of Hospital Infection (1991) 19 (Supplement

Clarithromycin community-acquired

A), 21-27

in the treatment of lower respiratory tract infections G. Anderson


Chest Clinic,

129 Stow Hill,


Gwent NP9 4GA


Clarithromycin is a macrolide with in-vitro activity against the organisms usually responsible for community-acquired pneumonia and acute exacerbations of chronic bronchitis. Three double-blind controlled studies each in pneumonia and chronic bronchitis are reviewed. In pneumonia clarithromycin is as effective as erythromycin and in acute-on-chronic bronchitis is as effective as ampicillin. In an open study of 46 patients with pneumonia due to Legionella pneumophila, resolution occurred in 93% with no deaths. The incidence of adverse events was 20% in 3437 patients. These were rarely severe. Clarithromycin is better tolerated than erythromycin and its twice daily dosage is likely to lead to better patient compliance.

Keywords: Pneumonia;





Recent recognition of new agents in the causation of community-acquired and acute exacerbations of chronic bronchitis, such as pneumonia, Chlamydia, Legionella and Mycoplasma, and the increasing prevalence of (3-lactamase-producing microorganisms, have required a fresh approach to the use of antibiotics in these infections. Macrolides, such as erythromycin, are known to be effective against organisms causing ‘atypical pneumonia’ but a disadvantage has been their poor performance against Haemophilus influenzae which is an important cause of lower respiratory tract infections in the community. Clarithromycin offers several advantages over the older compounds. Compared with erythromycin it is better absorbed, better tolerated, penetrates well into lung tissue and has in-vitro activity against Streptococcus pneumoniae, H. injluenzae, Moraxella catarrhalis and Mycoplasma pneumoniae.‘m4 Methods

The data were made available by the manufacturers (Abbott Laboratories) from a series of international trials; these are preliminary results which are not yet published and the final assessment of the role of clarithromycin must await such publication. The studies which will be considered here are three 019556701/91/09.4021+07

0 1991 The Hospital






G. Anderson

pivotal studies, each of treatment of pneumonia and acute exacerbations of chronic bronchitis. All were double-blind controlled studies of courses of oral clarithromycin 2.50 mg bd against an oral reference drug. In pneumonia the duration of treatment was 14 days and in acute-on-chronic bronchitis 7-14 days. For both diseases the diagnosis was based on a full medical history and examination. Entry into the study required that patients were considered by the clinician to be suitable for treatment at home with an oral antibiotic. The sputum was cultured before treatment commenced and antibiotic sensitivities of any respiratory pathogens were determined to clarithromycin and the reference drug. Measurements were made of haemoglobin, total and differential leucocyte count, blood urea, creatinine, aspartate transaminase, alanine transaminase, alkaline phosphatase, bilirubin and albumin. For patients in the pneumonia studies blood complement fixation titres were carried out for M. pneumoniae and C. pneumoniae (TWAR). In the pneumonia studies the diagnosis had to be confirmed radiologically within 24 h of trial entry. For patients with bronchitis a chest radiograph was performed only if pneumonia or some other chest disease was suspected or if the patient had not had a chest X-ray within the last 12 months. Patients were reassessed within 48 h of the last drug dose, when an enquiry of symptoms and possible side effects was made, physical examination repeated, drug compliance was measured and the various laboratory tests and chest radiographs (in the pneumonia studies) were repeated. Patients with pneumonia whose symptoms, signs and radiographs had not completely resolved were re-evaluated 6-8 weeks after starting treatment, and in patients with chronic bronchitis at 10-18 days after completing treatment. Patients were assessed as clinically cured if, in pneumonia, symptoms and signs had resolved or, in bronchitis, returned to baseline. They were recorded as clinically improved when symptoms and signs had improved but not resolved. In pneumonia, radiographic cure was recorded when the chest radiograph became normal and radiographic improvement when it was less abnormal than before treatment. Clinical and radiographic success was assessed by summating cure and improvement. In order to be evaluable patients were required to take at least 70% of the prescribed treatment and in the patients with chronic bronchitis only, were required to have pathogens isolated from the sputum culture before treatment. Results

Pneumonia There have been 12 trials of clarithromycin in community-acquired pneumonia. Two were open studies. The remaining ten were comparative and five were double-blind but numbers were relatively small in two of them and this review will describe the remaining three.


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Details of these three pneumonia studies are shown in Table I. In study M88-248,5 for evaluable patients there were no differences between treatments in clinical or radiological success rates but when analysed by intention to treat there was a clinical cure at 2 weeks in 45% in patients receiving clarithromycin compared to 25% in the erythromycin stearate in the symptom of cough was group (P = O-003) while improvement observed in 97% of patients receiving clarithromycin and 80% receiving erythromycin stearate (P=O*O7). When the data for the three trials were combined there were no significant differences between the treatment groups in age, sex, race, severity of the illness or number of respiratory tract infections within the last year. The response to treatment for evaluable patients is shown in Table II. Clarithromycin and the comparator drugs were both equally effective in achieving clinical and radiographic cure and success in eliminating The relatively low rate of radiological pathogens from the sputum. resolution is not surprising and reflects the usual delay in radiological

I. Summary


of clinical

studies comparing the use of clarithromycin erythromycin in the treatment of pneumonia

No. of patients




250 mg bd and drug




Erythromycin 250 mg qds





Erythromycin 500 mg qds



Erythromycin 500 mg qds







still recruiting



and interim results are given.

Clinical and radiological response in controlled pneumonia studies of clarithromycin therapy

Clinical cure rate Clinical success rate* Bacteriological cure rate Radiographic cure rate Radiographic success rate$ Radiographic cure rate at follow-up Radiographic success rate at follow-ups



62% 97% 89% 50% 88% 85% 95%

55% 96% 95% 65% 97% 79% 95%

* Clinical success defined as cure or improvement. t One patient had an indeterminate clinical response. $ Radiographic success defined as resolution or improvement. lj Persistence of H. infIuenzae in 3 patients. 5 Persistence of S. pneamoniae in 1 patient.

(75/121) (117/121) (25/28t)l (21/42) (37/42) (80/94) (89/94)

(54/99?) (94/99t) (18/19$) (22/34) (33/34) (63/80) (77/80)

G. Anderson


improvement after the symptoms and signs of pneumonia have cleared. There were more isolates of H. in&enzae in the clarithromycin group (15 vs 8). The in-vitro sensitivities of organisms isolated before treatment for all .patients entering the study are shown in Table III. Clarithromycin showed good in-vitro activity against the bacterial pathogens frequently responsible for community-acquired pneumonia. Analysis of clinical effectiveness on an intention to treat basis (excluding indeterminate responses) revealed clinical and 69/157 (44%) for cure rates of 89/159 (56%) f or clarithromycin erythromycin with a clinical success rate of 152/159 (96%) for clarithromycin and 1.5l/l 57 (96%) for erythromycin. Patients with positive serological evidence of pneumonia due to M. pneumoniae and C. pneumoniae (TWAR). Twenty-two clinically evaluable patients treated with clarithromycin and 13 with erythromycin had positive serological evidence of infection by M. pneumoniae or cure rate was 18/22 (82%) for C. pneumoniae (TWAR). Th e clinical at the last evaluation. clarithromycin and 12/13 (92%) f or erythromycin The corresponding radiographic success rates were 18/22 (82%) for clarithromycin and 13/l 3 (100%) for erythromycin. In summary clarithromycin has been assessed in three well-controlled studies in community-acquired pneumonia. These preliminary results suggest that clinically, bacteriologically and radiologically clarithromycin was at least as effective as erythromycin and in one study may have been more effective.’ Clarithromycin in pneumonia due to L. pneumophila. In an open uncontrolled trial clarithromycin was given to 46 patients with legionella Forty-four had previously been treated unsuccessfully with pneumonias. other antibiotics and seven had received erythromycin. Infection status was Table


Summary of clinical studies evaluating the use of clarithromycin Sensitivities of bacteria isolated before treatment (all patients) Clarithromycin


in pneumonia. Erythromycin

H. infEuenzae Number Full or intermediate Resistant


42 (481%) 4 (9%)


35 (13050%) 0

S. pneumoniae Number Full or intermediate Resistant

M. catarrhalis Number Full or intermediate Resistant


H. parainfIuen.zae Number Full or intermediate Resistant


32 ;A%) 3 (8%)


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considered to be ‘severe’ in 32 patients. The doses of clarithromycin ranged from 500 to 1OOOmg bd, based on the severity of infection. The mean duration of therapy was 27 days. The results are summarized in Table IV and clinical cure was claimed in 98% with a high level of radiographic improvement. None of the patients died and in the 40 patients where it was measured, the direct antigen fluorescent test for Legionella became negative after treatment. Acute exacerbations of chronic bronchitis In the 11 clinical trials reported so far, clarithromycin was given to 708 patients and the reference drug ampicillin to 539. Three of these trials were double-blind and randomized (Table V). Taking the studies together there were no significant demographic differences between treatment groups in age, sex, race or type of underlying pulmonary disease. The response to treatment is shown in Table VI. The commonest reason for Table



of clarithromycin

4:,44 (100%) 28/30 (93%)

V. Summary of clinical studies comparing the eficacy of clarithromycin 250 mg bd and ampicillin 250 mg qds in the treatment of acute-on-chronic bronchitis No. of patients

Study M87-076 M88-152* M87-003

225 157 125





46 44 43 1 12 14 4

Number of patients Evaluable Clinical cure Clinical improvment Radiographic cure Radiographic improvement Chest X-ray unchanged No X-ray done Clinical success Radiographic success


in legionella

still recruiting

Country USA USA Australia/Canada/S.


and interim results are given.

Table VI. The results mycin and ampicillin

of clinical studies comparing the eficacy of clarithroin the treatment of acute-on-chronic bronchitis

Treatment Number entering study Evaluable patients Clinical cure Clinical success Bacteriological cure rate

Clarithromycin 250 mg bd 247 E:: (79%) 80 (94%) 72 (85%)

Ampicillin 250 mg 6 hourly 260 :: (75%) 74 (93%) 75 (94%)


G. Anderson

Table VII. Summary of clinical studies evaluating the eficacy of clarithromycin and ampicillin in the treatment of acute-on-chronic bronchitis. Sensitivities of all bacteria isolated before treatment in both evaluable and non-evaluable patients Clarithromycin

Pathogen H. injluenzae Number Full or intermediate Resistant


S. pneumoniae Number Full or intermediate Resistant


M. catarrhalis Number Full or intermediate Resistant H. parainjluenzae Number Full or intermediate Resistant S. aureus Number Full or intermediate Resistant


:; (98%) 1 (2%)


i: (94%) 2 (6%)


i79 (95%) 2 (5%)


52 16 (31%) 36 (69%)

39 6 (15%) 33 (85%)

non-evaluability was failure to isolate a specific pathogen from sputum taken before treatment (clarithromycin 85 patients, ampicillin 87 patients). Clarithromycin and ampicillin were both effective in producing clinical and bacteriological improvement. The in-vitro sensitivities of the pathogens cultured are shown in Table VII. Clarithromycin was more active than ampicillin against M. catarrhalis, H. parainjluenxae and Staphylococcus

aureus. Evaluation of all patients (intention to treat analysis) excluding those with indeterminate responses revealed for clarithromycin a clinical cure rate of 108/220 (49%) and a clinical success rate of 187/220 (85%) and for ampicillin rates of 112/234 (48%) and 210/234 (90%), respectively. Adverse


Clarithromycin has been given to 3437 patients in phase II or III studies and the adverse effects found using the COSTART dictionary6 are shown in Table VIII. Of the 20% experiencing adverse effects the investigator considered them unrelated to clarithromycin in 46%, to be mild or moderate in 18% and severe in 1%. In one of the pneumonia studies’ the mean duration of therapy with clarithromycin was 13 days and with erythromycin stearate 10 days

Treatment Table



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Adverse effects of clarithromycin patients in phase II or III studies



in 3437

% Of patients

Digestive Body as a whole Metabolic/nutritional Nervous Skin/appendages Special senses Blood/lymphatic Cardiovascular Respiratory Urogenital Musculoskeletal

11 4 2 ; 2 1 : 1

Clarithromycin in the treatment of community-acquired lower respiratory tract infections.

Clarithromycin is a macrolide with in-vitro activity against the organisms usually responsible for community-acquired pneumonia and acute exacerbation...
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