Table 1. In vitro activity of ketolides and comparator macrolides against aerobic gram-positive bacteria

Organism

Ketolide

 

 

 

 

Macrolide

 

 

 

 

 

Telithromycin

Cethromycin

 

Azithromycin

Clarithromycin

 

MIC50

MIC90

Range

MIC50

MIC90

Range

MIC50

MIC90

Range

MIC50

MIC90

Range

 

 

 

 

 

 

 

 

 

 

 

 

 

Streptococcus pneumoniae

0.015

0.06

£0.001 - ³64

0.004

0.03

£0.001 - ³64

0.12

³64

0.008 - ³64

0.03

³64

0.001 - ³64

Erythromycin Susceptible

0.008

0.016

£0.001 - 0.12

0.004

0.004

£0.001 - 0.06

0.06

0.25

0.008 - 64

0.03

0.06

0.001 - 1

ErmB Resistance

0.06

0.12

£0.001 - ³64

0.004

0.06

0.002 - ³64

³64

³64

1 - ³64

³64

³64

0.25 - ³64

MefA Resistance

0.06

0.5

0.002 - 2

0.004

0.12

£0.002 - 1

4

16

0.5 - 64

1

4

0.06 - ³64

 

                        

Streptococcus pyogenes

0.015

0.015

0.002 - ³64

0.008

0.008

£0.002 - 32

0.12

0.25

0.001 - ³64

0.03

0.06

0.001 - ³64

Erythromycin Susceptible

0.015

0.015

0.002 - 0.25

0.008

0.008

£0.002 - 0.008

0.12

0.25

0.001 - 0.5

0.015

0.015

0.001 - 0.06

ErmA Resistance

0.06

0.12

0.008 - 0.25

0.03

0.06

£0.015 - ³1

32

³64

0.5 - ³64

8

8

0.25 - ³64

ErmB Resistance

2

16

0.12 - ³64

0.12

2

£0.002 - 32

³64

³64

0.5 - ³64

³64

³64

0.25 - ³64

MefA Resistance

0.5

0.5

0.004 - 2

0.12

0.12

£0.002 - 0.5

8

16

1 - 32

2

8

0.06 - 8

 

                        

Streptococcus agalactiae

0.015

0.06

0.004 - 2

0.008

0.03

0.008 - 0.12

0.06

0.12

0.008 - ³32

0.03

0.06

0.008 - ³32

Viridans group Streptococci

0.06

0.12

0.002 - 2

0.008

0.06

£0.008 - 1

2

8

0.008 - ³64

0.5

8

0.001 - ³64

 

                        

Staphlococcus aureus

0.06

0.12

0.008 - ³64

0.03

0.03

£0.008 - ³64

2

³64

0.25 - ³64

0.25

³64

0.06 - ³64

Erythromycin Susceptible

0.06

0.06

0.008 - 0.5

0.03

0.03

0.008 - 0.25

2

2

0.25 - ³16

0.25

0.25

0.06 - 0.5

Erythromycin Resistant

2

³64

0.03 - ³64

³64

³64

£0.008 - ³64

32

³64

0.5 - ³64

³64

³64

1 - ³64

CNS

0.06

32

0.03 - ³64

0.03

8

£0.015 - ³64

1

16

0.06 - ³64

0.25

³64

0.03 - ³64

 

                        

Enterococcus species

0.06

4

0.004 - ³64

0.03

8

0.004 - ³64

16

³64

0.06 - ³64

2

³64

0.03 - ³64

Enterococcus faecalis

0.06

4

0.004 - ³16

0.03

8

0.004 - ³64

16

³64

0.03 - ³64

2

³64

0.03 - ³64

Enterococcus faecium

8

8

0.015 - ³16

1

8

0.008 - ³64

16

16

2 - ³64

³64

³64

0.06 - ³64

Corynebacterium species

0.004

0.008

0.002 - ³64

0.008

0.008

0.002 - 0.5

³64

³64

£0.015 - ³64

0.008

0.008

0.004 - ³64

Listeria monocytogenes

0.06

0.06

0.03 - 0.06

0.03

0.03

0.03 - 0.06

1

1

0.5 - 2

0.12

0.12

0.06 - 0.25

 

Macrolide resistance genotypes named according to the proposal set forth by Roberts et al. (161)

MIC50 = minimum inhibitory concentration of 50% of isolates, MIC90 = minimum inhibitory concentration of 90% of isolates, n.d. = data not available, CNS = Coagulase negative Staphylococci

 

Adapted from References:

Telithromycin: (5, 7, 13-15, 20, 28, 47, 50, 54, 61, 67, 70, 77, 80, 90, 94-98, 102, 112, 113, 116, 118, 121, 123-125, 127, 129, 130, 133-135, 137, 144, 147, 160, 167, 169, 172, 173, 177, 183, 192, 193); Cethromycin: (7, 12, 31, 47, 49, 58, 74, 82, 83, 95, 101, 139, 157, 172-174, 176, 190, 192, 199); Clarithromycin: (7, 20, 28, 31, 47, 49, 54, 61, 67, 70, 74, 80, 82, 90, 94, 96-98, 101, 121, 123-125, 127, 133-135, 139, 144, 147, 157, 160, 167, 177, 183, 192, 193, 198) ; Azithromycin: (12, 15, 20, 31, 47, 49, 54, 61, 67, 70, 74, 80, 82, 94, 96-98, 101, 102, 116, 121, 123-125, 127, 133-135, 139, 144, 147, 157, 160, 167, 177, 183, 192, 193, 198, 199)

 

 

Table 2. In vitro activity of ketolides and comparator macrolides against aerobic gram-negative bacteria

Organism

Ketolide

 

 

 

 

Macrolide

 

 

 

 

 

Telithromycin

Cethromycin

 

Azithromycin

Clarithromycin

 

MIC50

MIC90

Range

MIC50

MIC90

Range

MIC50

MIC90

Range

MIC50

MIC90

Range

 

 

 

 

 

 

 

 

 

 

 

 

 

Haemophilus influenzae

1

2

0.002 - 16

2

4

0.001 - 16

2

4

0.001 - ³64

8

16

0.008 - ³64

Moraxcella catarrhalis

0.06

0.12

0.001 - 4

0.06

0.06

£0.002 - 0.5

0.06

0.12

0.008 - ³64

0.12

0.12

0.008 - ³64

Neisseria species

0.12

0.12

0.001 - 4

0.015

0.25

0.001 - 0.5

0.12

0.25

£0.015 - 8

0.25

1

0.001 - 8

Neisseria gonorrhoeae

0.06

0.12

0.002 - 1

0.015

0.25

0.001 - 0.5

0.12

0.25

0.015 - 0.5

0.25

1

0.001 - 2

Neisseria meningitidis

0.015

0.12

0.002 - 0.5

0.015

0.12

0.004 - 0.12

0.5

1

0.25 - 2

0.12

0.5

0.004 - 1

Bordetella pertussis

0.015

0.03

0.004 - 0.06

n.d

n.d

n.d.

0.03

0.06

0.008 - 0.06

0.06

0.06

0.015 - 0.12

Helicobacter pylori (Ery S)

n.d

0.5

n.d.

0.12

0.25

0.008 - 0.25

0.25

0.5

0.06 - 0.5

0.015

0.03

£0.004 - 0.03

Helicobacter pylori (Ery R)

n.d

³64

n.d.

32

³64

4 - 64

³64

³64

³64

n.d.

n.d.

n.d.

 

MIC50 = minimum inhibitory concentration of 50% of isolates, MIC90 = minimum inhibitory concentration of 90% of isolates, n.d. = data not available

Adapted from References:

Telithromycin: (7, 14, 24, 28, 61, 96, 97, 99, 102, 112, 146, 152, 165, 193); Cethromycin: (7, 12, 31, 45, 58, 74, 82, 83, 139, 149, 157);

Clarithromycin: (7, 14, 24, 28, 31, 45, 61, 74, 82, 94, 97, 99, 139, 146, 149, 152, 157, 165, 193, 198); Azithromycin: (12, 14, 24, 31, 45, 61, 74, 82, 94, 97, 99, 139, 146, 152, 157, 165, 193, 198)

 

 

Table 3. In vitro activity of ketolides and comparator macrolides against anaerobic bacteria

Organism

Ketolide

 

 

 

 

Macrolide

 

 

 

 

 

Telithromycin

Cethromycin

 

Azithromycin

Clarithromycin

 

MIC50

MIC90

Range

MIC50

MIC90

Range

MIC50

MIC90

Range

MIC50

MIC90

Range

 

 

 

 

 

 

 

 

 

 

 

 

 

Bacteroides species

8

³64

0.015 - ³64

4

4

0.001 - ³64

8

³64

0.06 - ³64

4

³64

0.06 - ³64

Bacteroides fragilis

16

16

0.06 - ³64

2

4

0.06 - ³64

8

³64

0.25 - ³64

2

³64

0.06 - ³64

Clostridium species

0.12

³64

0.004 - ³64

0.03

³64

0.004 - ³64

2

³64

0.12 - ³64

0.5

³64

0.06 - ³64

Clostridium perfringens

0.12

0.25

0.004 - 0.25

0.03

0.03

0.03 - ³64

0.5

1

0.25 - 4

0.5

1

0.12 - 1

Clostridium difficile

0.25

³64

0.03 - ³64

0.25

³64

0.03 - ³64

8

³64

0.5 - ³64

0.5

³64

0.12 - ³64

Fusobacterium species

³64

³64

0.008 - ³64

0.5

³64

0.008 - ³64

8

³64

£0.015 - ³64

³64

³64

£0.015 - ³64

Peptostreptococcus species

0.06

0.06

0.002 - ³64

0.03

0.03

0.004 - ³32

4

³64

0.015 - ³64

0.06

³64

£0.008 - ³64

 

MIC50 = minimum inhibitory concentration of 50% of isolates, MIC90 = minimum inhibitory concentration of 90% of isolates, n.d. = data not available

Adapted from References:

Telithromycin: (2, 7, 28, 41, 66, 80, 81, 125, 191); Cethromycin: (7, 41, 72, 82, 83, 139, 175); Clarithromycin: (7, 28, 41, 80-82, 125, 139, 175, 198); Azithromycin: (41, 80-82, 125, 139, 175, 198)

 

 

Table 4. Pharmacokinetic properties of telithromycin and cethromycin

Drug

Dosage

(mg)

% F

 

Cmax

(mg/mL)

Tmax

(h)

AUC

(mg*h/L)

T ½ 

(h)

Vd/F

(L)

% Protein

Binding

% Excreted

Unchanged

Dose Adjustment a

 

Effect of Food on Absorption b

References

 

 

 

 

 

 

 

 

 

 

Renal

Hepatic

 

 

Telithromycin

800

60

1.90

1.0

9.0

 7.2

n.d.

70%

12.7

Yes

No

«

 

(23, 27, 65, 108, 136, 150, 154) 

Cethromycin

 

 

 

 

100

200

400

600

800

1200

n.d.

0.14

0.18

0.61

1.19

0.99

1.17

0.9

1.5

2.3

2.7

3.9

5.1

0.63

0.87

3.84

6.83

9.55

10.96

3.6

5.3

6.7

5.6

6.7

6.6

940

1975

1366

1674

1255

1300

n.d.

n.d.

n.d.

n.d.

«

(155, 156)

 

150

n.d.

0.32

1.8

1.66

5.66

n.d

n.d.

n.d

n.d

n.d

n.d

(153)

 

n.d. = no data

F = bioavailability; Cmax = peak concentration reached in the plasma; Tmax = time to reach Cmax; AUC = area under the concentration time curve; T ½ = half life; Vd = volume of distribution

a: dosage adjustment refers to whether or not the ketolide requires any dosage adjustment in patients with impaired renal or hepatic function

b: effect of food on absorption refers to whether food increases (­), decreases (¯) or does not affect («) absorption

 

Table 5. Tissue distribution of telithromycin

 

Tissue/Plasma or Fluid/Serum Ratio

 

References

Site

Bronchial Mucosa a

Epithelial Lining Fluid a

Saliva c

Sputum e

Middle Ear Fluid d

Tonsils d

Sinus Fluid d

WBC a

Alveolar Macrophages a

PMNLs b

Telithromycin

12.1

16.8

1.6

4.8

2.4

7.8

4.0

³500

³500

135 - 613

(65, 76, 105, 108, 109, 119, 126, 128, 131, 148, 185, 188) 

 

PMNL = polymorphonuclear leukocyte

a: data reported as the ratio of tissue or fluid concentration over plasma concentration 24 hours after last dose.

b: results reported from in vitro experiments and show variation depending upon source of the PMNs, extracellular antibiotic concentration and time point of sample

c: results reported as a ratio of AUCsaliva/AUCplasma.

d: results reported as a ratio of tissue or fluid concentration over plasma concentration 6 hours after a single dose

e: results reported as a ratio of maximum sputum concentration/maximum plasma concentration after telithromycin 600 mg once daily for 7 days

 

 

 

Table 6.  Adverse Effects Reported for Telithromycin [Adapted from (108, 171)]

 

Adverse effects

Telithromycin

Gastrointestinal

 

Abdominal pain

+

Nausea

++

Vomiting

+

Diarrhea

+++

Blurred vision

+

Allergic reactions

+/-

Hepatic function abnormality

+

Ototoxicity

-

Taste perversion

+

Cardiovascular events

+/-

Central nervous system

 

   Headache

+

   Dizziness

+

            - indicates adverse effect has not been observed; +/- indicates adverse effect occurs in <1% of patients; + indicates that adverse effect occurs in 1 – 5% of patients; ++ indicates that adverse effect occurs in 5 – 10% of patients; +++ indicates adverse effect occurs in >10% of patients.

 


 

Figure 1. Chemical Structure of Telithromycin and Cethromycin.


 

Figure 2. Structure Activity Relationship of the Ketolide Antibiotics.


Figure 3. A: Schematic representation of the bacterial 23S rRNA secondary structure. Boxed are (B) hairpin 35 of domain II, and (C) the central loop of domain V of the rRNA. The encircled nucleotides A752, A2058, A2059 and G2505 (E. coli numbering) constitute the binding site for macrolide and ketolide antibiotics (92, 194)