Table 1. Spectrum of Activity Of Macrolide Antibiotics (wild strains) MIC values or ranges in g/ml)

Bacteria

Erythro-mycin

Roxithro-  mycin

Clarithro-mycin

Dirithro-mycin

Azithro-mycin

Mioca-mycin

Josa-mycin

Spira-mycin

Rokita-mycin

Staphylococcus aureus (MSSA) a

0.1-0.5

0.2-0.5

0.06-0.5

0.02-2

0.02-1

0.5-4

0.5-64

0.25-64

0.25-4

Streptococcus pneumoniae

0.015-1

0.05-0.2

0.015-0.5

0.06-1

0.06-2

0.12-0.5

0.03-0.12

0.015-0.03

0.12

Streptococcus pyogenes

0.03-0.06

0.03-0.06

0.015-0.015

0.03-0.12

0.03-0.12

0.25-0.5

0.06-0.25

0.06-0.12

0.12-0.25

Haemophilus influenzae

1-8

1-8

1-8

0.2-32

0.2-4

16  ->16

4-32

4-16

4-16

Chlamydia pneumoniae

0.06

0.25

0.007

0.5

< 2

 

4-32

4-16

 

Moraxella catarrhalis

0.1-0.5

0.5-2

0.06-2

0.1-1

0.01-0.1

 

0.25

4

 

Legionella pneumophila

0.1-1

0.06-0.5

0.1-0.5

0.5-4

0.125-0.5

0.1-0.5

0.5-1

8-64

0.12-0.25

Helicobacter pylori

0.1

0.07

0.03

0.06-0.5

0.2

 

0.5-1

8-64

 

Chlamydia trachomatis

0.06-1

0.015-2

0.004-0.2

1

0.03-0.06

0.06

 

 

 

Borrelia burgdorferi

0.03-0.12

0.015-0.12

0.015-0.12

< 0.5

0.015-0.12

 

 

 

 

Mycobacterium avium and complex

32-64

8-32

0.5-8

 

8-32

 

 

 

 

a MRSA are usually resistant to macrolides

Data from (45, 174, 175, 177, 327, 345, 354, 358)

Table 2. Clinically Relevant Mechanisms of Resistance to Macrolide Antibiotics, Phenotype and Frequency of the Resistant Strains.

Bacterial species

% resistance

mechanism

genetic support

phenotype

frequency

references

S. aureus

> 80 % MRSA

~ 40 % MSSA

Ribosomal methylation

erm(A), (C)

MLSB

> 80%

(378, 379)

efflux

msr(A)

MSB

< 10 %

Antibiotic inactivation

 

 

rare

S. pneumoniae

~ 30 %

Ribosomal methylation

erm(B)

MLSB

~ 65 %

(126)

23S rRNA mutation

 

ML

Rare

r-protein mutation

 

MSB

Rare

Efflux

mef(A)- mef(E)

M

~ 35 %

S. pyogenes

~ 10 %

Ribosomal methylation

erm(A), (B)

MLSB

~ 50 %

(126)

Efflux

mef(A)

M

~ 50 %

Haemophilus influenzae

rare

Ribosomal methylation

 

MLSB

 

(331)

23S rRNA mutation

 

ML

~ 10 %

r-protein mutation

 

MSB

~ 65 %

Efflux

 

M

~ 100 %

Helicobacter pylori

~ 10 %

23S rRNA mutation

 

ML

 

(282)

Mycoplasma

 

Ribosomal methylation

 

MLSB

 

(59)

 

 

23S rRNA mutation

 

ML

 

(249)

Mycobacteria

 

23S rRNA mutation

 

ML

 

(249)

Enterobacteriaceae

 

Antibiotic inactivation

ere

M

 

(249)

 

Table 3. Main Pharmacokinetic Properties of Macrolide Antibiotics

Pharmacokinetic parameter

Erythromycin
(500 mg bid)

(45)

Roxithromycin
(150 mg qd)

(349)

Clarithromycin
(250 mg qd )

(338, 339, 410)

Dirithromycin
(500 mg qd)

(45, 463)

Azithromycin
(500 mg qd)

(136, 338, 339)

Miocamycin
(600 mg qd)

(52)

Josamycin
(500 mg)

(59)

Spiramycin
(6 Mio U.I.) (59)

Cmax (mg/l)

3

6.8

6.8

0.2-0.6

0.4

2-3

1.2

1.2

Tmax (h)

1.9-4.4

2

2.7

3-5

2.5

2

1

2

T (h)

2

8-13

4.4

42

35-40

1

2

8

Vd (l/kg)

0.64

 

3-4

11

23-31

 

 

 

Bioavailability

25-60 %

72-85 %

55 %

6-14%

37%

 

 

 

Protein binding

65-90

73-96

40-70

15-30

12-40

 

10

12

Tissue/serum concentration

0.5

1-2

3-8

20-30

50-1150

 

2-20 b

1-30

AUC (mg.h/l)

4.4-14

70

4.1

3.8

2-3.4

3

7.9

8.5

 

Table 4. Dosages of Macrolides  

 

adult

child

Erythromycin

500 mg 4 X/day

12.5 mg/kg 4 X/day

Roxithromycin

150 mg 2 X/day

3 mg/kg 2 X/ day

Clarithromycin a

250 mg-1000 mg  2 X/day

7.5 mg/kg 2 X/day

Dirithromycin

500 mg 1 X/day

-

Azithromycin

500 mg 1 X/day or
500 mg on day 1 and 250 mg on days 2-5

10 mg/kg on day 1 and 5 mg/kg on days 2-5

Miocamycin a

600 mg 2 X/day

25 mg/kg 2 X/day

Spiramycin

3 Mio U 2-3 X/day

0.075-0.1 Mio U/kg  2-3 X/day

Josamycin a

500 mg 1000 mg 2 X/day

10-20 mg/kg 2-3 X/day

 a  a 3 X/day administration should be preferred to an increase of the dose given 2 X/day in case of less susceptible organism, based on pharmacodynamic considerations (time above MIC).
 

Table 5. Drug Interactions of Macrolides and Therapeutic Attitudes 

Macrolide

Totally contra-indicated

drugs

Drugs to use with caution (requiring a dose reduction and/or a therapeutic monitoring)

Erythromycin

astemizole

cisapride

ergotamine

terfenadine

 

oral anticoagulants

benzodiazepines

bromocriptine

carbamazepine

cyclosporin

clozapine

digoxin

felodipine

lovastatin

sildenafil

theophylline

Roxithromycin

astemizole

cisapride

ergotamine

terfenadine

benzodiazepines

bromocriptine

theophylline

Clarithromycin

astemizole

cisapride

ergotamine

terfenadine

oral anticoagulants

bromocriptine

carbamazepine

cyclosporine

clozapine

digoxin

theophylline

Dirithromycin

astemizole

cisapride

ergotamine

terfenadine

 

Azithromycin

astemizole

cisapride

ergotamine

terfenadine

 

Miocamycin

astemizole

cisapride

ergotamine

terfenadine

carbamazepine

cyclosporine

 

Josamycin

astemizole

cisapride

ergotamine

terfenadine

benzodiazepines

bromocriptine

carbamazepine

cyclosporine

theophylline

Spiramycin

astemizole

cisapride

ergotamine

terfenadine

 

Rokitamycin

astemizole

cisapride

ergotamine

terfenadine

 

 

(based on demonstration of increase in serum level by coadministration with macrolides [interaction with cytochrome P450]) (11, 333, 473)

 

Figure 1. Chemical structure of the macrolide antibiotics currently used in the clinics.  Theses are classified according to the number of atoms in the macrocycle.  All molecules possess an aminated sugar (desosamine) which confers to them a basic character responsible for their cellular accumulation  (azithromycin and erythromycylamine have a second aminated function and are therefore dibasic molecules, which explains their higher level of cellular accumulation).  Erythromycylamine is commercialized as a prodrug (dirithromycin) which is intrinsically inactive but regenerates erythromycylamine in vivo or in vitro (230).

 

Figure 2. Mechanism responsible for the inactivation of erythromycin in acidic medium.  The ketone in position 9 reacts with the hydroxyl in position 6 to generate a hemiketal, which reacts again with the hydroxyl in 12 to produce a ketal.  Both the hemiketal and the ketal are microbiologically inactive.  Neomacrolides (see Figure 1) were made are acidostable by either removing the 9-keto function and replacing it with another function (roxithromycin, erythromycylamine, azithromycin), or by substituting the 6-hydroxyl group (clarithromycin; the same approach has been followed for telithromycin).  16-membered derivatives are intrinsically stable because of the absence of a ketone function in the cycle.  Adapted from (231


 

Figure 3. Macrolides in interaction with their ribosomal target.  Upper panel: 50S ribosomal subunit of Deinococcus radiodurans in cross section, showing the path of the peptide through the tunnel from the peptidyl -transferase site to emerge of the subunit.  The elongating peptide is shown in light blue, the macrolide bound to the ribosome in red, and tRNA in green.  Lower panel: erythromycin in interaction with the ribosome, with the desosamine interacts with adenine 2058 shown in grey.  Color codes: dark blue: domain V; dark mauve: contacts between erythromycin and domain V, violet: domain II, light blue: domain IV; yellow ribbon; L4 protein; green ribbon, L22 protein.  The left panel is a view from the tunnel to erythromycin and the peptidyl transferase site; the right panel is a view from the peptidyl transferase site to the tunnel. The figure also shows the position of the bases involved in the interaction with the antibiotic.  Figure prepared by J.M. Harms, Max-Planck-Research Unit for Ribosomal Structure, Hamburg, Germany.

 


 

Figure 4. Metabolization of erythromycin by cytochrome P450 and formation of an inactive complex.  The tertiary amine of the desosamine is metabolized in nitroso-alkane, which forms a stable, inactive complex with the ion Fe2+ of the cytochrome.  This mechanism is responsible for the inhibition by macrolides of the metabolization of other drugs.  Adapted from (333).