test.5 These comparisons employed analyses of data without transformation (actual values), or transformations utilizing the difference from baseline or percent change from baseline. Probability values of less than or equal to 0.05 were considered to be statistically significant. fu:sULTS
Subjective symptoms (as manifested by cough frequency, cough severity, wheeze severity, and dyspnea) showed consistent statistically significant improvement during both courses of antibiotic therapy. The mean temperature did not leave the normal range, although it decreased significantly with both forms of therapy. The mean pulse and respiratory rate decreased similarly with both agents. Data from physical examination showed significant improvement during both therapies. Pulmonary function data, including FEF200-1200, FEV1, FEVo, and SVC, had statistically significant improvements, compared to the baseline, scattered in both treatment regimens. Table 1 shows the SVC as an example. The 24-hour sputum volume and sputum puru-
CHEST, 69: 5, MAY, 1976
lence had significant improvement over their baselines for both groups. For all of these variables, no significant differences were statistically detectable between the two antimicrobials. The sputum cytologic data are shown in Table 1. The cell concentration decreased for four comparisons made to the initial day for both ampicillin and methacycline. The number of polymorphonuclear neutrophils excreted per day closely paralleled these findings. The histiocytic response showed a significant increase only for one point of the methacycline group. Monocytes decreased significantly for four of the visits of patients receiving methacycline and two of the visits of patients receiving ampiciUin. The only significant difference between the two regimens with regard to cytologic findings occurred in the decreased number of monocytes per day at two observations ;n patients receiving methacycline. Exfoliated bronchial epithelial cells decreased for four and for five visits of the methacycline group and ampiciUin group, respectively. There were no significant alterations of eosinophils in the sputum. Analysis of the data from gram's stain (Table 1) shows that both antibiotics achieved a significant decrease in the number of Hemophilus influenzaelike organisms for four of the five Visits. Gram-positive diplococci and cocci decreased significantly at aU visits for both groups; however, ampicillin was significantly better than methacycline early in the therapeutic course. At no time during or after therapy were there significant increases of Staphylococcus-like organisms or gram-negative bacilli. The hemoglobin leveL hematocritic reading, and white blood cell count remained within normal limits throughout the study (Table 1); however, for three visits of the ampicillin group, the hemoglobin level decreased significantly, and for one visit of the methacycline group, the hematocrit reading decreased significantly. There were also statisticaUy significant differences when the two agents were compared. The white blood cell count decreased significantly for five of the visits by patients receiving methacycline and for two of the visits by patients receiving ampicillin. Analysis of the differential counts showed most of these changes to be secondary to decreases in the polymorphonuclear neutrophils in the peripheral blood. Patients using methacycline had significant increases in the blood urea nitrogen level for the four visits while receiving therapy, although the mean values were within normal limits. Ampicillin-treated individuals manifested no such occurrence. When the two regimens were compared, there were no statisticaUy significant differences between them. During therapy, no significant changes were noted
METHACYCUNE COMPARED WITH AMPICILLIN IN CHRONIC BRONCHmS 589
Table 2--.4dwer•e Reaction. in Sl PatieiiU Duriq Therapy wirla .4mpieillin and MerlaaeyeUne Adverse Reaction
Ampicillin Methacycline
Upper gastrointestinal Nausea Vomiting Indigestion or heartburn Epigastric pain Anorexia Oropharyngeal soreness
0 0 0
Lower gastrointestinal Diarrhea Soft stools Constipation Borborygmi
5 4 1 2
Postural hypotension
0
DizzineBB
7 2
a•
4* 5 2 1 1** 2** 1 1 1
0
1
Hives
0
1
Total
24
22
No. of individuals at risk
27
24
No. of individuals with reactions
15
9
*Responsible for discontinuation of therapy in one case each. ••Combination responsible for discontinuation of therapy in one case.
for the alkaline phosphatase level, serum glutamic oxaloacetic transaminase level, and urinalysis. Table 2 details the adverse reactions which were noted in the total group of 31 patients entered in the study. Of the 27 patients who were treated with ampicillin, 15 noted a total of 24 adverse reactions. One patient discontinued therapy because of heartburn and borborygmi. Nine of the 24 patients who received methacycline noted a total of 22 adverse reactions. Two of these patients discontinued therapy because of adverse reactions; one had nausea, vomiting, and dizziness, and the other had a sore mouth and throat, diarrhea, epigastric pain, nausea, and vomiting. The vast majority of adverse reactions were mild, and therapy was not altered. There is no statistically significant difference between the two drugs as related to the numbers of patients with adverse reactions or the numbers of adverse reactions. DISCUSSION
Ampicillin is of accepted efficacy in the treatment of acute bacterial exacerbations of chronic bronchitis. In previous investigations, it has been compared with several other antimicrobials. Ayliffe and Pride6 evaluated ampicillin, demethylchlortetracycline, and a combination of streptomycin and penicillin and found them comparably effective. A study comparing ampicillin to erythromycin showed the former to be superior in relieving subjective
590 CHODOSH, BAIGELMAN, MEDICI
symptoms. 7 Pines et al 8 compared ampicillin and pivampicillin, and both groups improved. Aitchison et al9 compared doxycycline with ampicillin and found both equally effective. In one report the trimethoprim-sulfamethoxazole combination was significantly superior to ampicillin in reducing the purulence and volume of the sputum. 10 Another investigation of the two agents was unable to demonstrate any differences.U Chodosh et al2 found the trimethoprim-sulfamethoxazole combination to have more significant decreases of the frequency of cough, pulse rate, rales and rhonchi, 24-hour sputum volume, number of neutrophils and bronchial epithelial cells in the sputum, and numbers of H influenzae on the gram stain. The group receiving ampicillin had statistically significant decreases of cough severity and prolongation of expiration. 2 Methacycline has been evaluated in several previous investigations. Marshall-Clarke 12 compared a regimen of 150 mg of methacycline four times a day for five days with a regimen of 250 mg of tetracycline four times a day for five days in a doubleblind crossover study. On initial bacterial cultures, fewer organisms resistant to methacycline were found. Pulmonary function tests were performed, but the results were not reported. Methacycline was superior in decreasing the purulence of the sputum, but no statistical analysis was presented. By overall clinical assessment, methacycline was better than tetracycline (P < 0.001). Thomson et al 13 did a noncomparative study of methacycline using 300 mg twice a day for at least five days. The purulence and volume of the sputum were decreased, as were the subjective cough, bronchospasm, and dyspnea. No statistical analysis was presented. Malone and associates•• compared two regimens of methacycline, 150 mg and 250 mg four times a day, with 250 mg of tetracycline four times a day and 250 mg of ampicillin four times a day. Drugs were taken in a doubleblind manner for 7 to 14 days. All groups were comparable for changes in sputum purulence, pulmonary function tests, and susceptibility of isolated organisms. Pugh and Page 15 compared the same four regimens as Malone et ai•• and found the regimen of 150 mg of methacycline less effective than the other three in overall clinical assessment. Both methacycline regimens and tetracycline therapy yielded greater improvement than ampicillin therapy with respect to forced vital capacity and FEV1. The FEF200-1200, the midexpiratory How, and the maximum voluntary ventilation did not demonstrate any inter- or intra-regimen changes. There was no statistical analysis. Whelton 16 attempted a study employing the same four regimens, but the report comments mostly on the difficulties
CHEST, 69: 5, MAY, 1976
encountered in defining an exacerbation, developing the protocol, and correlating the results. Subjective symptoms, as related by the patient, are the most difficult factors to quantitate and evaluate statistically; however, patients with chronic bronchitis may have minimal changes in more objective variables, such as the physical examination and pulmonary function tests. The previous studies that have monitored subjective symptoms have usually noted improvement for all of the treated groups without statistically significant inter-group differences.7·8·11•18•18•11 Our system for quantitating subjective symptoms permitted statistical demonstration of what is generally observed, decreasing of cough frequency and severity, wheeze severity, and dyspnea. The auscultatory examination of the chest presents difficulties comparable to the subjective symptoms. Perhaps because of these difficulties in quantitating and analyzing what is qualitatively noted, none of the previous studies monitored physical examination. In this study, we were able to show statistically many areas of improvement in the findings from the physical examination, although the differences between therapy with methacycline and with ampicillin were few. Pulmonary function tests are frequently used to demonstrate the efficacy of agents purported to have an effect on processes involving the lung; however, the possible changes in the lungs of a patient with chronic bronchitis may be of too small a magnitude to be delineated because of the variations manifested in the stable state. Several studies did monitor the peak expiratory flow rate,B.lll-20 and others mention doing pulmonary function tests. 9 •12•14- 16 In this study the improvements manifested by both groups lend objective documentation to the observed clinical impression. The 24-hour sputum volume is an established criterion for monitoring changes in the bronchopulmonary system. Although a decrease of sputum volume may be associated with a problem in mobilizing secretions and, therefore, may be an ominous sign, decreases are usually considered an improvement. Many studies measured sputum volume,1· 10•16•1S.22 and almost all found comparable decreases with all antimicrobials. Our study confirms that both methacycline and ampicillin effectively decrease sputum volume. The degree of purulence of the sputum is considered to be another factor for monitoring the inflammatory reaction in chronic sputum producers. The inference from many investigations is that purulence correlates only with bacterial infection; however, inflammatory reactions of diverse etiologies can result in the same finding. Several antibiotic studies
CHEST, 69: 5, MAY, 1976
have assessed the sputum purulence, 7 •9 •10•12 •14 ·ts.24 with most showing no significant differences in the decrease of purulence between the antibiotics. The present investigation shows comparable efficacy for both antibiotics. One of the difficulties in designing a study to evaluate the role of an antibiotic in acute exacerbations of chronic bronchitis is that one must be sure that the exacerbations are secondary to bacteria and not viruses, allergens, or irritants. Most studies have relied upon bacterial cultures and sensitivities as their only microbiologic confirmation. The most frequently implicated bacteria in exacerbations of bronchitis are H influenzae and Streptococcus pneumoniae, both of which can be found as normal oral flora. In the design of this study, as in a previous similar one,2 supporting gram-stain evidence for bacterial infection was required. Bacterial cultures and sensitivities played no role in our initial diagnosis and a minimal role in the ultimate assessment of efficacy. The de-emphasis of cultures in this study is based on the documented lack of correlation between sputum cultures and the clinical course of proven bacterial pulmonary infections.25 This investigation employed an additional factor in the initial evaluation and follow-up assessment of the patients. The use of nonmalignant cytologic examination of the sputum permitted us to ascertain that an increase of the inflammatory reaction was present and that the etiology was not allergic. Indices of subsiding inflammatory reaction should be a decrease of the total cells, polymorphonuclear neutrophils, and bronchial epithelial cells excreted, associated with a relative increase of histiocytes. The cytologic data confirm the clinical impression; both antibiotics are effective in decreasing the number of polymorphonuclear neutrophils and bronchial epithelial cells in the sputum. The paucity of changes in the numbers of histiocytes may reflect the variability of cellular defense responses by individual patients. The toxicity and side effects of ampicillin therapy are well known. In studies of acute exacerbations of chronic bronchitis that have been treated with ampicillin, nausea, stomach pain, diarrhea, gastrointestinal symptoms, rash, and hallucinations have been reported. 6 •11 •18 •19 In the only study of bronchitis employing methacycline that reported side effects, nausea and pruritis were noted.13 In other than bronchitic patients, the side effects of m.ethacycline have been similar in type to those noted with other tetracyclines. In our study, gastrointestinal side effects constituted the majority of those encountered. Adverse reactions were usually of a mild nature. Although not significantly different, 56 percent ( 15) of the patients receiving ampicillin had adverse re-
METHACYCUNE COMPARED WITH AMPICILUN IN CHRONIC BRONCHITIS 591
actions, as opposed to 38 percent (nine) of the patients receiving methacycline. This diHerence may represent a small factor in choosing one drug over another, since the efficacy of both agents was very similar. We have no hypothesis to explain the changes in the hemoglobin level and the hematocrit reading during ampicillin therapy, but this observation warrants further examination. The significant increase of blood urea nitrogen during methacycline therapy probably reflects the catabolic nature of this tetracycline analogue. Within a week of termination of methacycline therapy, the level of blood urea nitrogen had returned to baseline. Methacycline and ampicillin are effective antibiotics for treating acute bacterial exacerbations of chronic bronchitis. Although methacycline is not more effective than ampicillin, it does represent an alternative for individuals with penicillin sensitivity. The incorporation of objective measurements assists in the documentation of clinical observations and may serve to delineate subtle advantages or disadvantages of seemingly comparable therapies.
1 American Thoracic Society: Chronic bronchitis, asthma and pulmonary emphysema: A statement by the Committee on Diagnostic Standards for Nontuberculous Respiratory Diseases. Am Rev Respir Dis 85:762-768, 1962 2 Chodosh S, Eichel B, Ellis C, et al: Trimethoprim-sulfamethoxazole compared with ampicillin in acute infectious exacerbations of chronic bronchitis. J Infect Dis 128: (suppl) :S710-S718, 1973 3 Chodosh S: Examination of sputum cells. N Engl ] Med 282:854~7 . 1970 4 Chodosh S, Medici TC: The bronchial epithelium in chronic bronchitis: 1. Exfoliative cytology during stable, acute bacterial infection and recovery phases. Am Rev Respir Dis 104:888-898, 1971 5 Wilcoxon F, Wilcox RA : Some Rapid Approximate Statistical Procedures. Pearl River, N.Y., American Cyanamid Co, 1964 6 Ayliffe GAJ, Pride NB : Treatment of exacerbations of chronic bronchitis with ampicillin. Br Med J 2 :1641, 1962 7 Erythromycin in lower respiratory infections. Practitioner 204:315-317, 1970 8 Pines A, Greenfield JSB, Raafat H, et al: Acomparison of pivampicillin and ampicillin in exacerbations of chronic bronchitis. Br] Dis Chest 67:221-226, 1973
592 CHODOSH, BAIGELMAN, MEDICI
9 Aitchison WRC, Grant IWB, Gould JC : Treatment of acute exacerbations of chronic bronchitis. Br J Clin Pract 22:8, 1968 10 Hughes DTD: Single-blind comparative trial of trimethoprim-sulphamethoxazole and ampicillin in the treatment of exacerbations of chronic bronchitis. Br Med J 4:470-473, 1969 11 Trimethoprim-sulphamethoxazole in chronic bronchitis. Practitioner 203:817-819, 1969 12 Marshall-Clarke GB: A clinical trial of methacycline in chronic bronchitis. Presented at the Fourth International Congress of Chemotherapy, Washington, DC, Oct 17-21, 1965 13 Thomson DA, Huckbody ]A, Griffits EV, et al : Treatment of chronic bronchitis in general practice with methacycline. Br] Clin Pract 19:509-513, 1965 14 Malone DN, Gould JC, Grant IWB : Acomparative study of ampicillin, tetracycline hydrochloride and methacycline hydrochloride in acute exacerbations of chronic bronchitis. Lancet 2:594-596, 1968 15 Pugh DL, Page N: Acute exacerbations of chronic bronchitis. Br J Geriatr Pract 89-99, 1969 16 Whelton FJ : Experiences with antibiotic trials in chronic bronchitis. Public Health 84 :95-101, 1970 17 Darke C: Comparison of dimethylchlortetracycline with tetracycline in the treatment of chronic bronchitis. Tubercle 45:384-387, 1964 18 Elmes PC, King TKC, Langlads JHM, et al: Value of ampicillin in the hospital treatment of exacerbations of chronic bronchitis. Br Med J 2 :904-908, 1965 19 Pines A, Raafat H, Pluconski K, et al : Antibiotic regimens in severe and acute purulent exacerbations of chronic bronchitis. Br Med J 2 :735-738, 1968 20 Pines A, Raafat H, Greenfield JSB, et al : The management of purulent exacerbations of chronic bronchitis: A comparison of co-trimoxazole and tetracycline. Practitioner 208:265-267, 1972 21 Pines A, Plucinski K, Greenfield JSB, et al : Controlled comparison of lymecycline with tetracycline hydrochloride in exacerbations of chronic bronchitis. Br Med J 2:1495-1498, 1964 22 Lal S, Bahalla KK : Comparison of tetracycline and trimethoprim-sulphamethoxazole in acute episodes in chronic chest infections. Postgrad Med ] 45 ( suppl) :8688, 1969 23 Francis RS, May JR, Spicer CC: Influence of penicillin and tetracycline administered daily or intermittently for exacerbations of bronchitis. Br Med J 2:979, 1961 24 Gould JC : Treatment of respiratory infections: Cephalexin compared to doxycycline. Presented at the 12th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1972 25 Barret-Connor E : The nonvalue of sputum culture in the diagnosis of pneumococcal pneumonia. Am Rev Respir Dis 103:845-848, 1971
CHEST, 69: 5, MAY, 1976