The Journal ofInternational Medical Research 1991; 19: 373 - 383
Simplified Treatment of Acute Lower Respiratory Tract Infection with Azithromycin: a Comparison with Erythromycin and Amoxycillin R. Daniel and European Azithromycin Study Group Department ofClinical Research, Pfizer Central Research, Sandwich, UK
In two randomized, multicentre studies azithromycin treatment (1.5g in five or six doses over 5 days) was compared with erythromycin treatment (14 or 20 g in 28 or 40 doses over 7 or 10 days) and amoxycillin treatment (10.5 g in 21 doses over 7 days) in patients with acute respiratory tract infection. In the two separate studies, azithromycin gave complete clinical cure in 70% and 51%, respectively, of patients compared with in 60% of erythromycin- and 45% of amoxycillin-treated patients. Eradication of the main pathogens isolated at baseline (Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus) was comparable in the azithromycin, erythromycin and amoxycillin treatment groups. Efficacy was not affected by the presence or absence of underlying pulmonary disease. There were no major abnormalities in laboratory safety parameters and adverse events, principally mild/moderate gastro-intestinal symptoms occurred in 5% or 15%, respectively, of azlthromycla-treated patients com-
First made available while 'in press' to delegates of the 17th International Congress of Chemotherapy, Berlin, 23 - 28 June 1991. This defmitive version differs from the in press version in respect of the inclusion of additional author corrections received after the Berlin meeting. Received for publication 17 April 1991; accepted 21 May 1991. Address for correspondence: Dr R. Daniel, Department of Clinical Research, Pfizer Central Research, Ramsgate Road, Sandwich CT31 9NJ, UK.
© Copyright 1991 by Cambridge Medical Publications Ltd
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R. Daniel, European Azithromycin Study Group
pared with in 18 % or 17 %, respectively, of those receiving erythromycin or amoxycillin. It is concluded that azithromycin was as effective and better tolerated than erythromycin or amoxyciIlin. KEY WORDS: Azithromycin; erythromycin; amoxycillin; bronchitis; pneumonia.
INTRODUCTION
A
zithromycinis a new azalide antibiotic. It is chemically derived from the macrolide erythromycin but differs by the insertion of a nitrogen (aza-linkage) into position9a of the lactonering. This chemical modification has significantly improved the pharmacokinetic profile of azithromycin. In comparison with erythromycin, azithromycin has been shown to achieve good stability within the acidic environment of the stomach' and has reliable oral bioavailability.' The dibasic character (the amine groups) of the azalide structure has also enhanced the uptake of azithromycin into cells.v' This is reflected systemically by azithromycin's rapid distribution to the tissues. Azithromycin has achieved high, sustained tissueconcentrations and low serum concentrations.' A UK study conducted by Baldwin et al? found that active concentrations of azithromycin above the minimal inhibitory concentrations (MICs) for most key respiratory pathogens were maintained in pulmonary tissue for several days after a single 500 mg oral dose. The concentrations of azithromycin in the tissues and sites of infection are thought to be augmented by phagocyte uptake. Very high concentrations of azithromycin in alveolar macrophages have also been found. In vitro evidenceindicatesthat high intracellular concentrations of azithromycin may play a role in augmenting the activity of macrophages, which are an important component of the host immune defence against intracellular pathogens. Studies in patients with bronchitis have revealed a mean concentration of azithromycin in 374
sputum of 3.7 mg/kg 24 h after a single oral dose of 500 mg, with individual patients having concentrations of up to 9.5 rug/kg," These values greatly exceed the MICs of azithromycin against the principal pathogens of bronchitis. Azithromycin has good in vitro activity against clinically important respiratory pathogens," The classicalmacrolide spectrum of activity against Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes) and atypical respiratory pathogens (Mycoplasma pneumoniaei Legionella pneumophila' and Chlamydia species":") has been retained. Azithromycin has also demonstrated significant activity against Haemophilus influenzae and Branhamella catarrhalis, as well as other Gram-negative bacteria (Escherichia coli, Enterobacter aerogenesi.' The in vitro activity of azithromycin against H. influenzae and Branhamella catarrhalis has been shown to be significantly greater than that of macrolides and comparable to ampicillin." The activity of azithromycin was not diminished against either ~ lactamase- or penicillinase-producing strains.I-" The present paper describes two sequential, multicentre clinical studies carried out between 1986 and 1989. The first was a comparison of azithromycin and erythromycin and involved mainly patients with acute bronchitis, but included a minority of patients with pneumonia. The second study was designed to include only acute bronchitis cases and was comparative with amoxycillin.
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections PATIENTS AND METHODS
Patients Azithromycinlerythromycin study. Male or female patients aged 18 years or more were recruited to the study. Patients were required to have an acute bacterial infection of the lower respiratory tract. Patients with acute bronchitis, with or without underlying pulmonary disease, and acute exacerbations of chronic bronchitis were also included but patients with chronic pulmonary disease without an acute infective exacerbation were excluded. Patients with life-threatening conditions, cystic fibrosis, or known hypersensitivity to macrolides were excluded from the study. Other patients excluded were those who had received antibiotics in the 48 h preceding the start of the study, those with any past or present factor which may have affected drug absorption, those with evidence of drug or alcohol abuse, or women of child-bearing potential. If patients were receiving concomitant treatment with warfarin, carbamazepine and/or ergotamine, they were excluded. Azithromycinlamoxycillin study. Patients with acute bacterial or bronchopulmonary infection accompanied by the production of purulent sputum were included in the study. Other inclusion and exclusion criteria were the same as for the azithromycin/ erythromycin study except that women of child-bearing potential were included. Patients with known hypersensitivity to penicillin antibiotics were excluded from the study. Treatment Azithromycinlerythromycin study. Patients were allocated to either treatment group using a randomization list. Azithromycin was administered as two 250 mg doses separated by 12 h on day 1 followed by 250 mg/day azithromycin for days 2 - 5. Other patients received 500 mg erythromycin (as stearate) four times daily for 7 - 10 days; investigators were asked to regard 7 days as
the target duration of therapy but were allowed to extend erythromycin treatment for a further 3 days if results at day 7 indicated that this would be appropriate.
Azithromycinlamoxycillin study. Azithromycin was administered orally as a single dose of 500 mg on day 1 and as 250 mg/day on days 2 - 5. Patients assigned to the amoxycillin treatment group received 500 mg amoxycillin given orally three times daily for 7 days. Study design The study design was similar for both the azithromycin/erythromycin and azithromycin/amoxycillin studies. Patients were instructed to return for efficacy assessments within 48 h of the last dose of study medication and again 7 - 10 days after the last dose. Efficacy was calculated from data obtained at the latest examination in the period 10 - 15 days after the start of treatment. Clinical response was categorized by changes, compared to pretreatment, in the following parameters as appropriate: total and differential leucocyte counts; body temperature; frequencyand severityof cough; amount and degree of purulence of sputum; degree of dyspnoea; and severityof abnormal chest sounds or auscultation. If possible, a sample of sputum was obtained prior to treatment and cultured for the isolation and identification of causative pathogens. Further samples to determine the disappearance or persistence of baseline pathogens were sought at the two follow-up examinations. If clinical improvement led to an inability to produce sputum, baseline pathogens were assumed to have been eradicated. All bacteriology was carried out blind, without knowledge of which drug the patient had been allocated. Adverse events observed or volunteered at each visit were recorded. All such events occurring up to 35 days after the start of treatment and which were classified by the 375
R. Daniel, European Azithromycin Study Group
Table 1 Characteristics and treatment of patients with lower respiratory tract infections prior to treatment with azithromycin or erythromycin Characteristic
Azithromycin
Patients treated Male Female Total
Erythromycin
74 19 93
66 22 88
Patient age (years) Mean Range
57.7 27 -93
58.8 18 - 90
Diagnosis Acute bronchitis Pneumonia Other
72 (77%) 21 (23%) 0(0%)
66 (75%) 21 (24%) 1(1%)
Treatment Total dosage (g) Total no. of doses
1.5 6b
14 or 20' 28 or 40'
'Treatment for 10 days received by 20 patients. 'Azithromycm administered orally as two doses of 250 mg 12 h apart on day 1 and 250 mg/day on days 2 - 5.
investigators as related to study treatment, possibly related to study treatment, or in which no opinion on causality was offered were included in the results. Haematology, biochemistry and urinalysis safety parameters were recorded at each visit and again 28 days after the start of treatment. All deviations from within normal limits were classified as: transient and unrelated to study design; due to laboratory error; due to concomitant disease or medication; clinically insignificant; or related to study treatment. All abnormalities that were classified as being related to study treatment which were recorded up to 35 days after the start of treatment were included in the results. Statistical analysis The statisticaldifferencebetween treatments was determined by employing the x2-test with continuity correction. 376
RESULTS Azithromycin/erythromycin study A total of 181 patients (Table 1) were recruited from 12 study centres in seven European countries (Austria, Belgium, Denmark, France, Finland, FRG, The Netherlands, Norway) and randomized to either the azithromycin treatment group (93 patients) or the erythromycin treatment group (88 patients). In the study, 28 (30%) azithromycin and 35 (40%) erythromycin treatment group patients were aged over 65 years and all except four patients were white Europeans. The predominant diagnosis was acute bronchitis in both azithromycin and erythromycin treatment groups and pneumonia was diagnosed in 23% of azithromycin- and 24% of erythromycintreated patients. Of the bronchitis patients, some 60% presented with an acute exacerbation associated with underlying
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
conditions such as chronic bronchitis, asthma and chronic obstructive pulmonary disease, and the remainder presented with uncomplicated acute bronchitis. The percentage of patients with uncomplicated acute bronchitis was 40% and 36%, respectively, in the azithromycin and erythromycin treatment groups. Diseases other than the primary diagnosis were recorded at the start of treatment in 73% of patients in the azithromycin treatment group and in 77% of those in the erythromycin group. Cardiovascular conditions (hypertension, congestive heart failure, ischaernic heart disease) and other respiratory conditions, including chronic bronchitis, asthma and nasopharyngeal infections, were the predominant secondary diseases at the start of treatment. In view of the secondary diseases present, medication in addition to the study drugs was given during the study period; 71% of azithromycin- and 78% of erythromycin-treated patients received cardiovascular drugs (vasodilators,
cardiac glycosides), respiratory drugs (bronchodilators, mucolytics), corticosteroids and/or agents for the relief of upper respiratory tract infections. Intercurrent illness, mainly minor infections ofthe upper respiratory tract, arose during the study period in 7% and 10%, respectively, of azithrornycin- and erythromycin-treated patients. The majority of patients treated with erythromycin received treatment for 7 days but treatment for a further 3 days was necessary in 20 (23%) patients. Three azithromycin- and eight erythromycin-treated patients did not return for follow-up assessment of efficacy within the specified time window. Clinical cure was recorded in 63/90 (70%) azithromycin-treated patients compared with 48/80 (60% ) ofthose treated with erythromycin; there was no statistically significant difference (P = 0.228) in clinical efficacy between the two treatment groups. Azithromycin was effective against both uncomplicated acute bronchitis and
Table 2 Clinical efficacy by diagnosis of azithromycin or erythromycin in patients with lower respiratory tract infections Azithromycin a % cured
Erythromycin" % cured
Acute bronchitis
64
59
Acute exacerbation of chronic obstructive pulmonary disease
64
47
Acute bronchitis with asthma or other lung disease
75
78
Pneumonia
86
74
Diagnosis
aAzithromycin administered orally as two doses of 250 mg 12 h apart on day I and 250 mg/day on days 2 - 5. 'Erythromycin administered orally as 500 mg four times daily for 7 days; treatment for 10 days received by 20 patients.
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Table 3 Percentage of pathogens eradicated following treatment of patients with lower respiratory tract infections with azithromycin or erythromycin Azithromycina Pathogen Haemophilus influenzae Streptococcus pneumoniae Branhamella catarrhalis Staphylococcus aureus Others Total
Erythromycin"
No. of isolates
% eradicated
No. of isolates
% eradicated
21 18 3
18
19
81 83 100 92 63
15
78 90 100 91 87
74
80C
59
86
13
10
5 11
'Azithromycin administered orally as two doses of 250 mg 12 h apart on day I and 250 mg/day on days 2 - 5. bErythromycin administered orally as 500 mg four times daily for 7 days; treatment for 10 days received by 20 patients. 'P =0.432 vs erythromycin.
bronchitis presenting with underlying pulmonary disease or as an acute exacerbation of chronic disease (Table 2). In the 21patient sample, azithromycin was successful against pneumonia (86% cured) and acute bronchitis alone (66% cured). Erythromycin produced a similar clinical efficacy by diagnosis to azithromycin. Prior to treatment,one or more pathogens were isolated from 60 (65%) azithromycin treatment group patients and from 53 (60%) erythromycin-treated patients. After treatment with azithromycin 80% of pathogens were eradicated compared with 86% after erythromycin treatment (P = 0.432, Table 3). The number of principal pathogens of lower respiratory tract infections eradicated byazithromycin was81-1oo%, which was comparable to that of erythromycin (78 100%). Isolation of a different organism at the end of treatment to that cultured prior to treatmentoccurredin 10 (17%) azithromycintreated patients including two cases of H. influenzae and in 15 (28%) erythromycintreated patients including five case of H. influenzae. Among the patients that were bacteriologically positive before treatment,
378
pathogens resistant in vitro to the relevant study drug were isolated from 17 (28%) azithromycin and nine (17%) erythromycin treatment group patients. Of these resistant pathogens, 61% or 80%, respectively, were eradicated by azithromycin or erythromycin, including two of the three azithromycinresistant H. influenzae strains and all five azithromycin-resistant Staph. aureus strains. Adverse events were reported in five (5%) of all azithromycin-treated patients compared with 16 (18%) of all erythromycintreated patients (Table 4). Of these the most frequent complaints were gastrointestinal in both azithromycin (7/8 events: nausea, vomiting) and erythromycin (20/ 20 events: nausea, diarrhoea) treatment groups. A patient receiving erythromycin withdrew due to nausea and vomiting and one azithromycin-treated patient also had severe nausea and vomiting but was not withdrawn from treatment. Neither azithromycin nor erythromycin had any major or consistent effects on laboratory safety parameters; 18% of azithromycin- and 17% of erythromycintreated patients had possible treatment-
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
Table 4 Incidence of adverse events in patients with lower respiratory tract infections treated with azithromycin or erythromycin Measure Patients No. assessed No. with side-effects No. withdrawn from treatment Adverse events No. recorded No. classed as gastro-intestinal No. classed as dermal No. classed as severe
Azithromycina
Erythromycin"
93 5 (5%)
88 16 (18%)
0(0%)
1 (1%)
8
20
7 1 1
20 0 0
aAzithromycin administered orally as two doses of 250 mg 12 h apart on day I and 250 mg/day on days 2 - 5. "Erythromycin administered orally as 500 mg four times daily for 7 or 10 days.
Table 5 Characteristics and treatment of patients with lower respiratory tract infections prior to treatment with azithromycin or amoxycillin Characteristic
Azithromycin
Patients treated Male Female Total
6S 60 125
Patient age (years) Mean Range
50.5 18 - 88
Diagnosis Acute bronchitis Pneumonia Other
123 (98%) 1 (1%) 1 (1%)
Treatment Total dosage (g) Total no. of doses
I.S 5a
Amoxycillin
63 63 126
49.1 19 - 89
124 (98%) 2 (2%) 0(0%)
IO.S 21
"Azithrornycin administered orally as 500 rng on day I and 250 mg/day on days 2 - 5.
379
R. Daniel, European Azithromycin Study Group
related abnormalities. A similar pattern of scattered and infrequent abnormalities, mainly consisting of slight rises in liver function enzymes were reported in the azithromycin and erythromycin treatment groups. Azithromycin/amoxycillin study In nine study centres in four European
countries (Belgium, Finland, FRG, UK) 126 patients were allocated to treatment with amoxycillin and 125 with azithromycin (Table 5). In the study, 27 (22%) of the azithromycin-treated patients and 29 (23%) of the amoxycillin-treated patients were over 65 years of age; all patients were white Europeans. Of the amoxyallin-treated patients, 124 (98%) were diagnosed as suffering from acute bronchitis as were 123 (98%) of the azithromycin-treated patients. Only two (2%) patients in the amoxycillin treatment group had pneumonia compared
with one (1%) in the azithromycin treatment group. Of the bronchitis patients treated with azithromycin, 72% presented with an uncomplicated acute episode and the remainder presented with an acute exacerbation associated with underlying conditions such as chronicbronchitis, asthma and chronic obstructive pulmonary disease. Uncomplicated bronchitis was diagnosed in 76% of amoxycillin-treated patients. Concurrent disease was recorded in a total of 64 (51 %) azithromycin and in 57 (45%) amoxycillin patients; the nature of concurrent diseases was similar to that in the azithromycin/erythromycin study. Intercurrent illness, mainly minor upper respiratory tract infections, arose in 12 (10%) and 15 (12%), respectively, of azithromycin- and amoxycillin-treated patients. Concurrent treatment was given to 79 (63%) patients treated with azithromycin compared with 76 (60%)
Table 6 Clinical efficacy by diagnosis of azithromycin and amoxycillin in patients with lower respiratory tract infections Diagnosis
Azithromycina % cured
Amoxycillln" % cured
Acute bronchitis
57
52
Acute exacerbation of chronic obstructive pulmonary disease
34
13
Acute bronchitis with asthma or other lung disease
33
75
Pneumonia Total
_c
51d,e
100
4Y
"Azithromycin administered orally as 500 mg on day 1 and 250 mg/day on days 2 - 5. bAmoxycillin administered orally as 500 mg three times daily for 7 days. 'No patients assessed. dp =0.192 vs amoxycillin. '121 patients assessed. '120 patients assessed.
380
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
Table 7 Percentage of patbogens eradicated following treatment of patients with lower respiratory tract infections with azitbromycin and amoxycillin Azithremycin" No. of isolates
Pathogen
Haemophilus influenzae Streptococcus pneumoniae Branhamella catarrhalis Staphylococcus aureus Others Total
Amexycilhn"
% eradicated
No. of isolates
14 8 2 2 15
86 75 50 100 67
10
5 7 6 18
80 100 100 67 83
41
76c
46
85
% eradicated
aAzithromycin administered orally as 500 mg on day 1 and 250 mg/day on days 2 - 5. "Amoxycillin administered orally as 500 mg three times daily for 7 days. 'P = 0.420 vs amoxycillin.
amoxycillin-treated patients. Six amoxycillin- and four azithromycintreated patients did not return for assessment of efficacy within the specified time window. The incidence of clinical cure for amoxycillin-treated patients was 45% (54/
120) compared with 51% (62/121) for azithromycin (Table 6); this difference was not statistically significant (P = 0.192). In the azithromycin/amoxycillin study, clinical response was assessed as 'cured', 'improved' or 'failed'. The combined incidences of
Table 8 Incidence of adverse events in patients witb lower respiratory tract infections treated with azithromycin or amoxycillin Measure Patients No. assessed No. with side-effects No. withdrawn from treatment Adverse events No. recorded No. classed as gastro- intestinal No. classed as dermal No. classed as severe
Azithromycioa
Amoxycilliob
125 15 (12%)
126 21 (17%)
1 (1%)
2 (2%)
18
28
13
12 7 2
1 2
'Azithromycin administered orally as 500 mg on day 1 and 250 mg/day for days 2 - 5. "Amoxycillin administered orally as 500 mg three times daily for 7 days.
381
R. Daniel, European Azithromycin Study Group
cure plus improved were 96% (34% plus 62%) and 92% (13% plus 79%), respectively, for azithromycin and amoxycillin treatment groups. Pathogens were isolated from 37/126 (29%) patients in the amoxycillin-treatment group before treatment compared with 33/125 (26%) of those receiving azithromycin. The percentage eradication following azithromycin treatment of 76% was similar to that of amoxycillin (85%, P = 0.420, Table 7). The eradication of H. influenzae was similar for azithromycin and amoxycillin (86% compared with 80%). Isolation of a different organism at the end of treatment to that cultured prior to treatment occurred in eight (22%) amoxycillin treatment group patients and in seven (21%) treated with azithromycin including two cases of H. inj1uenzae. Before treatment pathogens resistant to azithromycin in vitro were isolated from two (6% ) patients, including one H. inj1uenzae infection; they were both eradicated following treatment. Of the amoxycillin-resistant pathogens, 78% (7/9) were eradicated. The incidence of adverse events in amoxycillin-treated patients was 17% and 12% in azithromycin-treated patients (Table 8). In both treatment groups, gastro-intestinal adverse events were the most commonly reported: 13/18 events of azithromycin(abdominal pain) and 12/28 events of amoxycillin-induced adverse events (abdominal pain/diarrhoea). A high incidence of skin rash was reported in amoxycillintreated patients (7/28 adverse events) compared with 1/18 adverse events in azithromycin-treated patients. Treatment was withdrawn in two (2%) amoxycillintreated patients who reported nervousness, nausea and vomiting, and severe diarrhoea and in one (1 %) azithromycin-treated patient due to nausea and vomiting. Only scattered and infrequent abnormalities in laboratory safety parameters were detected in azithromycin (10%) and amoxycillin (13%) treatment groups.
382
DISCUSSION
A short course of azithromycin given once daily for 5 days was as effective, both clinically and bacteriologically, in the treatment of acute bronchitis, with or without underlying pulmonary disease, as amoxycillin given three times daily for 7 days or erythromycin given four times daily for 7 or 10 days. When patients with underlying illness were compared, azithromycin and erythromycin appeared to be equally efficacious. Azithromycin also appeared to have application in the treatment of pneumonia, although further studies using large patient groups are required. Amoxycillin, however, appeared to be less successful than azithromycin in the treatment of chronic obstructive pulmonary disease. Consistent with the results of previous tissue kinetic studies.t-" once-daily administration of azithromycin was sufficient to eradicate key respiratory tract pathogens. Overall, azithromycin treatment was associated, with a lower incidence of adverse events than comparator drugs. Gastrointestinal adverse events were the most frequently reported in all treatment groups. A higher incidence of dermal adverse events was reported in the amoxycillin treatment group in comparison with azithromycin and erythromycin. The trials included a complete spectrum of bronchitic patients with both chronic bronchitis and acute bronchitis. In the azithromycin/erythromycin study, however, 30 - 40% of patients were over 65 years of age in comparison with only 22 - 23% of patients in the azithromycin/amoxycillin study. As a consequence, there was a higher proportion of patients in the former study group with chronic bronchitis and underlying pulmonary disease. Azithromycin was shown to be an effective treatment in both patient groups. The simpler and shorter azithromycin treatment regimen appears to have achieved the same degree of control of acute bronchitis and other infections of the lower respiratory
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
tract as standard regimens. A more convenient dosing regimen suggests there may be improved patient compliance in certain groups, notably elderly bronchitics. 9.
ACKNOWLEDGEMENT
The European Azithromycin Study Group acknowledge the assistance of Pfizer Central Research, Europe. REFERENCES 1. Fiese EF, Steffen SH: Comparison of the acid stability of azithromycin and erythromycin. J Antimicrob Chemother 1990; 25(suppl A): 3947. 2. Foulds G, Shephard RM, Johnson RB: The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25(suppl A): 73 - 82. 3. GladueRP,BrightGM,IsaacsonRE,etal:/nvitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrab Agents Chemother 1989; 33: 277 - 282. 4. Gladue RP, Snider ME: Intracellular accumulation of azithromycin by cultured human fibroblasts. Antimicrob Agents Chemother 1990; 34: 1056 -1060. 5. Baldwin DR, Wise R, Andrews JM, et al: Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J 1990; 3: 886 - 890. 6. Davies B, Maesen FPV, Gubbehnans R: Azithromycin (CP-62,993) in acute exacerbations of chronic bronchitis: an open clinical, microbiological and pharmacological study. J Antimicrob Chemother 1989; 23: 743 - 751. 7. Retsema J, Girard A, Schelkley W, et al: Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against Gramnegative organisms. Antimicrob Agents Chemother 1987; 31: 1939 - 1947. 8. Rylander M, Hallander HO: In vitro comparison
10.
II.
12.
of the activity of doxycycline, tetracycline, erythromycin and a new macrolide, CP-62,933, agonist Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum. Scand J Infect Dis 1988; 53: 12 - 17. Fitzgeorge RB, Featherstone ASR, Baskerville A: Efficacy of azithromycin in the treatment of guinea pigs infected with Legionella pneumophila by aerosol. J Antimicrob Chemother 1990; 25: 101 - 108. Chirgwin K, Roblin PM, Hammerschlag MR. In vitro susceptibilities of Chlamydia pneumoniae (Chlamydia sp. strain TWAR). Antimicrob Agents Chemother 1989; 33: 1634 -1635. Fenelon LE, Mumtaz G, Ridgway: The in vitro antibiotic susceptibility of Chlamydia pneumoniae. J Antimicrob Chemother 1990; 26: 763 - 767. Dunkin KT, Jones S, Howard AJ: The in vitro activity of CP-62.993 against Haemophilus influenzae, Branhamella catarrhalis, staphylococci and streptococci. J Antimicrob Chemother 1988; 21: 405 - 411.
APPENDIX The following investigators took part in the azithromycin/erythromycin study: Dr. M. Austgen, Miinnerstadt, FRG; Dr H.M. Beumer, Utrecht, The Netherlands; Prof. B. Christoforov, Paris, France; Dr A. Clauzel, Montpellier, France; Prof. J. Dry, Paris, France; Dr C. Gillard, Jumet, Belgium; Dr E. Haringer, Munich, FRG; Dr M. De Jonghe, Jumet, Belgium; Dr B. Nuchel-Petersen, Hellerup, Denmark; Prof. A. Pradalier, Paris, France; Dr T. Prigogine, Brussels, Belgium; Dr N. Ringdal, Molde, Norway; Dr P. Royset, Troms, Norway; Prof. O. Wieser, Klagenfurt, Austria. The following investigators took part in the azithromycin/amoxycillin study: Dr P.G. Davey, Dundee, UK; Dr P. Himanen, Turku, Finland; Dr J. Hosie, Glasgow, UK; Dr F. Kerler, Wendelstein, FRG; Dr K. Kothny, Munich, FRG; D.E. Machiels, Ottignies, Belgium; Dr J. Nikoskelainen, Turku, Finland; Dr W. Petro, Bad Reichenhall, FRG; Dr U. Rustemeier, Essen, FRG.
383
Simplified Treatment of Acute Lower Respiratory Tract Infection with Azithromycin: a Comparison with Erythromycin and Amoxycillin R. Daniel and European Azithromycin Study Group Department ofClinical Research, Pfizer Central Research, Sandwich, UK
In two randomized, multicentre studies azithromycin treatment (1.5g in five or six doses over 5 days) was compared with erythromycin treatment (14 or 20 g in 28 or 40 doses over 7 or 10 days) and amoxycillin treatment (10.5 g in 21 doses over 7 days) in patients with acute respiratory tract infection. In the two separate studies, azithromycin gave complete clinical cure in 70% and 51%, respectively, of patients compared with in 60% of erythromycin- and 45% of amoxycillin-treated patients. Eradication of the main pathogens isolated at baseline (Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus) was comparable in the azithromycin, erythromycin and amoxycillin treatment groups. Efficacy was not affected by the presence or absence of underlying pulmonary disease. There were no major abnormalities in laboratory safety parameters and adverse events, principally mild/moderate gastro-intestinal symptoms occurred in 5% or 15%, respectively, of azlthromycla-treated patients com-
First made available while 'in press' to delegates of the 17th International Congress of Chemotherapy, Berlin, 23 - 28 June 1991. This defmitive version differs from the in press version in respect of the inclusion of additional author corrections received after the Berlin meeting. Received for publication 17 April 1991; accepted 21 May 1991. Address for correspondence: Dr R. Daniel, Department of Clinical Research, Pfizer Central Research, Ramsgate Road, Sandwich CT31 9NJ, UK.
© Copyright 1991 by Cambridge Medical Publications Ltd
373
R. Daniel, European Azithromycin Study Group
pared with in 18 % or 17 %, respectively, of those receiving erythromycin or amoxycillin. It is concluded that azithromycin was as effective and better tolerated than erythromycin or amoxyciIlin. KEY WORDS: Azithromycin; erythromycin; amoxycillin; bronchitis; pneumonia.
INTRODUCTION
A
zithromycinis a new azalide antibiotic. It is chemically derived from the macrolide erythromycin but differs by the insertion of a nitrogen (aza-linkage) into position9a of the lactonering. This chemical modification has significantly improved the pharmacokinetic profile of azithromycin. In comparison with erythromycin, azithromycin has been shown to achieve good stability within the acidic environment of the stomach' and has reliable oral bioavailability.' The dibasic character (the amine groups) of the azalide structure has also enhanced the uptake of azithromycin into cells.v' This is reflected systemically by azithromycin's rapid distribution to the tissues. Azithromycin has achieved high, sustained tissueconcentrations and low serum concentrations.' A UK study conducted by Baldwin et al? found that active concentrations of azithromycin above the minimal inhibitory concentrations (MICs) for most key respiratory pathogens were maintained in pulmonary tissue for several days after a single 500 mg oral dose. The concentrations of azithromycin in the tissues and sites of infection are thought to be augmented by phagocyte uptake. Very high concentrations of azithromycin in alveolar macrophages have also been found. In vitro evidenceindicatesthat high intracellular concentrations of azithromycin may play a role in augmenting the activity of macrophages, which are an important component of the host immune defence against intracellular pathogens. Studies in patients with bronchitis have revealed a mean concentration of azithromycin in 374
sputum of 3.7 mg/kg 24 h after a single oral dose of 500 mg, with individual patients having concentrations of up to 9.5 rug/kg," These values greatly exceed the MICs of azithromycin against the principal pathogens of bronchitis. Azithromycin has good in vitro activity against clinically important respiratory pathogens," The classicalmacrolide spectrum of activity against Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes) and atypical respiratory pathogens (Mycoplasma pneumoniaei Legionella pneumophila' and Chlamydia species":") has been retained. Azithromycin has also demonstrated significant activity against Haemophilus influenzae and Branhamella catarrhalis, as well as other Gram-negative bacteria (Escherichia coli, Enterobacter aerogenesi.' The in vitro activity of azithromycin against H. influenzae and Branhamella catarrhalis has been shown to be significantly greater than that of macrolides and comparable to ampicillin." The activity of azithromycin was not diminished against either ~ lactamase- or penicillinase-producing strains.I-" The present paper describes two sequential, multicentre clinical studies carried out between 1986 and 1989. The first was a comparison of azithromycin and erythromycin and involved mainly patients with acute bronchitis, but included a minority of patients with pneumonia. The second study was designed to include only acute bronchitis cases and was comparative with amoxycillin.
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections PATIENTS AND METHODS
Patients Azithromycinlerythromycin study. Male or female patients aged 18 years or more were recruited to the study. Patients were required to have an acute bacterial infection of the lower respiratory tract. Patients with acute bronchitis, with or without underlying pulmonary disease, and acute exacerbations of chronic bronchitis were also included but patients with chronic pulmonary disease without an acute infective exacerbation were excluded. Patients with life-threatening conditions, cystic fibrosis, or known hypersensitivity to macrolides were excluded from the study. Other patients excluded were those who had received antibiotics in the 48 h preceding the start of the study, those with any past or present factor which may have affected drug absorption, those with evidence of drug or alcohol abuse, or women of child-bearing potential. If patients were receiving concomitant treatment with warfarin, carbamazepine and/or ergotamine, they were excluded. Azithromycinlamoxycillin study. Patients with acute bacterial or bronchopulmonary infection accompanied by the production of purulent sputum were included in the study. Other inclusion and exclusion criteria were the same as for the azithromycin/ erythromycin study except that women of child-bearing potential were included. Patients with known hypersensitivity to penicillin antibiotics were excluded from the study. Treatment Azithromycinlerythromycin study. Patients were allocated to either treatment group using a randomization list. Azithromycin was administered as two 250 mg doses separated by 12 h on day 1 followed by 250 mg/day azithromycin for days 2 - 5. Other patients received 500 mg erythromycin (as stearate) four times daily for 7 - 10 days; investigators were asked to regard 7 days as
the target duration of therapy but were allowed to extend erythromycin treatment for a further 3 days if results at day 7 indicated that this would be appropriate.
Azithromycinlamoxycillin study. Azithromycin was administered orally as a single dose of 500 mg on day 1 and as 250 mg/day on days 2 - 5. Patients assigned to the amoxycillin treatment group received 500 mg amoxycillin given orally three times daily for 7 days. Study design The study design was similar for both the azithromycin/erythromycin and azithromycin/amoxycillin studies. Patients were instructed to return for efficacy assessments within 48 h of the last dose of study medication and again 7 - 10 days after the last dose. Efficacy was calculated from data obtained at the latest examination in the period 10 - 15 days after the start of treatment. Clinical response was categorized by changes, compared to pretreatment, in the following parameters as appropriate: total and differential leucocyte counts; body temperature; frequencyand severityof cough; amount and degree of purulence of sputum; degree of dyspnoea; and severityof abnormal chest sounds or auscultation. If possible, a sample of sputum was obtained prior to treatment and cultured for the isolation and identification of causative pathogens. Further samples to determine the disappearance or persistence of baseline pathogens were sought at the two follow-up examinations. If clinical improvement led to an inability to produce sputum, baseline pathogens were assumed to have been eradicated. All bacteriology was carried out blind, without knowledge of which drug the patient had been allocated. Adverse events observed or volunteered at each visit were recorded. All such events occurring up to 35 days after the start of treatment and which were classified by the 375
R. Daniel, European Azithromycin Study Group
Table 1 Characteristics and treatment of patients with lower respiratory tract infections prior to treatment with azithromycin or erythromycin Characteristic
Azithromycin
Patients treated Male Female Total
Erythromycin
74 19 93
66 22 88
Patient age (years) Mean Range
57.7 27 -93
58.8 18 - 90
Diagnosis Acute bronchitis Pneumonia Other
72 (77%) 21 (23%) 0(0%)
66 (75%) 21 (24%) 1(1%)
Treatment Total dosage (g) Total no. of doses
1.5 6b
14 or 20' 28 or 40'
'Treatment for 10 days received by 20 patients. 'Azithromycm administered orally as two doses of 250 mg 12 h apart on day 1 and 250 mg/day on days 2 - 5.
investigators as related to study treatment, possibly related to study treatment, or in which no opinion on causality was offered were included in the results. Haematology, biochemistry and urinalysis safety parameters were recorded at each visit and again 28 days after the start of treatment. All deviations from within normal limits were classified as: transient and unrelated to study design; due to laboratory error; due to concomitant disease or medication; clinically insignificant; or related to study treatment. All abnormalities that were classified as being related to study treatment which were recorded up to 35 days after the start of treatment were included in the results. Statistical analysis The statisticaldifferencebetween treatments was determined by employing the x2-test with continuity correction. 376
RESULTS Azithromycin/erythromycin study A total of 181 patients (Table 1) were recruited from 12 study centres in seven European countries (Austria, Belgium, Denmark, France, Finland, FRG, The Netherlands, Norway) and randomized to either the azithromycin treatment group (93 patients) or the erythromycin treatment group (88 patients). In the study, 28 (30%) azithromycin and 35 (40%) erythromycin treatment group patients were aged over 65 years and all except four patients were white Europeans. The predominant diagnosis was acute bronchitis in both azithromycin and erythromycin treatment groups and pneumonia was diagnosed in 23% of azithromycin- and 24% of erythromycintreated patients. Of the bronchitis patients, some 60% presented with an acute exacerbation associated with underlying
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
conditions such as chronic bronchitis, asthma and chronic obstructive pulmonary disease, and the remainder presented with uncomplicated acute bronchitis. The percentage of patients with uncomplicated acute bronchitis was 40% and 36%, respectively, in the azithromycin and erythromycin treatment groups. Diseases other than the primary diagnosis were recorded at the start of treatment in 73% of patients in the azithromycin treatment group and in 77% of those in the erythromycin group. Cardiovascular conditions (hypertension, congestive heart failure, ischaernic heart disease) and other respiratory conditions, including chronic bronchitis, asthma and nasopharyngeal infections, were the predominant secondary diseases at the start of treatment. In view of the secondary diseases present, medication in addition to the study drugs was given during the study period; 71% of azithromycin- and 78% of erythromycin-treated patients received cardiovascular drugs (vasodilators,
cardiac glycosides), respiratory drugs (bronchodilators, mucolytics), corticosteroids and/or agents for the relief of upper respiratory tract infections. Intercurrent illness, mainly minor infections ofthe upper respiratory tract, arose during the study period in 7% and 10%, respectively, of azithrornycin- and erythromycin-treated patients. The majority of patients treated with erythromycin received treatment for 7 days but treatment for a further 3 days was necessary in 20 (23%) patients. Three azithromycin- and eight erythromycin-treated patients did not return for follow-up assessment of efficacy within the specified time window. Clinical cure was recorded in 63/90 (70%) azithromycin-treated patients compared with 48/80 (60% ) ofthose treated with erythromycin; there was no statistically significant difference (P = 0.228) in clinical efficacy between the two treatment groups. Azithromycin was effective against both uncomplicated acute bronchitis and
Table 2 Clinical efficacy by diagnosis of azithromycin or erythromycin in patients with lower respiratory tract infections Azithromycin a % cured
Erythromycin" % cured
Acute bronchitis
64
59
Acute exacerbation of chronic obstructive pulmonary disease
64
47
Acute bronchitis with asthma or other lung disease
75
78
Pneumonia
86
74
Diagnosis
aAzithromycin administered orally as two doses of 250 mg 12 h apart on day I and 250 mg/day on days 2 - 5. 'Erythromycin administered orally as 500 mg four times daily for 7 days; treatment for 10 days received by 20 patients.
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R. Daniel, European Azithromycin Study Group
Table 3 Percentage of pathogens eradicated following treatment of patients with lower respiratory tract infections with azithromycin or erythromycin Azithromycina Pathogen Haemophilus influenzae Streptococcus pneumoniae Branhamella catarrhalis Staphylococcus aureus Others Total
Erythromycin"
No. of isolates
% eradicated
No. of isolates
% eradicated
21 18 3
18
19
81 83 100 92 63
15
78 90 100 91 87
74
80C
59
86
13
10
5 11
'Azithromycin administered orally as two doses of 250 mg 12 h apart on day I and 250 mg/day on days 2 - 5. bErythromycin administered orally as 500 mg four times daily for 7 days; treatment for 10 days received by 20 patients. 'P =0.432 vs erythromycin.
bronchitis presenting with underlying pulmonary disease or as an acute exacerbation of chronic disease (Table 2). In the 21patient sample, azithromycin was successful against pneumonia (86% cured) and acute bronchitis alone (66% cured). Erythromycin produced a similar clinical efficacy by diagnosis to azithromycin. Prior to treatment,one or more pathogens were isolated from 60 (65%) azithromycin treatment group patients and from 53 (60%) erythromycin-treated patients. After treatment with azithromycin 80% of pathogens were eradicated compared with 86% after erythromycin treatment (P = 0.432, Table 3). The number of principal pathogens of lower respiratory tract infections eradicated byazithromycin was81-1oo%, which was comparable to that of erythromycin (78 100%). Isolation of a different organism at the end of treatment to that cultured prior to treatmentoccurredin 10 (17%) azithromycintreated patients including two cases of H. influenzae and in 15 (28%) erythromycintreated patients including five case of H. influenzae. Among the patients that were bacteriologically positive before treatment,
378
pathogens resistant in vitro to the relevant study drug were isolated from 17 (28%) azithromycin and nine (17%) erythromycin treatment group patients. Of these resistant pathogens, 61% or 80%, respectively, were eradicated by azithromycin or erythromycin, including two of the three azithromycinresistant H. influenzae strains and all five azithromycin-resistant Staph. aureus strains. Adverse events were reported in five (5%) of all azithromycin-treated patients compared with 16 (18%) of all erythromycintreated patients (Table 4). Of these the most frequent complaints were gastrointestinal in both azithromycin (7/8 events: nausea, vomiting) and erythromycin (20/ 20 events: nausea, diarrhoea) treatment groups. A patient receiving erythromycin withdrew due to nausea and vomiting and one azithromycin-treated patient also had severe nausea and vomiting but was not withdrawn from treatment. Neither azithromycin nor erythromycin had any major or consistent effects on laboratory safety parameters; 18% of azithromycin- and 17% of erythromycintreated patients had possible treatment-
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
Table 4 Incidence of adverse events in patients with lower respiratory tract infections treated with azithromycin or erythromycin Measure Patients No. assessed No. with side-effects No. withdrawn from treatment Adverse events No. recorded No. classed as gastro-intestinal No. classed as dermal No. classed as severe
Azithromycina
Erythromycin"
93 5 (5%)
88 16 (18%)
0(0%)
1 (1%)
8
20
7 1 1
20 0 0
aAzithromycin administered orally as two doses of 250 mg 12 h apart on day I and 250 mg/day on days 2 - 5. "Erythromycin administered orally as 500 mg four times daily for 7 or 10 days.
Table 5 Characteristics and treatment of patients with lower respiratory tract infections prior to treatment with azithromycin or amoxycillin Characteristic
Azithromycin
Patients treated Male Female Total
6S 60 125
Patient age (years) Mean Range
50.5 18 - 88
Diagnosis Acute bronchitis Pneumonia Other
123 (98%) 1 (1%) 1 (1%)
Treatment Total dosage (g) Total no. of doses
I.S 5a
Amoxycillin
63 63 126
49.1 19 - 89
124 (98%) 2 (2%) 0(0%)
IO.S 21
"Azithrornycin administered orally as 500 rng on day I and 250 mg/day on days 2 - 5.
379
R. Daniel, European Azithromycin Study Group
related abnormalities. A similar pattern of scattered and infrequent abnormalities, mainly consisting of slight rises in liver function enzymes were reported in the azithromycin and erythromycin treatment groups. Azithromycin/amoxycillin study In nine study centres in four European
countries (Belgium, Finland, FRG, UK) 126 patients were allocated to treatment with amoxycillin and 125 with azithromycin (Table 5). In the study, 27 (22%) of the azithromycin-treated patients and 29 (23%) of the amoxycillin-treated patients were over 65 years of age; all patients were white Europeans. Of the amoxyallin-treated patients, 124 (98%) were diagnosed as suffering from acute bronchitis as were 123 (98%) of the azithromycin-treated patients. Only two (2%) patients in the amoxycillin treatment group had pneumonia compared
with one (1%) in the azithromycin treatment group. Of the bronchitis patients treated with azithromycin, 72% presented with an uncomplicated acute episode and the remainder presented with an acute exacerbation associated with underlying conditions such as chronicbronchitis, asthma and chronic obstructive pulmonary disease. Uncomplicated bronchitis was diagnosed in 76% of amoxycillin-treated patients. Concurrent disease was recorded in a total of 64 (51 %) azithromycin and in 57 (45%) amoxycillin patients; the nature of concurrent diseases was similar to that in the azithromycin/erythromycin study. Intercurrent illness, mainly minor upper respiratory tract infections, arose in 12 (10%) and 15 (12%), respectively, of azithromycin- and amoxycillin-treated patients. Concurrent treatment was given to 79 (63%) patients treated with azithromycin compared with 76 (60%)
Table 6 Clinical efficacy by diagnosis of azithromycin and amoxycillin in patients with lower respiratory tract infections Diagnosis
Azithromycina % cured
Amoxycillln" % cured
Acute bronchitis
57
52
Acute exacerbation of chronic obstructive pulmonary disease
34
13
Acute bronchitis with asthma or other lung disease
33
75
Pneumonia Total
_c
51d,e
100
4Y
"Azithromycin administered orally as 500 mg on day 1 and 250 mg/day on days 2 - 5. bAmoxycillin administered orally as 500 mg three times daily for 7 days. 'No patients assessed. dp =0.192 vs amoxycillin. '121 patients assessed. '120 patients assessed.
380
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
Table 7 Percentage of patbogens eradicated following treatment of patients with lower respiratory tract infections with azitbromycin and amoxycillin Azithremycin" No. of isolates
Pathogen
Haemophilus influenzae Streptococcus pneumoniae Branhamella catarrhalis Staphylococcus aureus Others Total
Amexycilhn"
% eradicated
No. of isolates
14 8 2 2 15
86 75 50 100 67
10
5 7 6 18
80 100 100 67 83
41
76c
46
85
% eradicated
aAzithromycin administered orally as 500 mg on day 1 and 250 mg/day on days 2 - 5. "Amoxycillin administered orally as 500 mg three times daily for 7 days. 'P = 0.420 vs amoxycillin.
amoxycillin-treated patients. Six amoxycillin- and four azithromycintreated patients did not return for assessment of efficacy within the specified time window. The incidence of clinical cure for amoxycillin-treated patients was 45% (54/
120) compared with 51% (62/121) for azithromycin (Table 6); this difference was not statistically significant (P = 0.192). In the azithromycin/amoxycillin study, clinical response was assessed as 'cured', 'improved' or 'failed'. The combined incidences of
Table 8 Incidence of adverse events in patients witb lower respiratory tract infections treated with azithromycin or amoxycillin Measure Patients No. assessed No. with side-effects No. withdrawn from treatment Adverse events No. recorded No. classed as gastro- intestinal No. classed as dermal No. classed as severe
Azithromycioa
Amoxycilliob
125 15 (12%)
126 21 (17%)
1 (1%)
2 (2%)
18
28
13
12 7 2
1 2
'Azithromycin administered orally as 500 mg on day 1 and 250 mg/day for days 2 - 5. "Amoxycillin administered orally as 500 mg three times daily for 7 days.
381
R. Daniel, European Azithromycin Study Group
cure plus improved were 96% (34% plus 62%) and 92% (13% plus 79%), respectively, for azithromycin and amoxycillin treatment groups. Pathogens were isolated from 37/126 (29%) patients in the amoxycillin-treatment group before treatment compared with 33/125 (26%) of those receiving azithromycin. The percentage eradication following azithromycin treatment of 76% was similar to that of amoxycillin (85%, P = 0.420, Table 7). The eradication of H. influenzae was similar for azithromycin and amoxycillin (86% compared with 80%). Isolation of a different organism at the end of treatment to that cultured prior to treatment occurred in eight (22%) amoxycillin treatment group patients and in seven (21%) treated with azithromycin including two cases of H. inj1uenzae. Before treatment pathogens resistant to azithromycin in vitro were isolated from two (6% ) patients, including one H. inj1uenzae infection; they were both eradicated following treatment. Of the amoxycillin-resistant pathogens, 78% (7/9) were eradicated. The incidence of adverse events in amoxycillin-treated patients was 17% and 12% in azithromycin-treated patients (Table 8). In both treatment groups, gastro-intestinal adverse events were the most commonly reported: 13/18 events of azithromycin(abdominal pain) and 12/28 events of amoxycillin-induced adverse events (abdominal pain/diarrhoea). A high incidence of skin rash was reported in amoxycillintreated patients (7/28 adverse events) compared with 1/18 adverse events in azithromycin-treated patients. Treatment was withdrawn in two (2%) amoxycillintreated patients who reported nervousness, nausea and vomiting, and severe diarrhoea and in one (1 %) azithromycin-treated patient due to nausea and vomiting. Only scattered and infrequent abnormalities in laboratory safety parameters were detected in azithromycin (10%) and amoxycillin (13%) treatment groups.
382
DISCUSSION
A short course of azithromycin given once daily for 5 days was as effective, both clinically and bacteriologically, in the treatment of acute bronchitis, with or without underlying pulmonary disease, as amoxycillin given three times daily for 7 days or erythromycin given four times daily for 7 or 10 days. When patients with underlying illness were compared, azithromycin and erythromycin appeared to be equally efficacious. Azithromycin also appeared to have application in the treatment of pneumonia, although further studies using large patient groups are required. Amoxycillin, however, appeared to be less successful than azithromycin in the treatment of chronic obstructive pulmonary disease. Consistent with the results of previous tissue kinetic studies.t-" once-daily administration of azithromycin was sufficient to eradicate key respiratory tract pathogens. Overall, azithromycin treatment was associated, with a lower incidence of adverse events than comparator drugs. Gastrointestinal adverse events were the most frequently reported in all treatment groups. A higher incidence of dermal adverse events was reported in the amoxycillin treatment group in comparison with azithromycin and erythromycin. The trials included a complete spectrum of bronchitic patients with both chronic bronchitis and acute bronchitis. In the azithromycin/erythromycin study, however, 30 - 40% of patients were over 65 years of age in comparison with only 22 - 23% of patients in the azithromycin/amoxycillin study. As a consequence, there was a higher proportion of patients in the former study group with chronic bronchitis and underlying pulmonary disease. Azithromycin was shown to be an effective treatment in both patient groups. The simpler and shorter azithromycin treatment regimen appears to have achieved the same degree of control of acute bronchitis and other infections of the lower respiratory
Azithromycin, erythromycin and amoxycillin in lower respiratory tract infections
tract as standard regimens. A more convenient dosing regimen suggests there may be improved patient compliance in certain groups, notably elderly bronchitics. 9.
ACKNOWLEDGEMENT
The European Azithromycin Study Group acknowledge the assistance of Pfizer Central Research, Europe. REFERENCES 1. Fiese EF, Steffen SH: Comparison of the acid stability of azithromycin and erythromycin. J Antimicrob Chemother 1990; 25(suppl A): 3947. 2. Foulds G, Shephard RM, Johnson RB: The pharmacokinetics of azithromycin in human serum and tissues. J Antimicrob Chemother 1990; 25(suppl A): 73 - 82. 3. GladueRP,BrightGM,IsaacsonRE,etal:/nvitro and in vivo uptake of azithromycin (CP-62,993) by phagocytic cells: possible mechanism of delivery and release at sites of infection. Antimicrab Agents Chemother 1989; 33: 277 - 282. 4. Gladue RP, Snider ME: Intracellular accumulation of azithromycin by cultured human fibroblasts. Antimicrob Agents Chemother 1990; 34: 1056 -1060. 5. Baldwin DR, Wise R, Andrews JM, et al: Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J 1990; 3: 886 - 890. 6. Davies B, Maesen FPV, Gubbehnans R: Azithromycin (CP-62,993) in acute exacerbations of chronic bronchitis: an open clinical, microbiological and pharmacological study. J Antimicrob Chemother 1989; 23: 743 - 751. 7. Retsema J, Girard A, Schelkley W, et al: Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against Gramnegative organisms. Antimicrob Agents Chemother 1987; 31: 1939 - 1947. 8. Rylander M, Hallander HO: In vitro comparison
10.
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of the activity of doxycycline, tetracycline, erythromycin and a new macrolide, CP-62,933, agonist Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum. Scand J Infect Dis 1988; 53: 12 - 17. Fitzgeorge RB, Featherstone ASR, Baskerville A: Efficacy of azithromycin in the treatment of guinea pigs infected with Legionella pneumophila by aerosol. J Antimicrob Chemother 1990; 25: 101 - 108. Chirgwin K, Roblin PM, Hammerschlag MR. In vitro susceptibilities of Chlamydia pneumoniae (Chlamydia sp. strain TWAR). Antimicrob Agents Chemother 1989; 33: 1634 -1635. Fenelon LE, Mumtaz G, Ridgway: The in vitro antibiotic susceptibility of Chlamydia pneumoniae. J Antimicrob Chemother 1990; 26: 763 - 767. Dunkin KT, Jones S, Howard AJ: The in vitro activity of CP-62.993 against Haemophilus influenzae, Branhamella catarrhalis, staphylococci and streptococci. J Antimicrob Chemother 1988; 21: 405 - 411.
APPENDIX The following investigators took part in the azithromycin/erythromycin study: Dr. M. Austgen, Miinnerstadt, FRG; Dr H.M. Beumer, Utrecht, The Netherlands; Prof. B. Christoforov, Paris, France; Dr A. Clauzel, Montpellier, France; Prof. J. Dry, Paris, France; Dr C. Gillard, Jumet, Belgium; Dr E. Haringer, Munich, FRG; Dr M. De Jonghe, Jumet, Belgium; Dr B. Nuchel-Petersen, Hellerup, Denmark; Prof. A. Pradalier, Paris, France; Dr T. Prigogine, Brussels, Belgium; Dr N. Ringdal, Molde, Norway; Dr P. Royset, Troms, Norway; Prof. O. Wieser, Klagenfurt, Austria. The following investigators took part in the azithromycin/amoxycillin study: Dr P.G. Davey, Dundee, UK; Dr P. Himanen, Turku, Finland; Dr J. Hosie, Glasgow, UK; Dr F. Kerler, Wendelstein, FRG; Dr K. Kothny, Munich, FRG; D.E. Machiels, Ottignies, Belgium; Dr J. Nikoskelainen, Turku, Finland; Dr W. Petro, Bad Reichenhall, FRG; Dr U. Rustemeier, Essen, FRG.
383
