Macrolide antibiotics in respiratory diseases. Recommendations of the Polish Expert Group — AD 2015

Andrzej Emeryk1, Henryk Mazurek2, Michał Pirożyński3, Janusz Klatka4, Wojciech Służewski5, Adam Antczak6, Małgorzata Bartkowiak-Emeryk7, Magdalena Kowalska1, Agata Dutkowska6

1Clinic of Lung Disease and Pediatric Rheumatology, Medical University, Lublin, Poland

2Department of Pneumonology and Cystic Fibrosis, National of Tuberculosis and Lung Diseases Research Institute, Rabka, Poland

3Department of Allergology, Centre of Postgraduate Medical Education, Warsaw, Poland

4Department and Clinic of Otolaryngology and Laryngological Oncology, Medical University, Lublin, Poland

5Clinic of Infectious Disease and Child Neurology, Medical University, Poznań, Poland

6Clinic of Pulmonology and Pulmonary Oncology, Medical University, Łódź, Poland

7Department and Clinic of Clinical Immunology, Medical University, Lublin, Poland

 

 

Macrolide antibiotics in respiratory diseases. Recommendations of the Polish Expert Group — AD 2015

The authors declare no financial disclosure

 

 

Table of contents:

1. Introduction

2. Macrolide antibiotics — general characteristic

3. Macrolides in upper respiratory tract infections in children

4. Macrolides in upper respiratory tract infections in adult

5. Macrolides in lower respiratory tract infections in children

6. Macrolides in lower respiratory tract infections in children

7. Macrolides in chronic obstructive pulmonary disease (COPD)

8. Macrolides in asthma

9. Macrolides in cystic fibrosis (CF)

10. Macroilides in bronchiectases of non-CF etiology, including primary ciliary dyskinesia (PCD)

11. Macrolides in pertussis

12. Macrolides in respiratory tract infections caused by non-tuberculous mycobakteria (NTM) in adults

 

1. Introduction

Together with beta-lactams, macrolides are the most frequently used group of antibiotics, especially in ambulatory care setting [1]. Therapeutic effectiveness of macrolide antibiotics and prevention against drug-resistance depend on their appropriate usage, based on rational, current recommendations.

These recommendations are based on following conditions:

— new publications, with better methodology, regarding effectiveness of different macrolides in already known indications for this group of antibiotics, e.g. infectious diseases of respiratory tract;

— new indications for macrolides in infectious and non-infectious diseases of respiratory tract;

— development of new macrolide antibiotics;

— new data about safety of macrolides.

Additionally, there is already 5 years, since the polish recommendations of using of antibiotics (including macrolides) in non-hospital (community-acquired) respiratory tract infections were evolved by group of specialists of National Program of Antibiotics Protection (Narodowego Programu Ochrony Antybiotyków) and published in 2010 [2]. Additional important reason was a lack of current polish guidelines regarding place of macrolides in therapy of respiratory tract in hospitalized patients (pediatric as well as adult population).

The committee evolving the Recommendations consisted of specialists in pneumonology, allergology and laryngology, including pediatricians and internists from several clinical sites in Poland.

Presented Recommendations pertain to using of macrolides in patients with infectious or non-infectious diseases of respiratory tract, treated in outpatients’ clinic as well as in hospital setting. Recommendations were based on analysis over 1450 original papers, meta-analyses or reviews regarding macrolides, published between 01. of January 1980 and 01. of September 2015, available through PubMed literature database. Single, clinically important publications from previous years or publications from other literature databases were also considered.

Guidelines included into Recommendations were supported by the categorization, resulting from analysis of studies’ results based on Evidence Based Medicine (EBM) [3]. Some of recommendations are supported by systemic review of publications (where available), which results in the most credible way justify making of therapeutic decision [4]. Results of meta-analyses, recommendations of scientific societies and experts groups (including Polish) were also considered, introducing the categorizations according to strength and quality of evidence.

Categorization of evidence is based on analysis of evidence supporting particular suggestion of management (Table 1). On the contrary, the strength of recommendations reflects the effectiveness, with which this recommendation could beneficially influence the clinical states of patient. The recommendations type A have the highest strength and type D — the weakest.

 

Table 1. Categorization of recommendations [5, 6]

Categories of evidence

Strengh of guidelines (recommendations)

Ia — evidence based on meta-analysis of randomized controlled trials

Ib — evidence based on at least one randomized controlled trial

IIa — evidence based on at least one controlled trial without randomization

IIb — evidence based on at least one experimental trial of other type

III — evidence based on non-experimental descriptive trials, like comparative, correlative or case-control study

IV — evidence based on reports or experts’ opinions or clinical experience or both

A — directly based on evidence of category I

B — directly based on evidence of category II or recommendations extrapolated from evidence of category I

C — directly based on evidence of category III or recommendations extrapolated from evidence of category I or II

D — directly based on evidence of category IV or recommendations extrapolated from evidence of category I, II or III

 

Recommendations A presents the recommendations directly based on randomized, controlled clinical trials (categories of evidence Ia and Ib). Weaker recommendation (B) results from observational studies or other types of experimental trials (categories of evidence IIa and IIb) or recommendations extrapolated from evidence category I. Much weaker recommendations (C) are based either on single case-reports, comparative or correlation studies (categories of evidence III) or recommendations extrapolated from evidence category I or II. The weakest recommendations (D) are directly based on categories of evidence IV, e.g. evidence from opinions of experts committee or clinical authorities or both or recommendations extrapolated from evidence category I, II or III [7]. The recommendations could be either positive or negative [additional sign (−) in text].

Recommendations are intended for physicians of all specialties, including mainly general practitioners, pediatricians, internists, pulmonologists, laryngologists and allergologists.

They are presented as follow (in majority separately for children and adults):

1. Infectious disease of upper respiratory tract:

— pharyngitis or/and tonsillitis,

— otitis,

— acute rhinosinusitis (inflammatory process involving the mucus membranes of the paranasal sinuses and nasal cavity),

— chronic rhinosinusitis.

2. Infectious disease of lower respiratory tract:

— bronchitis (and tracheitis),

— bronchiolitis,

— exacerbation of chronic obstructive pulmonary disease (COPD),

— pneumonia (community-acquired, hospital-acquired [nosocomial]).

3. Cystic fibrosis.

4. Asthma.

5. Other chronic diseases of respiratory tract:

— protracted bacterial bronchitis,

— bronchiectases,

— primary ciliary dyskinesia (PCD).

6. Pertussis.

7. Infectious of respiratory tract elicited by nontuberculous mycobacteria (NTM).

 

2. Macrolide antibiotics — general characteristic

Macrolide antibiotics (monocycle lactones) comprise increasingly bigger and continuously widening group of popular antibiotics, which basic element of chemical structure is lactone cycle. Particular macrolides vary depending on size of cycle, basic skeleton and type of carbohydrate [8]. According to the structure of lactone cycle, all macrolides are divided into 14-, 15- or 16-carbon (Table 2) [9, 10].

 

Table 2. Classification of macrolide antibiotics depending on number of carbons in lactone cycle

C 14

C 15

C 16

Erythromycin

Oleandromycin

Roxytromycin

Clarithromycin

Diritromycin

Fluritromycin

Telitromycin

Azithromycin (azalide)

Josamycin

Spiramycin

Midecamycin

 

The most number of antibiotics is in group with lactone cycle containing 14 and 16 carbons. The first one includes the oldest antibiotic - erythromycin (isolated in 1952 and marketed in 1965). Additional macrolides belonging to 14-carbones group include: oleandromycin, roxitromycin, clarithromycin, diritromycin, fluritromycin, telitromycin and others are being during preclinical and clinical trials. One of the most popular macrolides – clarithromycin (6-O-metylerythromycin) was synthesized through methylation of one of hydroxyl groups in 14-elements macrolide cycle in 1984 and registered in 1991.

Spiramycin, josamycin and midecamycin are antibiotics with the cycle containing 16 carbons, and the representative of azalide group is azithromycin [11−13]. Some authors distinguish subclass of macrolides called ketolides, which includes for example telithromycin and cethromycin. Primary indications for this group of macrolides are respiratory tract infections, including pneumonia elicited by pathogens resistant for others macrolides [13]. There are ongoing studies on new macrolides (miokamycin, rokitamycin, rozaramycin, fludritromycin, cethromycin and others) [14, 15].

Macrolides are considered to be bacteriostatic. Mechanism of action of all drugs from this group is similar and based on inhibition of proteins synthesis on the level of ribosome 50S [16]. Antibiotics well penetrate into the cells, among them pulmonary macrophages and multinuclear granulocytes, where they act synergistically with processes of intracellular killing. They are characterized by relatively wide spectrum, as they act on selected Gram-positive bacteria species Streptococcus and Staphylococcus, Gram-negative species Neisseria, Moraxella, Bordetella, Haemophilus as well as so called atypical pathogens: Chlamydia trachomatis, Chlamydophila pneumoniae, Mycoplasma pneumonia, and Legionella pneumophila [17, 18]. They also show multiple anti-inflammatory, immunomodulatory and anti-viral properties, which allow potentially used them in the treatment of asthma, cystic fibrosis and other inflammatory diseases of respiratory tract. The most important macrolides properties are as follow [9, 19−28]:

— inhibition of proliferation and stimulation of apoptosis of lymphocytes, neutrophils and eosinophils,

— inhibition of proinflammatory cytokines secretion and superoxidantes from neutrophils,

— inhibition of neutrophils chemotaxis,

— inhibition TNF-α (tumor necrosis factor alfa) secretion in bronchial epithelium,

— potentiating of macrophage phagocytosis,

— inhibition of NF-kappaB and AP-1 activation,

— inhibition of proinflammatory cytokines secretion from bronchial epithelium and other cells,

— stimulation of IFNβ (interferon), INFγ and ISG synthesis,

— decreasing of phagocyte capacity of multinuclear cells,

— decreasing of mucus secretion in respiratory tract.

The most important pharmacokinetic properties of macrolides registered in Poland are summarized in Table 3 [9, 10, 29−37].

 

Table 3. The most important pharmacokinetic properties of macrolides registered in Poland

Pharmacokinetic properties of selected macrolides

Erythromycin*

Roxitromycin

Clarithromycin

Azithromycin

Spiramycin

Influence of food on the bioavailability

Decrease

Decrease

Increase or no effect

Decrease

No effect

Bindign with serum proteins

70%

96%

70%

12–52%

10%

1−2 hrs.

10.5−20 hrs.

3.3−5.8 hrs.

36 hrs.

8 hrs.

Serum concentrtation

0.3−1.9 mg/l

2.6−10.1 mg/l

1−3 mg/l

0.4−0.5 mg/l

43.3 mg/l

No of doses per day

2−4

1−2

1−2

1

2−3

Parenteral formulation

Yes

No

Yes

Yes

No

Main excretion route

Bile — 80%
Urine — 2.5%

Feces — 65%
Urine — 12%

Bile — 30%
Urine — 40%

Bile — 88%
Urine — 12%

Bile — 80−95% Urine ≤ 10%

Dose reduction

Liver insufficiency

Liver insufficiency

Kidney insufficiency

Liver insufficiency

Liver insufficiency

Interactions. All macrolides inhibit CYP3A izenzymes (the most strongly erythromycin, roxitromycin and clarithromycin — moderately, azithromycin and piramycin — the most weakly)

For example teophiline, digoxin, ciclosporine, ergotamine, warfarin, midazolam, triazolam, mukolytics, bromocriptine, carbamazepine, phenytoin, valproic acid, oral contraceptive drugs, antiarrhythmic drugs Ia class

For example digoxin, teophiline, ciclosporine, ergotamine, warfarin, midazolam, triazolam, ergot alkaloids, dizopiramide, antiarrhythmic drugs Ia and III class, vitamin K antagonists

For example teophiline, ciclosporine, warfarin, carbamazepine, lovastatin, simvastatin, oral andidiabetic drugs, insulin, ergotamine, rifabutine, fluconazole, ritonavir, dizopiramide, omeprazole, sildenafil, tolterodine

For example neutralizing drugs, ergot alkaloids, digoxin, nelfinavir, oral anticoagulants like coumarin, cisapride

Levodopa, carbidopa

*Not applied to erythromycin estolate

 

Each described above macrolide has its own advantages and limitations. For example the benefit of azithromycin is short administration time (usually 3−5 days) and clarithromycin, azithromycin and partially roxitromycin show many proven anti-inflammatory properties [19]. Efficacy of macrolide antibiotics depend among others on drug concentration in affected tissues. Table 4 shows the concentrations of selected macrolides in respiratory tract (defined as multiple of serum level) [8].

 

Table 4. Concentrations of selected macrolide antibiotics in respiratory tract (defined as multiple of serum level) [8]

Antibiotic

Lung parenchyma

Mucosa of respiratory tract

Bronchial secretion

Erythromycin

2.0−5.0

Lack of data

Lack of data

Spiramycin

5.0−10.0

15.0−20.0

3.0−6.0

Roxitromycin

0.6−0.9

Lack of data

1.0−16.0

Clarithromycin

6.0−18.0

App. 4.0

Lack of data

Azithromycin

20.0−100.0

30.0

2.5−5.0

Dirytromycin

19.0−40.0

26.0−34.0

5.0−6.0

 

Based on the data from Table 4 it is clear, that macrolides (except roxitromycin) achieve the significantly higher concentrations in respiratory tract and lung parenchyma than in serum, which determines their outstanding clinical in lower respiratory tract infections, regardless of patient’s age. Special advantages of clarithromycin justify its usefulness and popularity in the treatment of respiratory tract infections in children and adults, also in Poland. The most important are as follow [31]:

— high activity against atypical and typical pathogens many Gram+ and Gram- bacteria,

— high activity in Haemophilus influenza infections (14-hydroxy-clarithromycin metabolite of clarithromycin acts — twice as many stronger than clarithromycin itself);

— high concentrations in tissues and cells, which favors high clinical and microbiological activity;

— resistance for beta-lactamases (other pharmacologic group than beta-lactams);

— intravenous and oral form available, allowing so called sequence therapy;

— administration twice or once per day;

— lower risk of selection of the strains macrolide-resistant as compared with azithromycin.

Table 5 shows macrolides available in Poland together with their formulations and typical dosage [33−37].

 

Table 5. Macrolides available in Poland together with their formulations and typical dosage (as of 1. of April 2015, in alphabetical order)

Chemical name

Form

Dosage in children

Dosage in adults

Azithromycin

Tablets

Powder for oral suspension

Granules for oral suspension

Powder for solution for intravenous infusions

10 mg/kg 1 ×/d for 3 days

Adults and children > 45 kg 500 mg 1 ×/d for 3 days or alternative dosage: 500 mg 1 ×/d in the first day, then 250 mg 1 ×/d for 4 days

Erythromycin

Tablets

Children up to 8 years of age 30−50 mg/kg/d in 3−4 doses

Adults and children up to 8 years of age 1−2 g/d in 3−4 doses, in sev ere infections up to 4 g/d.

Clarithromycin

Tablets

Granules for oral suspension

Powder for solution for intravenous infusions

Extended-release film-coated tablets

7.5 mg/kg 2 ×/d 
(children < 8 kg — 7.5 mg/kg 2 ×/d, 8−11 kg — 62.5 mg 2 ×/d,

12−19 kg — 125 mg 2 ×/d,

20−29 kg — 187.5 mg 2 ×/d, 30−40 kg — 250 mg 2 ×/d)

Maximum dose 500 mg 2 ×/d.

500−1000 mg/d in 1 or 2 doses

Roxitromycin

Tablets

Tablets for oral suspension

5−8 mg/kg /d in 2 doses

every 12 hrs.

(children 6−11 kg — 25 mg 2 ×/d, 12−23 kg — 50 mg 2 ×/d,

24−40 kg — 100 mg 2 ×/d)

150 mg every 12 hrs.

Spiramycin

Film-coated tablets

Basic dose 150.000 IU/kg/d

in 2−3 doses, the dose could

be increased up to 300.000 IU/kg/d

in 2−3 doses

Basic dose 6 mln IU/d in 2 doses, the dose could be increased up to 9 mln IU/d in 3 doses.

Pneumonia in adults could be community-acquired (of mild, moderate or severe clinical course) and hospital-acquired (nosocomial). Antibiotic therapy depends on clinical course of community-acquired pneumonia, however in patients with nosocomial pneumonia the choice of antibiotic is based on risk factors of infections caused by particular pathogens and knowledge about local drug-resistance and dissemination of particular microorganisms. Macrolide antibiotics are often a part of dual-agent combination therapy.

 

3. Macrolides in upper respiratory tract infections in children

Macrolide are used in the following infectious diseases of upper respiratory tract in children: acute pharyngitis or/and tonsillitis, acute otitis media and acute rhinosinusitis. It should be remembered, that recently in Poland approximately 10−15% strains of Streptococcus pyogenes indicate resistance to macrolides [18].

 

Acute pharyngitis or/and tonsillitis

There are some controversies regarding advisability of using any antibiotics in streptococcal pharyngitis [38]. Recent meta-analysis did not also define any clear conclusions regarding preferable antibiotics [39]. Acute pharyngitis or/and tonsillitis elicited by Streptococcus pyogenes should be treated in Polish conditions with oral phenoxymethylpenicyllin in the total dose of 100.000−200.000 IU/kg/day given twice daily for 10 days. In patients with low susceptibility or in case of any difficulties with oral administration of antibiotic banzathine benzylpenicyllin should be given intramuscularly in single dose of 600.000 IU in children with the weight < 30 kg or 1.2 million IU in children with the weight ≥ 30 kg [2, 40]. Atypical microorganisms could be a pathogen or co-pathogen in acute pharyngitis or/and tonsillitis [41].

  1. In streptococcal pharyngitis macrolides should be exclusively indicated in patients with immediate hypersensitivity reactions to beta-lactam antibiotics [IbA] [2, 42, 43].

  2. Due to difficult prediction of sensitivity for antibiotics, in patients with streptococcal pharyngitis macrolides should be used together with assessment of drug-resistance to erythromycin [IVD] [2, 44].

  3. Macrolides could be given in acute pharyngitis elicited by Mycoplasma pneumoniae or/and Chlamydophila pneumoniae [IVD] [41].

  4. The dosage of macrolides should be as follow: clarithromycin 15 mg/kg/d in 2 doses for 10 days; azithromycin in total daily dose 12 mg/kg for 5 days or 20 mg/kg/d for 3 days; erythromycin 30−50 mg/kg/d in 2−4 doses for 10 days (erythromycin should be last-choice antibiotic).

 

Acute otitis media

Immediate administration of antibiotic (first-choice drug: amoxicillin or amoxicillin with clavulanate) in acute otitis is indicated only in selected groups of children [45−47]: at the age below 6 months, with high pyrexia and vomiting, at the age below 2 years with bilateral otitis and otorrhea. In other cases of otitis without complications watchful observation should be introduced, without immediate antibiotic’s administration [47].

 

  1. Macrolide is indicated in case of delayed hypersensitivity reactions to all beta-lactam antibiotics or immediate hypersensitivity reactions to any beta-lactam antibiotic or any other reasons making impossible the administration of antibiotic from this group [IbA] [2, 48].

  2. Macrolides with proven efficacy in the treatment of acute otitis media include: clarithromycin and azithromycin [IbA] [49−51]. Other macrolides (for example spiramycin) don’t act at all on Haemophilus influenzae or act but only in high concentrations (roxitromycin, erythromycin) [52−54].

  3. Dosage of macrolides in acute otitis media:

— clarithromycin in children at the age above 6 months 15 mg/kg/d in 2 doses for 10 days, and in older children 250−500 mg every 12 hours for 10 days,

— azithromycin could be administered in 3 schedules of dosage: for 5 and 3 days or in high single dose [55].

 

Acute rhinosinusitis

There are some controversies regarding antibiotic therapy in acute rhinosinusitis. Clinical practice highly differs from the management recommended in recent guidelines and consensuses. Antibiotic is indicated in initial treatment of acute rhinosinusitis in children with intense onset or exacerbating course of disease [7, 56−58]. In children with refractory disease with the sign and symptoms including plugging of nose or/and cough lasting for at least 10 days (without significant improvement) antibiotics could be administered but watchful observation could be also good option (additional observation for 3 days) [58]. Amoxicillin or amoxicillin with clavulanate is the first line therapy in children with acute rhinosinusitis and indications to antibiotic therapy [58−60]. Antibiotic should be introduced immediately after diagnosis is established and administered for 10 to 14 days [57]. Recommended doses: amoxicillin in children with weight ≥ 40 kg 1.500−2.000 mg every 12 hours; in children with weight to 40 kg 75−90 mg/kg/d in 2 doses every 12 hours [2]. Levofloxacin could be an alternative in cases of immediate hypersensitivity to beta-lactam antibiotics in older children [60]. Combination of clindamycin with cephalosporin III generation (cefixime, cefpodoxime) is indicated in case of delayed hypersensitivity to penicillin [60]. In corrected treatment of acute rhinosinusitis amoxicillin with clavulanate should be used, especially if previous treatment with amoxicillin failed. The dose of amoxicillin in children with weight < 40 kg is 75−90 mg/kg/d in 2 doses for 10 days [2]. In case of delayed hypersensitivity to penicillin cefuroxime should be used at this stage of therapy (2 × 500 mg/d in children with weight ≥ 40 kg and 30 mg/kg/d in 2 doses for 10 days in children with weight < 40 kg) [2].

 

  1. In cases of immediate hypersensitivity to beta-lactam antibiotics clarithromycin is indicated in 15 mg/kg/d in 2 doses for 10 days [IIaB] or in children with weight over 40 kg in the dose of 250–500 mg given every 12 hours for 14 days. Azithromycin is recommended in children with weight over 40 kg in the dose of 250–500 mg given once daily for 3 days [IIIbC] [2, 61].

  2. In corrected treatment of acute rhinosinusitis in cases of immediate hypersensitivity to beta-lactam antibiotics clarithromycin should be used: in children with weight ≥ 40 kg 2 × 500 mg/d, and in children with weight < 40 kg 15 mg/kg/d in 2 doses for 10 days [IIbC] [2].

 

Chronic rhinosinusitis

 

  1. Antibiotic therapy (local, systemic) is not recommended in chronic rhinosinusitis in children (with or without polypes). Negative recommendation regardless of groups of antibiotics or schedules of their administration [IbA-, IIIC-, IVD-] [7].

 

4. Macrolides in upper respiratory tract infections in adult

Macrolide are used in the following infectious diseases of upper respiratory tract in adults: acute pharyngitis or/and tonsillitis, acute otitis media and chronic rhinosinusitis.

 

Acute pharyngitis or/and tonsillitis

Acute pharyngitis or/and tonsillitis elicited by Streptococcus pyogenes should be treated with oral phenoxymethylpenicyllin in the total dose of 2−3 million IU/kg/day given twice daily for 10 days, and in some clinical situations with banzathine benzylpenicyllin, given intramuscularly in single dose of 1.2 million IU [2, 62, 63].

 

  1. In streptococcal pharyngitis or tonsillitis macrolides should be exclusively indicated in patients with immediate hypersensitivity reactions to beta-lactam antibiotics [IbA] [39, 63].

  2. Macrolides could be given in acute pharyngitis elicited by Mycoplasma pneumoniae or/and Chlamydophila pneumoniae with typical dosage [IVD] [41, 64].

 

Acute bacterial rhinosinusitis

In adults with acute bacterial rhinosinusitis of mild or moderate clinical course, lasting shorter than 7−10 days the strategy of watchful waiting and observation could be employed without antibiotic therapy.2 Antibiotics are indicated in following clinical situations: severe course of infection, with intense bone pain of face and pyrexia exceeding 380C, lack of improvement after 7−10 days, deterioration of signs and symptoms after initial alleviation, occurrence of complications [7, 60]. Antibiotics give only moderate improvement [65]. Antibiotic of choice in acute rhinosinusitis (with severe/moderate clinical course) is amoxicillin or amoxicillin with clavulanate (preferably) [2, 7, 60]. Amoxicillin should be used for 5−7 days in high doses 1.500−2.000 mg every 12 hours [2]. Another way of therapy is administration of amoxicillin for 10 days in the dose of 500−750 mg every 8 hours [66, 67]. In corrected treatment of acute rhinosinusitis in adults amoxicillin with clavulanate should be used, especially if previous treatment with amoxicillin failed [2]. The doses of amoxicillin: 1.500−2.000 mg every 12 hours for 10 days. In case of non-immediate hypersensitivity to penicillin cefuroxime should be used in the dose 2 × 500 mg/d [2].

 

  1. Macrolides are indicated in cases of immediate hypersensitivity to beta-lactam antibiotics [IVD] [2].

  2. Dosage of macrolides: clarithromycin 250−500 mg every 12 hours for 14 days or azithromycin in single dose of 2 g (in form of microspheres [IIB] [2].

 

Chronic rhinosinusitis

There are no high-quality evidence (randomized, placebo-controlled clinical trials with appropriate sample size), which could confirm, that antibiotic therapy has any effect in long-term treatment of adults with chronic rhinosinusitis [68]. There is a lot of lower-quality studies, confirming benefits from treatment with different macrolides, given for many weeks in patients with chronic rhinosinusitis, including undergone endoscopic procedures [7, 69].

 

  1. In patients with chronic rhinosinusitis without polypes long-term therapy with oral macrolides in recommended for ≥ 4−12 weeks [IIaC] [7, 70]. In a subgroup of patients with serum IgE level within normal range this recommendation is even stronger [IbA] [7].

  2. In patients with chronic rhinosinusitis with polypes long-term therapy with oral macrolides in recommended (≥ 4−12 weeks) [IbA] [71].

  3. In patients with mixed form of chronic rhinosinusitis long-term therapy with oral macrolides (≥ 4−12 weeks) is not recommended [IbC-] [72].

  4. In patients with chronic rhinosinusitis long-term therapy with oral macrolides (≥ 4−12 weeks) is recommended during preoperative management [IIaB] [70].

  5. In patients with chronic rhinosinusitis during preoperative management long-term therapy with oral macrolides in low doses (erythromycin) (≥ 4−12 weeks) [73] or clarithromycin in the dose of 200 mg/d for 6 months (improved clinical course in patients after functional endoscopic sinus surgery [FESS]) is recommended [IIbB] [74].

  6. Long-term therapy with low doses of clarithromycin (250 mg/d) controls eosinophilic inflammation and prevent the recurrence of polypes in nose after FESS [IbB] [75].

  7. In patients with high risk of recurrences after FESS despite local corticosteroids administration adding of azithromycin is recommended (3 × 250 mg/week) [IIbB] [76].

 

Acute otitis media

 

  1. Macrolides as first line drugs are indicated in the treatment of acute otitis media only in patients with immediate allergy to any beta-lactam antibiotic or delayed hypersensitivity reactions to all beta-lactams [IIbB] [18, 48].

  2. it is recommended to use macrolides active against Haemophilus influenzae — clarithromycin or azithromycin [IIIC] [18].

 

Dosage of macrolides: clarithromycin 250−500 mg every 12 hours for 10 days, azithromycin 500 mg once per day for 3 days or 500 mg once per day in the first day and then 250 mg once per day for 4 days.

 

5. Macrolides in lower respiratory tract infections in children

Lower respiratory tract infections there is a group of infectious diseases including: acute bronchitis, protracted bronchitis, bronchiolitis and pneumonia.

 

Acute bronchitis

Acute bronchitis without complications is treated only symptomatically, without antibiotic [77].

 

  1. Elective administration of macrolide antibiotic is justified in cases when atypical etiology (Mycoplasma pneumoniae or Chlamydophila pneumoniae) or pertussis (Bordetella pertussis) is suspected [IVC] [78−80].

  2. Dosage: clarithromycin 15 mg/kg/d in 2 doses for 7−10 days, and azithromycin 10 mg/kg once daily in first day and then 5 mg/kg once daily for 4 consecutive days [77].

 

Protracted bronchitis

Secondary bacterial infections in children often have a clinical picture of so called protracted bacterial bronchitis (manifesting with productive cough, lasting > 4 weeks without tendency to resolution). Usually protracted bacterial bronchitis is elicited by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis or Staphylococcus aureus.

 

  1. Antibiotic of choice in protracted bacterial bronchitis is amoxicillin with amoxicillin with clavulanate [IbA] [81].

  2. Macrolide could be also used, e.g. clarithromycin [IVD] [82] in typical doses for at least 10−14 days (up to 6 weeks) [77].

 

Bronchiolitis

Routine administration of antibiotics is not justified, and this is only indicated in patients with bronchiolitis of severe clinical course, required intubation, in patients with immunological deficiencies or with complications of bacterial etiology (e.g. otitis media, pneumonia or sepsis) [83−85].

 

  1. The indication for antibiotic therapy of child with bronchiolitis could be exclusively Mycoplasma or Chlamydia etiology [IVD] [85, 86].

  2. Clarithromycin (in typical doses) could shorten hospitalization, time of beta-mimetics administration as well as reduce the serum level of inflammatory markers [IIIC] [87].

 

Community-acquired pneumonia

Pneumonia is divided into 2 types, community-acquired and hospital-acquired (nosocomial), depending on where infection had place. Hospital-acquired cases are defined as pneumonia occurring after 48 from hospital admission in patients without intubation at the time of admission. Primary criterion of antibiotic’s choice in the treatment of hospital-acquired pneumonia in patient’s age, mainly due to most frequent etiology factors, which dominate in particular age groups [2]. Macrolide antibiotics in some clinical situations could be a part of dual-agent combination therapy.

 

  1. In children at the age between 3. week and 3. month with the clinical picture suggesting subacute form of pneumonia (without fever, interstitial location, infection of Chlamydia trachomatis suspected) intravenous macrolide could be first-line drug [IVD] [2].

  2. In children at the age between 3. month and 5. month there are no indications to routine therapy with macrolides, and amoxicillin is antibiotic of choice [2]. In this group of patients macrolides could be indicated in case of clinical picture suggesting atypical microorganism infection or when such infection is serologically confirmed, and usually macrolide is administered in combination with beta-lactam antibiotic [IVD] [88, 89].

  3. In children at the age between 5 and 15 years beta-lactam antibiotic with anti-pneumococcal activity is recommended, depending on suspected either typical or atypical etiology (amoxicillin, ampicillin) [2] or macrolide (if clinical picture suggests atypical etiology (Mycoplasma pneumoniae or Chlamydophila pneumoniae) [2], especially in children with bilateral, parahilar radiographic findings or wheezing) [IIbC] [89].

  4. Pneumonia caused by Mycoplasma or Chlamydia in children in every age group should be treated with macrolide antibiotic [IVD] [79, 80, 90−94]. Recommended treatment time is 7−10 days or 7−14 days and 5 days for azithromycin [IVD] [2, 93].

  5. In children with lower respiratory tract infections with immediate allergy (type I) to amoxicillin, clarithromycin should be antibiotic of choice (alternative treatment) [IVD] [2].

  6. In more severe forms of pneumonia (especially in hospitalized children or in children with concomitant diseases) it is recommended to combine of macrolide with beta-lactam antibiotic [IVD] [88].

  7. In case of no evident improvement after monotherapy with beat-lactam antibiotic (especially in children between 5 and 15 years) and with suspicious of atypical etiology or doubts regarding etiology of community-acquired pneumonia macrolide should be added to existing treatment (so called corrected treatment) [IIIC] [2, 88].

 

6. Macrolides in lower respiratory tract infections in children

Lower respiratory tract infections in adults include: acute bronchitis and tracheitis, protracted bronchitis and pneumonia.

 

Acute bronchitis and tracheitis

In general no antibiotic therapy is recommended in acute bronchitis in adults [95, 96]. In patients with acute bronchitis and tracheitis antibiotic therapy could be indicated if signs and symptoms last longer than 7−10 days [97]. In patients with long-lasting cough (> 3 weeks) up to 20% of infections could be caused by Bordetella pertussis [98].

 

  1. Elective administration of macrolide antibiotic is justified in cases when atypical etiology (Mycoplasma pneumoniae or Chlamydophila pneumoniae) or pertussis (Bordetella pertussis) is suspected [IVC] [18].

 

Dosage: clarithromycin 500 mg every 12 hours or 500 mg every 24 hours for 7−10 days or azithromycin 500 mg once daily for 3 days or 500 mg once daily in first day and then 250 mg once daily for 4 consecutive days or in single dose of 2 g (in form of microspheres) [18].

 

Pneumonia

Pneumonia in adults could be community-acquired (of mild, moderate or severe clinical course) and hospital-acquired (nosocomial). Antibiotic therapy depends on clinical course of community-acquired pneumonia, however in patients with nosocomial pneumonia the choice of antibiotic is based on risk factors of infections caused by particular pathogens and knowledge about local drug-resistance and dissemination of particular microorganisms. Macrolide antibiotics are often a part of dual-agent combination therapy.

 

Community-acquired pneumonia of mild clinical course

  1. First line treatment of community-acquired pneumonia in adults should considered Streptococcus pneumoniae etiology and amoxicillin should be used in the dose of 1 g 3 ×/d [IIIA] [2].

  2. In young adults with community-acquired pneumonia of mild clinical course without concomitant diseases macrolides could be also used in first line treatment [IIIB] [2].

  3. When empirical therapy should be widened adding of macrolide antibiotic is recommended or exchanging antibiotic to macrolide in patients with amoxicillin monotherapy [IaD] [98, 99].

  4. In acute lower respiratory tract infections azithromycin seems to have advantage over amoxicillin with clavulanate in first line treatment [IaB] [100].

  5. In case of hypersensitivity reaction type I, when beta-lactam antibiotics could not be used in the treatment of patients with community-acquired pneumonia macrolides should be used:

— oral clarithromycin in the dose of 500 mg 2 ×/d;

— intravenous azithromycin in the dose of 500 mg 1 ×/d for 2 days and then 500 mg 1 ×/d per os (p.o.) for 3−5 days [2].

 

Community-acquired pneumonia of moderate clinical course

  1. In patients with pneumonia of moderate (moderate to severe) clinical course empirical therapy with oral macrolide and amoxicillin in typical doses is recommended [IaB] [101].

  2. In case of no improvement, when amoxicillin was used in first line treatment and there is still indication to antibiotic therapy, combining cephalosporine III generation (ceftriaxone or cefotaxime) with macrolide is recommended [IIIA] [2]. Nevertheless these antiobiotics are not optimal choice for Staphylococcus aureus etiology and they are ineffective against non-fermenting Gram-negative rods (e.g. Pseudomonas aeruginosa).

  3. If intravenous therapy should be used in patient penicillin-intolerant, monotherapy with levofloxacine or combination of cephalosporine II or III generation with clarithromycinis recommended [IIID] [102].

  4. Time of treatment of community-acquired pneumonia without complications of mild and moderate-to-severe clinical course should be approximately 7 days or 3 days since clinical course is established [IIA] [2].

 

Community-acquired pneumonia of severe clinical course

  1. In severe community-acquired pneumonia, requiring treatment in intensive care unit caftriaxone or cefotaxime together with macrolide is recommended [IB] [2, 103].

  2. Duration of antibiotic therapy in community-acquired pneumonia of severe clinical course should be 7−10 days, and in clinically justified situations and in case of suspicious of Staphylococcus aureus or Enterobacteriacae etiology this time could be up to 14–21 days [IIIC] [104].

  3. In cases with intolerance of panicyllin, combination of cephalosporine II or III generation with clarithromycin is recommended, instead of amoxicillin with clavulanate [IIIC] [102].

  4. In multi-drug therapy adding of macrolide is preferable comparing to fluorochinolone, considering its immnomodulative effects [IB] [105, 105].

 

Nosocomial pneumonia

Treatment should be initiated with intravenous antibiotics. Possible modifications should be based on clinical response’s assessment in 2. or 3. treatment day and results of culture. Combination therapy should last up to 7 days, prolongation of treatment could favor colonization of respiratory tract with drug-resistant bacteria and pneumonia recurrences. When antibiotic therapy is accurate, time of treatment should be shortened from 14−21 days up to even 7 days, providing good clinical response (this not applies to nosocomial pneumonia of Pseudomonas aeruginosa etiology) [107].

  1. Azithromycin should not be a standard empirical therapy of nosocomial pneumonia considering its cardiotoxicity, especially in risk groups [IIID] [108].

 

Pneumonia of known or non-specific etiology

  1. In suspicious of pneumonia elicited by Mycoplasma pneumoniae the treatment of choice is oral or intravenous clarithromycin in the dose of 500 mg every 12 hours [IIIA] [109].

  2. In Legionella pneumophila infection macrolide is an alternative drug of second line in relation to fluorochinolone [IIbB] [110−112]. However, among macrolides azithromycin seems to have similar efficacy to fluorochinolone [IIaB] [113], [IIbB] [114].

  3. Legionellosis of severe clinical course needs to be treated with combination of fluorochinolone and macrolide, and duration of therapy could be from 7 to 21 days, depending on severity of disease [IVD] [115].

  4. Macrolides could be a therapy of first line in patients with cryptogenic, organizing penumonia [IVD] [116, 117].

 

7. Macrolides in chronic obstructive pulmonary disease (COPD)

Infectious exacerbations of COPD

Antibiotic therapy should be used in infectious exacerbations of COPD when the following criteria are met [118−120]:

a) patient has all three symptoms: increased dyspnoe, increase of sputum production, new-onset of purulent sputum change in character of sputum (Anthonissen type I),

b) two among above mentioned symptoms are present but the main is a purulent sputum (Anthonissen type II),

c) exacerbation of COPD which could require invasive or non-invasive assist ventilation.

The type of empirical antibiotic therapy of COPD exacerbation depends on severity of exacerbation and the risk of Pseudomonas aeruginosa infection [119, 121, 122].

 

  1. In patients with mild or moderate-to-severe exacerbation of COPD without the risk of Pseudomonas aeruginosa infection macrolides or levophloxacin are an alternative to amoxicillin with clavulanate [IIB] [121, 123].

  2. In case of hypersensitivity type III to amoxicillin with clavulanate cefuroxime should be used, whereas in case of hypersensitivity type I — macrolide active against Haemophilus influenzae (clarithromycin or azithromycin) or fluorochinolone active against Streptococcus pneumoniae (levofloxacin or moxifloxacin) (IIIA) [2].

  3. Macrolide could be a therapy of first line in suspicious of infection caused by atypical microorganism [IVD] [124−126].

 

Prevention of COPD exacerbation

 

  1. It has been shown beneficial influence of long-term (6–12 months) administration of macrolides (azithromycin, clarithromycin and erythromycin) in profilaxis of COPD exacerbations, indicating however some risk of drug-resistance stimulation [IaA] [127−130].

  2. Long-term therapy with macrolide in order to prevent COPD exacerbations could be used in patients with moderate and severe COPD, with one or more exacerbations during last year despite optimal daily inhled therapy [IbA] [128].

  3. Long-term azithromycin treatment should not be used in COPD patients with history of heart disease, especially Q-T prolongation or ventricular arrhythmia [IVD-] [131, 132].

  4. Described therapy does not affect the number of hospitalizations and the risk of death. Long-term administration of antibiotics in COPD increases resistance to macrolides [IVD] [133, 134].

 

8. Macrolides in asthma

From many years there are ongoing studies, assessing the possibility of using other properties of macrolides (despite antibiotic activity) in the long-term treatment of asthma, prevention of excarbation as well as during exacerbations of this disease. However, till date none of macrolide antibiotic was included into global or the most importnatn local guidelines of asthma treatment [135−137].

 

  1. Macrolides (troleadomycin, roxitromycin, azithromycin) administered for meny weeks (6−52 weeks) as add-on drug with oral glicocorticosteroids in steroide-dependent asthma in children improve FEV1 and decrease the daily dose of steroids needed to maintain of disease control [IbC] [138].

  2. Macrolides (troleadomycin, roxitromycin, clarithromycin, azithromycin) used for 6−22 weeks as add-on therapy with existing treatment in children and adults with chronic asthma relief clinical symptoms of disease, improve spiromtric parameters and disease-related quality of life as well as decrease hyperreactivitiy of bronchial tree [IaC] [139, 140].

  3. Macrolides (roxitromycin) give beneficial clonical and spirometric effect in chronic asthma in patients with infection caused by atypical microorganism, mainly in neutrophilic asthma [IbC] [141, 142].

  4. Macrolides (azithromycin) could be used in prevention of exacerbations in adult patients with severe non-eosinophilic asthma (as add-on therapy with inhaled glicocorticosteroids and long-acting beta agonists [LABA]) (IbC) [143].

  5. There is no unequivocal, strong evidence according usage of macrolides in exacerbations of asthma in children in adults [144−146]. Clarithromycin could give beneficial clinical effect in the exacerbations treatment in children with episodic/mild asthma (3 weeks of therapy with typical doses) [IIbC] [144]. Telitromycin administered in typical doses for 10 days beneficially affects the clinical course of asthma exacerbations in adults [IbC] [147].

  6. Macrolides could be an alternative for other antibiotics in children and adults with asthma excarbations caused by atypical microorganism [IVD] [148].

 

9. Macrolides in cystic fibrosis (CF)

During exacerbations of brochopulmonary disease 2−3 antibiotics are given for approximately 14 days. In patients without Pseudomonas aeruginosa infection until culture results are available the empirical treatment is used, with the activity spectrum against H. influenzae and S.aureus (semi-synthetic penicillins or cephalosporins resistant to beta-lactamase or clarithromycin) [149, 150]. During the treatment of chronic brochopulmonary disease in CF there are mainly used other than antibiotic activities of some macrolides, e.g. immunomodulatory effect [149−152]. Long-term administration of azithromycin descreased the frequency of excarbations and overall antibiotics consumption, and in patients at the age > 6 years with chronic infaction of Pseudomonas aeruginosa additionally better maintained patent airways [150−153].

 

  1. In acute respiratory tract infections in patients with CF, macrolides could be considered only in case of suspicious of H. influenzae or S. aureus infection or in high probability of atypical or pertussis etiology — till receiving the results of sputum culture or serological tests [IVD] [149].

  2. Long-term (for many months or many years) administration of low doses (anti-inflammatory) of azithromycin in all patients with chronic brochopulmonary disease (regardless of infectious factor and patient’s age) is recommended [IIIC for clinical symptoms and IaA for spirometry] [150−153]. Azithromycin dosage: 250 mg (patients with weight 25−40 kg) or 500 mg (patients with weight > 40 kg) 3 times per week (or every other day) [149].

 

Long-term administration of azithromycin descreased the frequency of excarbations and overall antibiotics consumption, and in patients at the age > 6 years with chronic infaction of Pseudomonas aeruginosa additionally better maintained patent airways [150−153].

 

10. Macroilides in bronchiectases of non-CF etiology, including primary ciliary dyskinesia (PCD)

In patients with bronchiectases of non-CF etiology antibiotics are used to treat the exacerbations, eradicate the first infection caused by potentially dangerous pathogens as well as in long-term treatment [154−156]. Good experience with long-term administration of azithromycin in CF led to trying to use this antibiotic also in patients with bronchiectases of different etiology [154−156], including primary ciliary dyskinesia (PCD) [157].

 

  1. Macrolides (azithromycin, erythromycin, roxitromycin, clarithromycin) administered in anti-inflammatory dose for 2−6 months in patients with bronchiectases of non-CF etiology decrease frequency of excarbations and volume of sputum, reduce decreasing of FEV1 as well as improve quality of life [IaA] [158].

  2. Majority of available data is for azithromycin administered for 3 or 6 months in low doses (anti-inflammatory) and used 3 times per week in patients with exacerbations occurring at least 3 times per year or protracted symptoms (longer than 6 months). Treatment with azithromycin, especially patients with Pseudomonas aeruginosa infection decreases frequency of excarbations and volume of sputum, reduces decreasing of FEV1 as well as improves quality of life [IaA] [159−164].

  3. Decreased frequency of excarbations and slightly reduced volume of sputum and decreasing of FEV1 rate were also observed in patients with long-term administration of erythromycin [IbA] [159, 164].

 

11. Macrolides in pertussis

Macrolide antibiotics play a major role in profilaxis and treatment of pertussis [164−166]. In patients with allergy or intolerance to macrolides trimethoprim/sulfamethoxazole could be an option [167].

 

  1. Preventive administration of macrolide should be considered in persons exposed to pertissis (especially in patients with high risk of complications) and during epidemy [IbB] [165, 166].

  2. Azitrhomycin in preferable macrolide antibiotic in the treatment and prevention of Pertussis in children and adults [IbA] [164, 165, 168, 169]. Dosage in children: 10 mg/kg/d for 3 days or 10 mg/kg/d in the first day, then 5 mg/kg/d for 2–5 days. Dosage in adults: 500 mg/d for 3 days or 500 mg in the first day, then 250 mg/d for 2–5 days.

  3. In children with pertussis at the age between 6 months and 16 years clarithromycin could be an alternative to azithromycin [IbB] [170]. Dosage of clarithromycin in children: 7.5 mg/kg 2 ×/d for 7 days. Dosage of clarithromycin in adults: 500 mg 2 ×/d for 7 days.

 

12. Macrolides in respiratory tract infections caused by non-tuberculous mycobakteria (NTM) in adults

Mycobakterioses are the diseases caused by atypical or non-tuberculous mycobakteria (NTM). The most often NTM include Mycobacterium avium complex (MAC, Mycobacterium avium and Mycobacterium intracellulare) and Mycobacterium abscessus. Mycobakterioses are the most freguent in patients with HIV infection, with immunosuppressive conditions, with history of tuberculosis, miner’s lung, CF, COPD and in heavy drinkers [171−173]. Recommendations regarding treatment of mycobakterioses were developed based on observation of small group of patients and experts’ opinions. Macrolide antibiotics are important element of multi-drug strategies and the treatment last for many months or years [174].

 

  1. Basic drug in the treatment of infections caused by MAC is clarithromycin or azithromycin, which is combined with etambutol (EMB) and rifampicin (RMP) or rifabutin [IVD] [175, 176]. For clarithromycin drug-sensitivity of MAC should be assessed [IIIC] [177].

  2. Mycobakteriosis caused by Mycobacterium kansasii is treated with isoniazid (INH), RMP and EMB or RMP, EMB and macrolide (clarithromycin, azithromycin) [IVD] [175]. In case of resistance to RMP it is recommended to use the drugs of in vitro confirmed sensitivity in triple-drug schedule including: clarithromycin or azithromycin, moxifloxacin, EMB, sulfamethoxazole or streptomycin (SM) [IVD] [178].

  3. In Mycobacterium abscessus infections 3 or 4 among following drugs are used: amikacin, imipenem, cefoxitin, tigecycline, linezolid, macrolide [IV] [172, 176].

  4. Treatment of infection of Mycobcterium abscessus subsp. boletti includes administration of macrolide in combination with two among following drugs: amikacin, cefoxitin, imipenem, linezolid [IVD] [172, 176].

  5. Mycobakteriosis caused by Mycobacterium xenopi and Mycobacterium malmoense is treated leczy as mycobakteriosis MAC [IVD] [179, 180].

  6. Mycobakteriosis caused by Mycobacterium fortuitum is treated according to drug-sensitivity: with azithromycin or clarithromycin plus EMB or RMP with possible adding one or more among following drugs: doxycycline, amikacin, imipenem, fluorochinolone, sulfonamide, cefoxitin [IVD] [174, 175].

  7. In the treatment of MAC in patients with HIV infection at least two drugs are used — clarithromycin or azithromycin and EMB, also rifabutin is added as third drug [IVD] [180].

 

Initial dosage of clarithromycin in infections caused by NTM in adults is 1 g/d in 2 doses. If there is no clinical or microbiological improvement after 3–4 weeks the dose could be increased to 2 g/d in 2 doses. In prevention of infections caused by MAC in adults clarithromycin is recommended 1 g/d in 2 doses. Azithromycin in MAC infections in adults is used in the dose of 250 mg/d.

 

Conflict of interest

The authors decleare no conflict of interes.

 

Address for correspondence: Andrzej Emeryk, Clinic of Lung Disease and Pediatric Rheumatology, Medical University, ul. A. Gębali, 120−093 Lublin, tel. 81 718 54 77, e-mail: andrzejemeryk@plusnet.pl

DOI: 10.5603/PiAP.2016.0003

Received: 12.11.2015

 

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Czasopismo Pneumonologia i Alergologia Polska dostęne jest również w Ikamed - księgarnia medyczna

Wydawcą serwisu jest "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail: viamedica@viamedica.pl