Drug Investigation 6 (Suppl. 1): 35-42, 1993 0114-2402/93/0100-00351$4.00/0 © Adis International Limited. All rights reserved. DISUP3651

Clinical Efficacy and Place of Spiramycin in the Treatment of Acute Respiratory Tract Infections Claude Carbon Service de Medecine Interne, Bichat - Claude Bernard University Hospital, Paris, France

Summary

Spiramycin exhibits comparable in vitro efficacy to erythromycin, with a good level of in vitro activity against intracellular pathogens responsible for community-acquired pneumonia. Data from a small number of clinical trials suggest that it may provide an alternative to erythromycin, especially in those infections caused by intracellular pathogens (Mycoplasma, Legionella and Chlamydia). The pharmacokinetic properties and good tolerability of spiramycin are a potential advantage in the treatment of some community-acquired pneumonias. Further extensive comparative studies are necessary to better delineate the use of spiramycin in these indications. As with other macrolides, increasing resistance among group A streptococci, Streptococcus pneumoniae and Haemophilus injluenzae limits the' use of spiramycin as first-line therapy for acute otitis media, sinusitis or community-acquired pneumonia in some areas.

1. Clinical Aspects and Pathoaetiology of Acute Respiratory Tract Infections 1.1 Pharyngitis and Tonsillitis

Although viruses are the main cause of these diseases, together with various streptococci and other bacteria, group A ~-haemolytic streptococci remain the main target of therapy because of their involvement in early suppurative and late immunological complications. These pathogens are involved in about 30% of cases, the majority of which occur in children between 5 and 8 years of age. Group A ~-haemolytic streptococci cannot be diagnosed accurately on clinical grounds, and a positive culture from a throat swab specimen is necessary. The rapid diagnostic methods based on the detection of streptococcal antigen are still of rather limited interest, as their sensitivity ranges from 60 to 95%; confirmation of negative tests by culture is therefore necessary. Group A streptococci are

usually susceptible to macrolides, particularly the 14-membered compounds (Acar & Goldstein 1993). However, resistance to erythromycin is currently being reported in several countries, reflecting wide use of macrolides in the community. A recent study from Finland (Seppala et al. 1992) reported an alarming and drastic increase in the incidence of . macrolide-resistant group A strepto.:occ; ;~rom 4% in 1988 to 24% in 1990). This suggests that the usual therapeutic practice of using macrolides in place of penicillin in penicillin-allergic patients may not be advisable. 1.2 Acute Otitis Media Acute otitis media (AOM) is a frequenCdisorder in children between 6 to 24 months of age. Although it has traditionally been diagnosed on the basis of clinical suspicion confirmed by otoscopy, several methods have substantially improved the

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diagnosis of ear effusion: pneumatic otoscopy, tympanometry and acoustic reflectometry. The pathogens involved in AOM.· as found in several studies by needle aspiration of ear fluid. are Streptococccus pneumoniae, Haemophilus inJluenzae (20 to 30% of cases ;90% nontypable. 10% group b; 20 to 30% (3-lactamase-producing) and Moraxe/la catarrhalis (50 to 90% (3-lactamase-producing). Other pathogens that may be involved include viruses. Mycoplasma and. in infants. Chlamydia trachomatis. Against erythromycin-susceptible pathogens, spiramycin exhibits a pattern of in vitro efficacy close to that of erythromycin (Acar & Goldstein 1993), with MIC90 values of 16 mg/L against H. influenzae, and an MIC range of 0.06 to 0.12 against erythromycin-susceptible S. pneumoniae and of I to 4 mg/L against M. catarrhalis. However, it has to be noted that the frequency of resistance to macrolides among H. injluenzae and pneumococci is increasing in several countries (Geslin et al. 1992). These organisms are also resistant to spiramycin. Macrolides are no longer considered as first-line therapy for AOM because of the resistance patterns of the main causative pathogens and also some pharmacokinetic considerations, mainly relating to erythromycin (limited intestinal absorption and low levels achieved in the middle ear). 1.3 Sinusitis

Acute sinusitis is a common disorder in children and adults. Early diagnosis is required to allow prompt management and avoid life-threatening complications, such as brain abscess or septicaemia. The precise microbial aetiology is determined by direct aspiration of the sinus, although alternative, less invasive techniques are currently being investigated. S. pneumoniae (20 to 35%) and noncapsulated H. injluenzae (6 to 26%) are the main pathogens, while M. catarrhalis, Staphylococcus aureus or anaerobes are less frequently involved. Macrolides as monotherapy are not considered as a first-line choice in sinusitis, for the reasons already stated in section 1.2.

1.4 Bronchitis It is important to distinguish acute infection occurring in otherwise healthy persons from acute infectious exacerbations of chronic disorders of the bronchial tree.

1.4.1 Acute Bronchitis Acute bronchitis is an inflammatory condition of the bronchial tree associated with an infectious process. Generally, acute bronchitis occurs in winter, as do most acute respiratory tract infections. The main aetiological agents are viruses: influenza and parainfluenza, adenovirus, rhinovirus, coronavirus, respiratory syncytial virus and coxsackie virus (A21). Mycoplasma pneumoniae, Bordetella pertussis and C pneumoniae are the main non viral aetiological agents. The role of S. pneumoniae and H. injluenzae is difficult to assess because these pathogens are residents of the upper respiratory tract of normal individuals, and the role of secondary bacterial invasion is not well documented (Ellner 1988). Attacks of acute bronchitis may be exacerbated by cigarette smoking or exposure to fumes. Treatment of acute bronchitis in otherwise healthy patients requires symptomatic measures, mainly for cough relief, reduction offever and prevention of drying of bronchial secretions. Antibacterial therapy is not indicated. 1.4.2 Acute Exacerbations of Chronic Bronchitis Chronic bronchitis is usually diagnosed in patients who have coughed up sputum on most days during at least 3 consecutive months for more than 2 consecutive years, unless asthma, bronchiectasis or tuberculosis is present. Emphysema often complicates the clinical presentation and the 2 diagnoses are usually lumped together. The causes of chronic bronchitis are not completely elucidated, although cigarette smoking, exposure to fumes and dust in the environment and infection have been implicated as major factors. Infection is not the sole factor involved in acute exacerbations of chronic bronchitis (Bates 1982;

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Spiramycin in Respiratory Tract Infections

Chodosh 1991). This has been clearly established by Fagon et al. (1990), who investigated 54 patients with acute episodes who had been receiving mechanical ventilation because of hypercapnic respiratory failure. Cultures of protected brush specimens demonstrated no pathogen growth in 50% of patients; however, fever was significantly more frequent in patients with infection. Mortality rates, duration of mechanical ventilation and hospitalisation were not significantly different between patients with bronchial microflora treated with appropriate antimicrobial therapy and patients without bronchial microflora who were or were not receiving empirical treatment. Chronic colonisation of the airways with pneumococci and noncapsulated strains of H. injluenzae occurs in at least 50% of affected patients. Other bacteria such as haemolytic species of streptococci, S. aureus and Gram-negative bacilli are less frequent (5 to 10% of cases), and M. pneumoniae can be identified in sporadic cases. Viruses are also frequent causes of seasonal infections. The only way to adequately identify causative bacteria in acute episodes is to use protected brush fiberoptic bronchoscopy, in order to avoid any contamination by bacteria present in the upper airways. Obviously, this invasive investigation is not appropriate in the majority of cases. If the aetiology is unknown, empirical antibacterial therapy is justified. Several other techniques can be used in order to identify aetiological microorganisms. Sputum examination with Gram stain and subsequent quantitative culture can be considered as valid only if less than 10 squamous cells and more than 25 leucocytes are seen per low-power field. More than 10 5 to 107 colony-forming units (CFU)/ml are required on culture to incriminate the pathogen. For samples obtained by bronchoscopic protected brush, 103 CFU /brush are enough for diagnosis (Fagon et al. 1990). The appropriate investigation depends on the severity of the clinical presentation; severe episodes may require invasive investigations. In addition, the failure of an initial empirical therapy mandates microbiological tests so that the therapeutic regimen can be modified as soon as possible.

The effectiveness of antibacterial therapy in acute exacerbations of chronic bronchitis has been a matter for prolonged debate in the literature. It is difficult to perform clinical trials in this indication, and very few trials fulfil the optimal criteria for allowing valid conclusions regarding the efficacy of a treatment over either placebo or alternative treatments. However, there is general agreement on the usefulness of antibacterial therapy in acute exacerbations of chronic bronchitis, since infection is probably the main cause of decompensation and the most common cause of death among those patients. Moreover, antibacterial therapy appeared to decrease the incidence of morbidity and shorten the time missed from work (Anthonisen et al. 1987; Chodosh 1991; Nicotra et al. 1982). Several comparative studies failed to demonstrate the superiority of one regimen vs another. In nonsevere cases, the patient may be treated at home. Oral antibacterial therapy should be started, on the basis of what is known about the current susceptibility profile of aetiological organisms. The chosen compound must be well tolerated, cheap and convenient to administer, and preferably have a low dosing frequency. Tetracyclines and macrolides have been shown to be effective in this indication. However, their efficacy can be limited by the emergence of resistance of both S. pneumoniae and H. injluenzae. Ampicillin (or amoxicillin) has been extensively prescribed; a 7- to IO-day course of treatment is usually given. In case of failure of initial therapy with a iJ-Iactam, the use of a macrolide can be considered in order to cover possible Mycoplasma infection. In severe cases, hospitalisation is required so that supportive therapy, such as intravenous hydration and supportive respiratory measures, can also be given. Investigative tests that should be carried out include chest x-ray, blood gas monitoring, and invasive search for aetiological agents. The place of macrolides as first-line choice in these cases is very limited. 1.5 Pneumonia Infectious pneumonia is still a leading cause of death due to infection in some populations, such as the elderly. Clinical manifestations of pneu-

38

monia may be subtle and sometimes confusing, depending on the age of the patient, the aetiology of infection and whether underlying disease is present. The aetiological agents vary according to (i) the type of host (otherwise healthy patients vs patients with underlying immunosuppressive disease, alcoholism, etc), (ii) the source of infection (pneumonia acquired in the community, during hospital care or in a nursing home), (iii) the clinical presentation (acute symptomatology; infection occurring during an epidemic; coexisting extrapulmonary symptoms suggesting a particular organism such as Legionella). The radiographic pattern is not specific for any single agent. The search for an aetiology may be more difficult in elderly than in young patients: a pathogen was identified in only 30% of patients aged> 65 years, vs 54% in younger adults, in the study by Marrie et al. (1985). Because of the mortality risk associated with pneumonia, particularly when treatment is delayed, empirical therapy should cover the most likely pathogens. The decision about whether to perform invasive investigations is made mainly on the basis of signs of severity, risk of unusual causative pathogens (i.e. opportunistic), or the interpretation of clinical failure after initial empirical therapy. Sputum examination is simple and safe, as previously discussed. Examination of Gramstained bacterial flora may assist in diagnosis. Blood cultures are positive in about 10 to 15% of cases and do not contribute to diagnosis and early management (Levy et al. 1988). Pleural aspiration may help to identify the pathogen and to decide whether drainage is necessary. The protected brush specimen technique has been established as the reference technique. Additionally, the use ofbronchoalveolar lavage has recently been suggested to be of value in establishing the diagnosis of nosocomial pneumonia (Chastre et al. 1989). Microscopic identification of bacteria within cells recovered by lavage may provide a sensitive and specific means of early and rapid diagnosis. In community-acquired pneumonia, the main pathogens may differ according to the locale. Table I shows the main agents identified in 3 recent studies performed in hospitalised patients with com-

Drug Invest. 6 (Suppl. I) 1993

munity-acquired pneumonia. S. pneumoniae and H. injluenzae were the main pathogens. In con-

trast, studies performed in general practice indicate that about 25% of patients are infected with intracellular pathogens: C. pneumoniae. M. pneumoniae. Coxiella burnetii and, less frequently, Legionella pneumoniae (Erard et al. 1991; Marston et al. 1991). Spiramycin exhibits similar in vitro activity to the other macrolides against intracellular pathogens, especially against C. trachomatis and L. pneumophila (Bornstein et al. 1985; Bryskier 1992). Once the diagnosis of community-acquired pneumonia is suggested, the problem is to decide whether hospitalisation is necessary. Five predisposing factors for a complicated course of the disease have been identified by Fine et al. (1990) in a prospective cohort study of community-acquired pneumonia. The odds ratio for age> 65 years was 2.7, for comorbid illness, 3.2; for temperature more than 38°-3C, 4.1; for immunosuppression, 12.0; and for a high risk aetiology (staphylococci, Gram-negative bacilli, aspiration and postobstructive pneumonia), 23.3. Antibacterial therapy should be started promptly, and should be selected with regard to the most likely pathogens, their known susceptibility to antibacterials, ease of administration, tolerability, and potential drug interactions with current medications taken by the patient. In patients treated outside the hospital. initial therapy with amoxicillin/clavulanic acid at a dose of Ig 3 times daily is recommended in areas where the frequency of resistance of S. pneumoniae and H. injluenzae to erythromycin is high. In other places, a macrolide can be used as a first-line choice for the treatment of outpatients with communityacquired pneumonia. In cases requiring hospitalisation, a combination of ampicillin (or amoxicillin) or a cephalosporin with either an intravenous macrolide or a fluoroquinolone to cover Legionella may be recommended. The antibacterial spectrum of macrolides does not include the microorganisms involved in nosocomial pneumonia, except L. pneumophila. Therefore, their use is envisaged only in combin-

39

Spiramycin in Respiratory Tract Infections

Table I. Causative pathogens in community-acquired pneumonia in 4 recent studies Pathogens

Patients with pathogen isolated (%) Fang et al. (1990)

Karalus et al. (1991)

Burman et al. (1991)

In

In

In

= 359)

= 92]

= 196)

Potgieter and Hammond (1992) In

Streptococcus pneumoniae Haemophilus influenzae Mycoplasma pneumoniae Influenza viruses Legionella spp. Chlamydia pneumoniae Moraxella catarrhalis Aerobic Gram-negative bacilli Staphylococcus aureus Others Unknown

15

34

32

11

5

30 13

7

5 20 10 4

9 9 2

5

6 1

0

2 0

6 3 16 33

= 95)

1

1 13

5 3 3 28

ation therapy with other compounds when legionellosis is suspected (Carbon & Rubinstein 1993).

2. Evaluation of Spiramycin in Respiratory Tract Infections (Excluding Atypical Pneumonia) 2.1 Bacterial Tonsillitis Manolopoulos et al. (1989) compared spiramycin (lg twice daily) and phenoxymethylpenicillin (I MU 3 times daily) in the treatment of 55 patients with acute bacterial tonsillitis. The most frequently isolated pathogens were streptococci, about one-third of which were group A iJ-haemolytic streptococci. There was one clinical failure among the patients treated with penicillin, and none in the spiramycin group. No adverse effects were reported in either group. 2.2 Sinusitis The clinical and bacteriological efficacy and safety of spiramycin and doxycycline were compared in a randomised study in adult patients with acute sinusitis. Sinusitis was confirmed by clouding of the nasal sinuses at x-ray examination and a positive pre therapy culture in a sample taken by aspiration as near the ostium of the sinus as pos-

18 36

8 3 23

sible (Boezeman et al. 1988). Spiramycin Ig twice daily was given for 10 days, and doxycycline was adminis.tered as a single daily dose of 200mg on day I, followed by 100 mg/day for the remainder of the course. 33 patients were enrolled (15 treated with spiramycin, 18 with doxycycline) and 27 were evaluated. Nine patients were cured in each group, while 3 and 5 patients, respectively, were clinical failures. It is difficult to draw any conclusions from this very small number of patients. 2.3 Lower Respiratory Tract Infections A double-blind randomised multicentre trial involving 23 centres was carried out in general practice to compare spiramycin and doxycycline in patients suffering from pneumonia or acute exacerbations of chronic bronchitis (Biermann et al. 1988). Spiramycin 3MU 3 times daily was administered on day I, followed by 3MU twice daily for 4.5 days (total duration of treatment 5.5 days); a single dose of doxycycline 200mg was given on the first day, followed by iOOmg for 8 days (total duration 9 days). Efficacy of treatment was evaluated on clinical symptoms and patients' evaluation on a visual analogue scale. Among the 221 patients enrolled (mean age 49 years), 91 in the spiramycin group and 100 in the doxycycline group were ev-

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aluable for efficacy. There was no difference between the 2 treatment groups in terms of cure rate (82 vs 80%) and patients' evaluation, or in the incidence of adverse effects (21 of 91 vs 21 of 100, mainly relating to the gastrointestinal tract). 2.4 Lower Respiratory Tract Infections in Elderly Patients Spiramycin and erythromycin were compared in the treatment of lower respiratory tract infections in 198 outpatients and institutionalised elderly patients (mean age 61.7 years), in an open randomised trial (De Cock & Poels 1988). Spiramycin (lg given in 2 daily doses) was administered to 97 patients (44 males, 53 females) and erythromycin (either as Ig twice daily or 500mg 3 times daily) to 101 patients (55 males, 46 females). Bronchitis was diagnosed in 155 patients, 96 of whom had acute exacerbations of chronic bronchitis, 26 with bronchopneumonia, and 17 with pneumonia. Both groups were comparable for diagnosis, fever, general condition, and presence of purulent sputum. Overall, 76.3% of patients treated with spiramycin vs 63.4% of patients treated with erythromycin were cured. 6.2 vs 17.8% of the patients in the 2 groups, respectively, did not benefit from antibacterial therapy. These between-group differences were significant (p < 0.05). Treatment was prematurely withdrawn in 4 patients treated with spiramycin (all because of inefficacy); in the erythromycin group, 13 patients discontinued therapy because of inefficacy (n = 2), adverse effects (n = 9) or both (n = 2) [p < 0.05]. Adverse effects were mostly of gastrointestinal origin, and were significantly more frequent in the erythromycin group (47 of 99 patients vs II of 93 with spiramycin).

3. Efficacy in Atypical Pneumonia 3.1 Preclinical Studies In guinea-pigs infected with Legionella spp. via an aerosol, spiramycin 150 mg/kg achieved a survival rate of 100% at I X the lethal dose for 50% of the group (LDso), and 87.5% at 10 X the LDso, with both prophylactic and therapeutic regimens.

The pI:Ophylactic efficacy of spiramycin appeared to be superior to that of erythromycin (Nowicki et al. 1988). Spiramycin (30 mg/kg/day intraperitoneally at 48, 54 and 72 hours after bacterial challenge) and erythromycin lactobionate (administered in a similar regimen) appeared to provide similar protection in a guinea-pig model of severe legionellosis serogroup I after intraperitoneal injection (Dournon & Rajagopalan 1988). All infected untreated animals died within 4 days of infection, vs 45.5% of spiramycin- and 50% of erythromycin-treated animals. Spiramycin, injected subcutaneously at a 50 mg! kg dose, 24 and 48 hours after intraperitoneal challenge with C. psittaci (LDso) achieved a 100% recovery rate in mice, vs a 100% mortality within 3 weeks among untreated animals. The livers of mice recovering after therapy showed significantly fewer chlamydial antigens than controls (Orfila et al. 1988). 3.2 Clinical Studies Large prospective randomised studies comparing the efficacy of antibacterials in the treatment of pneumonia caused by intracellular pathogens are lacking for at least 2 reasons: these infections are rare and difficult to diagnose within a reasonable period of time. It is therefore necessary to discuss retrospectively the results of some multicentre studies, or to analyse the response to therapy in small open noncomparative trials. Intravenous spiramycin has been evaluated in the treatment of severe legionellosis in immunocompromised or otherwise healthy patients (Mayaud et al. 1988). 10 patients were treated in the same intensive care unit for pneumonia caused by L. pneumophila serogroup I, diagnosed by direct fluorescence (n = 3), positive culture (n = 2) and/ or seroconversion (n = 9). Seven patients were immunosuppressed, the remaining 3 being heavy smokers and/or alcoholics. All had consistent radiographic findings. All patients received spiramycin intravenously at a dose of 3MU 3 times daily for at least 8 days followed by the same dose given orally. All patients became afebrile within 4 days,

41

Spiramycin in Respiratory Tract Infections

and 7 patients recovered completely. Three deaths were observed, related to very severe underlying disease, but in 2 of these cases postmortem examination failed to demonstrate persistence of L. pneumophila in the lungs. In another study (Vachon & Kernbaum 1986), spiramycin cured 18 of 18 patients with pneumonia caused by M. pneulI1oniae, 13 of 14 with legionellosis, 16 of 16 with chlamydial infections and I with pneumonia caused by C burnetii. Although the number of cases was small, these results appear to be comparable to those obtained with other macrolides. Treatment was well tolerated.

4. Conclusions Spiramycin exhibits similar antimicrobial properties to the other macrolides. Its pharmacokinetic properties, namely the high intracellular concentrations achieved and its long intracellular elimination half-life, together with its good tolerability, make it an interesting alternative to the other macrolides in the treatment of acute respiratory tract infection. In community-acquired pneumonia not requiring hospitalisation, and in areas where pneumococci and H. influenzae exhibit low resistance to macrolides, spiramycin may represent a good choice as first-line therapy. This is also the case with regard to the treatment of acute exacerbations of chronic bronchitis. In other epidemiological situations, macrolides alone are not suitable for firstline therapy of community-acquired pneumonia. It must be emphasised that clinical experience with spiramycin in the treatment of these infections remains limited. There is good evidence for the efficacy of this compound against intracellular pathogens responsible for acute pneumonia. The parenteral form of the compound can be used for initial therapy in acute, and even severe, infections. Spiramycin can be used in conjunction with a iJ-lactam in severe community-acquired pneumonia, in order to broaden the antibacterial coverage, although clinical experience in this situation is limited. The recommended dose in adults is 2 to 3MU 2 to 3 times daily for the oral form. The intraven-

ous formulation can be administered at a dose of 1.5 to 3MU, every 8 hours, as a I-hour infusion. Spiramycin and other macrolides are not recommended for the treatment of AOM or sinusitis as first-line choice in patients who cannot tolerate penicillin, but can be used as an alternative to penicillin in streptococcal pharyngitis in areas where the resistance rate to macrolides remains low. Additional studies assessing the cost/advantages and benefits of spiramycin in comparison with the other macrolides are warranted.

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Correspondence and reprints: Prof. Claude Carbon. Service de Mooecine Interne, Bichat - Claude Bernard University Hospital, 46, rue Henri Huchard,·75877 Paris Cedex 18, France.