Scandinavian Journal of Infectious Diseases

ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19

Comparative effects of clarithromycin and erythromycin on the normal intestinal microflora Bo Brismar, Charlotta Edlund & Carl ERIK Nord To cite this article: Bo Brismar, Charlotta Edlund & Carl ERIK Nord (1991) Comparative effects of clarithromycin and erythromycin on the normal intestinal microflora, Scandinavian Journal of Infectious Diseases, 23:5, 635-642, DOI: 10.3109/00365549109105189 To link to this article: http://dx.doi.org/10.3109/00365549109105189

Published online: 08 Jul 2009.

Submit your article to this journal

Article views: 14

View related articles

Citing articles: 2 View citing articles

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [University of California, San Diego]

Date: 15 April 2016, At: 19:05

Scand J Infect Dis 23: 635442, 1991

Comparative Effects of Clarithromycin and Erythromycin on the Normal Intestinal Microflora BO BRISMAR’, CHARLOTTA EDLUND’ and C A R L ERIK NORD’ ’

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

From the Departments of ‘Surgery and ‘Microbiology, Huddinge University Hospital. Karolinska Inslitute and ’National Bacteriological Laboratory, Stockholm, Sweden 10 healthy volunteers received 250 mg of clarithromycin orally q 12 h for 7 days and 10 other volunteers 1000 mg of erythromycin ethylsuccinate orally q 12 h for 7 days. Stool specimens were collected before, during and after antibiotic administration. In the clarithromycin group, the numbers of streptococci and enterobacteria decreased among aerobic microorganisms while in the erythromycin group streptococci, enterococci and enterobacteria decreased and staphylococci increased during antibiotic administration. The anaerobic intestinal microflora was also affected. The alterations were more pronounced in the volunteers receiving erythromycin than in those having clarithromycin.

C . E . Nord, MD, PhD, Department of Microbiology, Huddinge University Hospital, S-141 86 Huddinge, Sweden

INTRODUCTION Oral antibiotics which are excreted in the bile, in the intestinal mucosa or are incompletely absorbed are known to affect the normal intestinal microflora (1). Several adverse effects have been described. One is the development of antibiotic resistance among the bacteria in the normal microflora. A second effect is overgrowth of microorganisms already present, such as Candida albicans, which may cause systemic infections in immunocompromised patients and of Clostridium difficile, which may lead to diarrhoea or colitis. A third consequence is the reduction of colonization resistance, i.e. the resistance displayed by the host to implantation of new microorganisms in the normal intestinal microflora. Clarithromycin is a new acid stable derivate of 14-membered macrolides with an antibacterial spectrum similar to erythromycin, but a significantly increased potency against microorganisms traditionally considered to be susceptible to erythromycin (2). Clarithromycin achieves higher serum levels after oral administration than erythromycin and has a serum half-life which is twice that of erythromycin ( 3 ) . Clarithromycin is expected to retain the clinical indications of erythromycin, which are respiratory tract infections, skin and soft tissue infections and genital tract infections caused by erythromycin susceptible microorganisms. All new antibiotics which are going to be used in clinical medicine should be investigated for their influence on the normal intestinal microflora (4). The aim of the present study was to compare the effect of clarithromycin and erythromycin on the normal human intestinal microflora.

MATERIAL A N D METHODS Subjects 20 volunteers, 10 men and 10 women (mean age 32 years, range 20-43), participated in the investigation. They were healthy according to medical history, physical examination and clinical laboratory tests. The volunteers had not taken any antimicrobial agents during the previous 3 months. No

636 B. Brismar et al.

S c a d J Infect Dis 23

Table I . Concentration of clarithromycin in faeces of 10 volunteers receiving 250 mg clarithromycin every 12 h for 7 days

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

Day

0 2 4 7 9 11 14 21

Clarithromycin in faeces (mg/kg) Mean value

SEM

Range

0 100 81 92 59 6 0 0

0 f 24 f 12 f20 f15 * 4 0 0

0 41-243 39-128 41-194 25-1 11 @29 &1 0

other medication was allowed during the investigation period. The subjects were informed both verbally and in writing about the aim of the study and they gave their consent to participate. The study was approved by the Ethics Committee of Huddinge University Hospital, Karolinska Institute, Sweden.

Antibiotic administration 10 volunteers were given 250 rng of clarithromycin orally b.i.d. for 7 days and the other 10 volunteers 1000 mg of erythromycin ethylsuccinate orally b i d . for 7 days. The tablets were taken with 50 rnl of water.

Sampling procedures for assay of clarithromycin and erythromycin Stool specimens were taken before antibiotic administration and on the 2nd, 4th and 7th days during the administration period and again 2, 4, 7 and 14 days after withdrawal of the antibiotic. The specimens were collected in sterile plastic containers and stored at -70°C until assayed.

Assay of clarithromycin and erythromycin in faeces The faecal concentrations of clarithromycin and erythromycin respectively were determined by the agar diffusion method. The test medium was Bacto Antibiotic Medium No. 1 (Difco) and the indicator strain was Sarcina lutea ATCC 9341. The concentrations of clarithromycin and erythromycin were determined

Table 11. Concentrations of erythromycin in faeces of 10 volunteers receiving 1000 mg erythromycin every 12 h for 7 days Day

0 2 4

7 9 11 14 21

Erythromycin in faeces (mgikg) Mean value

SEM

Range

0 347 820 978 699 360 2 0

0 f52 f157 f219

0 295-399 416-1329 705-141 2 345-929 1-1080

3~10.5 f226 +1 0

0

Clarithrom icin and erythromycin and intestinal microflora 637

Scand J Infect Dis 23

CLARITHROMYCIN

CLARITHROMYCIN I

I

I

-

I

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

,

3 I

I

I

t

1

907-

6-

54-

3-

,

s

I

.

'

.

8

I

,

,

. .

1

.

.

I

:

= ; I

i

1

I

I

I

,

,

6-

. . .

4 - .

.

9

.

I

:

1 1

9 0

-

7

-

6

-

5 4

-

3

-

s2

-

7

-

6

5 4

,-

22

-

,

,

9 0

-

8

8

:l 4

ENTEROBACTERIA

I

-

1

< 2 * l

-

-

BAClLL I

90 7-

1

4

I

STAPHYLOCOCCI MICROCOCCI

< Z - @ I I

c3

, , ,

I

.

7

,

,

ESCHERICHIA COLl

7

I

B

,

8

ENTEROCOCCI

2

I

CORYNEBACTERIA

STREPTOCOCCI

I

,

,

,

YEAST

3

: 0

2

4

7 9 1 1 1 4

21

0

2

4

7 9 1 1 1 4

21

DAYS DAYS Fig. 1 . Effect of clarithromycin on the aerobic intestinal nn icroflora of 10 volunteers given 250 mg b.i.d for 7 days (= interpolated geometric mean values).

in relation to diameters of inhibition zones caused by known concentrations of the antibiotics from the standard series. From stock solution, standard solutions were prepared in faeces.

Processing of specimens for microbiological analysis The stool specimens were suspended in prereduced peptone-yeast extract medium. They were diluted,

638 B. Brismar et al.

Scand J Infect Dis 23

CLARITHROMYCIN 1

1

1

1

1

1

I

1

1

,

1

87-

,

,

I

1

1

I

I

-

CLOSTRIDIA

9-

ANAEROBIC COCCI

9

CLARITHROMYCIN

r

8-

654-

-

12 3-

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

I

,

,

,

I

,

VEILLONELLA

987654-

352-

-., I

-

. L

1

. . -..

9-

I

l

l

I

I

BACTEROIDES

07

j

6

5 4 5 23

EUBACTERIA

.O

2

4

7

9 11

14

21

DAYS

1

1

0

'

2

1

'

4

1

1

7 9 1 1

'

1

14

21

DAYS

Fig. 2. Effect of clarithromycin on the anaerobic intestinal microflora of 10 volunteers given 250 mg b.i.d. for 7 days (= interpolated geometric mean values).

inoculated on selective media, and manipulated as described by Heimdahl and Nord ( 5 ) . Aerobic and anaerobic microorganisms were identified using morphological, biochemical, serological tests and gas-liquid chromatography. The antibiotic susceptibility for clarithromycin and erythromycin was determined for different new colonizing bacterial strains isolated from stool specimens before treatment, on the 7th day of treatment and again 14 days after the withdrawal of the antibiotics.

I

l

l

I

9-

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

zI

8 -

re

5-'

0

4 -

rn I

3 -

.

.

...

0

b

I

I

.

l

l

I

l

.

3 5 2 - 1 2

0

I

I

l

I

I

l

l

I

.-

5 2 -

1

-

9

.

.

= : l

l

I

I

I

I

I

1

1

I

1

I

ESCHERICHIA COLl

.

..-

I I

ENTEROEACTERIA

I

-

I -

.l

l

I

I

6 5 -

I

I

-

1 1

-

-

. 1

,

a -

.

. 1

-

9 -

-

a -

5 - .

-

I

BACILLI

6 -

-

-

I

9 7 -

I

I

7 -

1

7 -

1

9,

6 5 -

-

a 7 6 5 -

I

a-

.. .. ~

1

7 -

-

..' . I

1

CORYNEEACTERIA

,

STAPHYLOCOCCI

9 -

I

s

I

7 6 - ' .

1

l

a -

I

I

ENTEROCOCCI

v , ~ ~ - II I z a 0 re 0

I

l

9 -

-

I

9 -

a

-

'

w

Y

I

1

-

I

rn

I

l

STREPTOCOCCI

a765-

l

.

,

,

I

,

,

I

YEAST

98 ? -

65-

.

4 -

3 -

I

=

I

.

I

i -

22I

,

,

I

l

l

1

-

RESULTS

Concentrations of clarithromycin and erythromycin in faeces The mean faecal concentrations of clarithromycin are shown in Table I . The concentrations varied between 25 and 243 mg/kg during days 2-9. The concentrations of erythromycin in faeces were several times higher than those of clarithromycin. High concentrations of

640 B. Brismar et al.

Scand J Infect Dis 23

ERYTHROMYCIN

ERYTHROMYCIN ,

ANAEROBIC COCCI

8 -

7 -

6 -

6

3

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

52

I

,

I

___i/ LACTOBACILL I

52

,

,

1

.

. ..

I

1

I

'

I

l

l

1 1 1 I

,

,

. I

87 -

.-

54

v, = z

52

U U K 0

3

0 I a

W i n

:I,-

I

52

,

B 9 8 7 5

9 -

t- '.... -A. :

. ..

8'

.

4

1 3I = 52 -

' I

(3

s

.. 8

7 -

5 4 -

I

I

7 '

I

,

/1

I

,

,

I

I

BACTEROIDES

.

I

I

6' 5 ' 4 '

3 52

.

...

8

EUEACTERIA

9 8 6 -

1 1 1

I '

VEILLONELLA

9 -

6 m

1

CLOSTRlDlA

9-

0

2 '4

7

9 11

14

21

DAYS .

1

J'li

3 22 I

-

0

2

4

7 9 1 1 1 4

21

DAYS Fig. 4. Effect of erythromycin on the anaerobic intestinal microflora of 10 volunteers given 1000 mg b.i.d. for 7 days (= interpolated geometric mean values).

erythromycin were detected in faeces from the first day of administration until 4 days after withdrawal of the antimicrobial agent (Table 11).

Effect of clarithromycin on the intestinal microflora The aerobic intestinal microflora was partly affected by the administration of clarithromycin (Fig. 1). The numbers of streptococci and enterobacteria were suppressed during the

Scand J Infect Dis 23

Clarithromycin and erythromycin and intestinal microflora 641

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

administration of clarithromycin but returned to normal levels 2 weeks after the administration period. No significant changes were seen in the numbers of enterococci, staphylococci, micrococci, bacilli, or corynebacteria. Two subjects became colonized by Candida albicans ( 102-103 CFU/g) during clarithromycin administration. In the anaerobic microflora, the numbers of lactobacilli, bifidobacteria, and bacteroides were suppressed by clarithromycin administration (Fig. 2). The number of lactobacilli was reestablished in all subjects on day 21. while bifidobacteria and bacteroides did not recover in numbers in all volunteers within 2 weeks after the administration period. Anaerobic cocci, eubacteria, clostridia, and veillonella did not change significantly in numbers during the investigation period.

Effect of erythromycin on the intestinal microflora The aerobic intestinal microflora was considerably affected by the erythromycin administration (Fig. 3). Streptococci were eliminated and the number of enterobacteria was strongly suppressed during the administration period. There was a minor reduction in the numbers of enterococci and corynebacteria, while the number of staphylococci increased in 6 subjects during the administration of erythromycin. Five volunteers became colonized by C. albicans during the antibiotic administration (102-104 CFU/g). The aerobic microflora returned to almost pretreatment levels within 21 days. The anaerobic intestinal microflora was strongly suppressed by the administration of erythromycin (Fig. 4). The numbers of lactobacilli, bifidobacteria, clostridia, and bacteroides were markedly reduced during the administration period. Two subjects became colonized by resistant clostridia during the administration of erythromycin. The numbers of lactobacilli and bifidobacteria returned to normal levels on day 21, while clostridia and bacteroides did not return to pretreatment levels in all volunteers within 2 weeks after the erythromycin administration.

Side effects Seven subjects experienced side effects during the investigation period. In the clarithromycin group, 1 volunteer suffered from mild diarrhoea and 1 complained of tiredness. In the erythromycin group, 6 adverse effects were reported by 5 subjects: nausea (2 subjects), abdominal pain, meteorism, vertigo, and itching. The symptoms were mild to moderate and resolved without specific measures except for the volunteer suffering from abdominal pain, where a dosage reduction of erythromycin was done. No change was noticed in serum or urine chemistry.

DISCUSSION The bioavailability of orally administered erythromycin is influenced by the acidity in the stomach, and individual variations of absorbance are common (6). Clarithromycin is an acid stable macrolide derivate with higher bioavailability than erythromycin. Earlier ecological studies of erythromycin have shown that the agent causes high levels in the intestine and causes reductions in numbers of both aerobic and anaerobic bacteria (7). Overgrowth of resistant microorganisms induced by lowered colonization resistance has also been reported after erythromycin administration (7). Pseudomembranous colitis due to Clostridium difficile caused by erythromycin therapy has been reported in Sweden (8). The results of the present study indicate lower intestinal concentrations of clarithromycin than of erythromycin which is in accordance with the superior absorption of clarithromycin. The alterations in the intestinal microflora reflect the concentrations of antibiotics in faeces for the two agents. Administration of clarithromycin caused moderate suppression of both

Downloaded by [University of California, San Diego] at 19:05 15 April 2016

642 B. Brismar et al.

Scand J Infect Dis 23

the aerobic and anaerobic intestinal microflora and no overgrowth of resistant microorganisms was seen. The aerobic and anaerobic microflora returned to pretreatment levels in most subjects within 2 weeks after the administration period. Administration of erythromycin lead to strong suppression of the aerobic intestinal microflora with more pronounced effects on streptococci and enterococci compared to clarithromycin. Overgrowth of resistant staphylococci was seen in 6 volunteers, and 5 subjects became colonized by yeasts during the administration period compared to 2 volunteers in the clarithromycin group. The impact on the anaerobic intestinal microflora was more pronounced in the erythromycin group than in the clarithromycin group. Clostridia were reduced in numbers in 7 subjects receiving erythromycin and new colonization with resistant clostridia was noticed in 2 volunteers. Erythromycin is known to b e associated with gastrointestinal side effects. 5-30% of patients treated with erythromycin are reported to experience gastrointestinal side effects depending on the dose (9). The side effects are often mild and transient but occasionally lead to interrupted treatment. The gastrointestinal side effects are probably caused by degradation products formed under acidic conditions in the stomach (10) and by the marked disturbances of the normal gastrointestinal microflora (7). 5/8 side effects reported by the volunteers in the present study were of gastrointestinal nature. In the clarithromycin group, 2 subjects suffered from adverse effects, mild diarrhoea and tiredness, respectively. Five subjects receiving erythromycin reported 6 side effects, 4 of which were gastrointestinal. In conclusion, the results of the present study indicate that clarithromycin causes less pronounced alterations in the aerobic and anaerobic intestinal microflora and seems to cause fewer gastrointestinal side effects compared to the older macrolide compound erythromycin. REFERENCES 1. Nord CE, Edlund C. Impact of antimicrobial agents on the intestinal microflora. J Chemother 2: 218-237, 1990. 2. Kirst HA, Sides GD. New directions for macrolide antibiotics: Structural modifications and in vitro activity. Antimicrob Agents Chemother 33: 1413-1418, 1989. 3. Kirst HA, Sides GD. New directions for macrolide antibiotics: Pharmacokinetics and clinical efficacy. Antimicrob Agents Chemother 33: 1419-1422, 1989. 4. Nord CE. Studies on the ecological impact of antibiotics. Eur J Clin Microbiol Infect Dis 9: 517-518, 1990. 5. Heimdahl A, Nord CE. Effect of phenoxymethylpenicillin and clindamycin on the oral, throat and faecal microflora of man. Scand J Infect Dis 10: 233-242, 1979. 6. Simon C . Pharmacokinetics of erythromycin in healthy adults and in adults with respiratory infections. Curr Med Res Opin 6, Suppl 8: 17, 1980. 7. Heimdahl A, Nord CE. Influence of erythromycin on the normal human flora and colonization of the oral cavity, throat and colon. Scand J Infect Dis 14: 49-56, 1982. 8. Aronsson B, Mollby R , Nord CE. Antimicrobial agents and Clostridium difficile in acute enteric disease. Epidemiological data from Sweden 1980-1982. J Infect Dis 151: 476481, 1985. 9. Keller H, Follath F. Erythromycin. In: Dukes MNG, ed. Meyler’s side effects of drugs, 11th ed. Amsterdam: Elsevier, 557, 1988. 10. Omura S, Tsuzuki K, Sunazuka T, Marui S, Toyoda H, lnatomi N, Itoh 2. Macrolides with gastrointestinal motor stimulating activity. J Med Chem 30: 1941-1943, 1987.