A comparison of the in-vitro activity of clarithromycin, a new macrolide antibiotic, with erythromycin and other oral agents.

Journal of Hospital

Infection

(1991)

19 (Supplement

A), 3-9

A comparison of the in-vitro activity of clarithromycin, a new macrolide antibiotic, with erythromycin and other oral agents A. King Department

and I. Phillips

of Microbiology, UMDS, St. Thomas’ Hospital, London SE1 7EH

Summary:

On the basis of minimum inhibitory concentrations clarithromycin (6-0-methylerythromycin), a new macrolide, was found to be slightly more active than erythromycin against Staphylococcus aureus, enterococci. Moraxella catarrhalis, Gardnerella vaginalis, Bacteroides fragilis (sensu stricto) and B. ureolyticus and slightly less active against coagulase-negative staphylococci, cz- and P-haemolytic streptococci, Haemophilus injluenzae, Campylobatter coliljejuni and the B. melaninogenicusloralis groups. There was complete cross-resistance between the two agents. Reports of potentiation of the activity against Haemophilus influenzae of clarithromycin by its own metabolite and by human serum appear to operate in vivo, and therefore the new agent shows great promise, especially for the treatment of respiratory tract infections. Keywords:

Clarithromycin;

bacterial

susceptibility;

in-vitro

tests.

Introduction Clarithromycin is a new macrolide with a 14-membered ring identical to that of erythromycin, but with a methoxy group rather than an OH group at position 6. This results in improved pharmacological properties and slight but significant differences in antimicrobial activity.‘p2 We investigated the in-vitro activity of clarithromycin and erythromycin, and a number of unrelated, commonly used, oral antibiotics, against a collection of recent clinical isolates of bacteria known to be within the spectrum of the two agents. Materials

and methods

The organisms included in the study are listed in Table I: they were all recent clinical isolates from patients attending St. Thomas’ Hospital, with the exception of one strain of penicillin-resistant Streptococcus pneumoniae from South Africa, kindly provided by Prof. H. J. Koornhof. The antibiotics used were donated by their respective manufacturers. 019S-67Ol:9ljO9AOO3+07

$03 00/O

Q 1991 The Hosprtal

3

Infecmn

Soaety

A. King and I. Phillips

4 Table

I. Comparative

in-vitro activity of clarithromycin

and other oral compounds MIC

(mg 1-l)

Organism (number of isolates)

Compound

Range

MI%

MIC,,

Geometric mean

S. aureus (40)

Clarithromycin Erythromycin Amoxycillin Amoxy/clav Trimethonrim Cefaclor Ciprofloxacin Clindamycin

0.06-> 128 0.066> 128 0.06-32 0.12-16 0.03-8 2-> 128 0.12-2 0.0330.25

0.12 0.12

8 32 8 4 0.5 >128

0.46 0.61 0.69 0.54 0.23 14.9 0.33 0.09

Clarithromycin Erythromycin Amoxycillin Amoxy/clav Trimethonrim Cefaclor * Ciprofloxacin Clindamycin

0.12-> 128 0.12->32 0.03-32 0.03-8 0.12-> 128 0.5> 128 0.06-0.5 0.03- > 32

Clarithromycin Ervthromvcin Amoxycillk Amoxy/clav Trimethoprim Cefaclor Ciprofloxacin Clindamycin

0.1220.25 0.064.25

S. epidermidis (20)

S. saprophyticus

(20)

Other coagulase-negative staphylococci (20)

S. pneumoniae (20)

cr-Haemolytic streptococci

(18)

0~06-0~5 0.124.5 0.0330.25 l-8 0~25-0.5 0.0660.5

;:; 0.25 i.25 0.12 t A.25 1 i.25 0.06

:::2 >128 >32 32 1 >128 128 0.5 0.25

2.83 2.14 1.46 0.44 4.00 6.73 0.23 0.12

0.25 0.25 0.5 0.5 0.25

0.24 0.17 0.37 0.37 0.13 6.06 0.48 0.12

0.25 0.12 0.5 0.5 0.12 8 0.5 0.12

i.5 0.12

Clarithromycin Erythromycin Amoxvcillin Amoxy/clav Trimethoprim Cefaclor Ciprofloxacin Clindamycin

0.12-> 128 0.12-> 128 0.06-64 0.03-l 6 0.25-> 128 0.5-B 128 0.06-l 0~060~25

0.12 0.25 0.5 0.25 1

32 64 64 4

k25 0.12

0.5 0.25

Clarithromycin Erythromycin Amoxycillin Trimethoprim Cefaclor Ciprofloxacin Clindamycin

0.06-> 128 0.06-> 32 0.004-l 0.12-64 0.12-32 0.5-2 0.06- > 32

0.12 0.06 0.008 1 0.5

0.12 0.12 0.016


0.0330.5 0.016-0.12 0~0160~25 0.03-> 128 0.06-16 0.5-2 0~008-0~12

0.12 0.03 0.03 1 4

1;:

h.12

A.03

0.48 0.73 1.23 0.42 1.62 6.06 0.25 0.12

; 2 0.12

0.13 0.11 0.011 1.32 0.55 1.27 0.15

0.12 0.06 0.03 16 16 2 0.06

0.09 0.03 0.04 1.47 2.94 1.17 0.03

In-vitro

activity Table

of clarithromycin

5

I. continued MIC

(mg I-‘)


Compound

Range

P-Haemolytic streptococci groups A, C, G (40)


0.03-2 0.008-2 0.004-0.016 0.06-0.5 0.06-0.5 0.254 0.008-0.12

0.06 0.03 0.008 0.25 0.12 0.5 0.03

0.06 0.06 0.008 0.25 0.25 1 0.03

0.06 0.04 0.008 0.21 0.17 0.62 0.02

S. ugaluctiue (25)


0.03-0.25 0.01 GO.03 0.03.0.06 0.06-l 0.5-2 0.5-2 0.03-0.06

0.06 0.03 0.03 0.5 1 1 0.06

0.12 0.03 0.03 0.5 2 2 0.06

0.06 0.03 0.03 0.38 1.06 0.87 0.05

Enterococci


0.12-> 128 0.25-> 128 0.12-16 0.016-32 128%> 128

0.5

1

1 0.5 0.03

2 8 0.5

(25)

0.54 0.06->

MIC,

MI%

128

>I28

Geometric mean

2 16

0.06 1.18 0.74 0.07 82.1 1.06 6.59

>128 1 8

H. influenzae (38)

Clarithromycin Erythromycin Amoxycillin Amoxy/clav Trimethoprim Cefaclor Ciprofloxacin Clindamycin

4-32 2-16 0.25-> 128 0.25-l 0.06-0.5 4-128 0.004-0.016 4-64

8 4 0.5 0.5 0.12 16 0.016 32

16 16 16 1 0.25 32 0.016 64

8.15 5.07 1.12 0.58 0.14 20.3 0.011 21.8

M. catarrhalis (20)

Clarithromycin Erythromycin Amoxycillin Amoxy/clav Trimethoprim Cefaclor Ciprofloxacin Clindamycin

0.06-0.25 0.06-0.5 0.008-4 0.008-0.25 8-64 0.254 0.002-0.03 4-16

0.12 0.12 1 0.03 16 1 0.016 16

0.12 0.12 2 0.25 32 2 0.03 16

0.12 0.12 0.29 0.05 18.4 1 .oo 0.02 11.3

C. coliljejuni (20)

Clarithromycin Erythromycin Amoxycillin Cefaclor Ciprofloxacin Clindamycin

0.254 0.25-2 l-64 32-> 128 0.06-0.5 0.12-l

1 0.5 4 64 0.12 0.25

2 1 8

0.81 0.47 3.86 73.5 0.10 0.31

>I28 0.12 0.5


6

Table

I. continued MIC

MI%


Compound

Range

N. gonorrhoeae

Clarithromvcin Erythromycin Amoxycillin Amoxy/clav Cefaclor Ciprofloxacin Clindamycin

0.03-l 0.03-l 0.03-64 0.03-2 0.03-g 0~002--@25 0.25-4

0.25 0.12 0.12 0.12 0.5 0.002 1


0.001+008 0~001-0~03 0~016-0~25 0.06-2 2-64 0.5-2 0.004-0.06

0.004 0.016 0.03 0.5 4 1 0.03

Clarithromycin Erythromycin Amoxycillin Amoxy/clav Ciprofloxacin Clindamycin

0.12-S 128 0.12-> 32 0.25-> 128 0.12-g l-64 0.008- > 128

2

Clarithromycin Erythromycin Amoxycillin Ciprofloxacin Clindamycin

0.016-32 0.016-32 0.002-64 0.06-l 6 0~001-0~25

0.06 0.25 0.5 1 0.008


l-8 0.25-l 0.03-0.12 0~0160.06 0.12-0.5

2 0.25 0.06 0.03 0.12


0.5> 32 0.066> 32 0.016-0.12 l-2 0.004-0.06

4


(5.5)

G. ouginalis (20)

B. jragilis

group

(64)

B. oralisl melaninogenicus group

(64)

B. ureolyticus

(10)

Fusobacterium spp

(18)

Peptostreptococcus SPP. (40)

Clostridium spp. (24)

Mobiluncus spp.

(20)

3; 0.5 8 1

(mg 1-l)

MIC,

Geometric mean 0.24 0.13 0.19 0.18 0.47 0.005 1.18

0.008 0.03 0.25 322 i.06 16 16 128 3; 4 0.25

0.004 0.009 0.05 0.42 7.21 I.37 0.025 2.83 3.17 22.1 0.75 6.88 0.73

i.016

0.07 0.22 0.68 1.08 0.008

ii.5 0.06 0.06 0.5

2.14 0.35 0.05 0.04 0.18

z.06 1 0.03

>32 16 o-12 2 0.06

6.60 3.17 0.06 1.26 0.03

0.0084 0.0084 0.008-32 0.12-g 0.002+25

1 0.5 1.12 0.5 0.06

; 8 2 0.12

0.37 0.26 0.14 0.49 0.04


0.12-> 32 0.12-> 32 0.008-32 0.12-64 0.016> 128

: 0.25 4 1

Clarithromycin Erythromycin Amoxycillin Clindamycin

0.002-0.06 0~002-0~12 0.0330.25 0.008-0.03

0.008 0.004 0.06 0.016

I:,

1.26

>32 >32 4

A::8 2.75 0.87

0.016 0.008 0.12 0.03

0.007 O-005 0.07 0.018

i!

In-vitro

activity

of clarithromycin

7

Minimum inhibitory concentrations (MICs) were determined by a previously described agar-dilution method.3 The medium used for aerobic organisms was Diagnostic Sensitivity Test agar (Oxoid CM 261). This was supplemented with 5% saponin-lysed horse blood for fastidious organisms adenine dinucleotide for Haemophilus plus 10mg 1-l nicotinamide The medium used for anaerobic organisms was in.uenzae. Wilkins-Chalgren agar (Oxoid CM 619) supplemented with 5% lysed horse blood. The inoculum, delivered by a multi-point inoculator, was lo4 colony forming units (cfu) per spot. The MIC was the lowest concentration that completely or almost completely inhibited the growth of the organism. Results

The range of MICs, MIC 50 s and MIC 90s and geometric mean MICs are listed in Table I. Clarithromycin was slightly more active against 5’. aureus than but since this effect was mainly seen among the more erythromycin, resistant strains, the MIC 50 was the same. There was no correlation with penicillin resistance, but methicillin-resistant strains were resistant to both macrolides. We did not assess dissociated resistance to clindamycin. Both macrolides were less active against 5’. epidermidis than against aureus. Multiple resistance was common. In contrast, strains of s. and to other S. suprophyticus were more sensitive to both macrolides antibiotics tested. A penicillin-resistant strain of S. pneumoniae was highly resistant to the macrolides but all other isolates of this species were inhibited by low streptococci concentrations of both agents. For other ol-haemolytic erythromycin was slightly more active than clarithromycin. Resistance was seen only to trimethoprim. One isolate of S. pyogenes was resistant to both macrolides but all other streptococci of Lancefield groups A, C and G were inhibited by low concentrations of all agents tested. With the exception of the macrolides, Streptococcus ugalactiae was slightly less sensitive than other P-haemolytic streptococci to the antibiotics tested. Clarithromycin was more active than erythromycin against enterococci. These organisms were invariably resistant to cefaclor and clindamycin, and exhibited a variable susceptibility to amoxycillin. The strains of H. injkenzae examined exhibited universal resistance to clindamycin, and were inhibited only by rather high concentrations of cefaclor. The P-lactamase-producing strains were resistant to amoxycillin but sensitive to amoxycillin-clavulanate. The MICs of clarithromycin were slightly higher than those of erythromycin, but neither was very active against this species. Strains of M. catarrhalis, N. gonorrhoeae and G. vaginalis were highly susceptible to both macrolides and the differences in the respective activities of these two agents for these organisms were minor. The macrolides also

8


showed useful activity against C. jejuni/coli, erythromycin having slightly greater potency. Macrolide resistance was seen in all groups of anaerobes, but was particularly common among fusobacteria, the B. fragilis group and clostridia, especially C. d@cile and C. clostridiiforme. There was little difference between the two macrolides for these groups. Clarithromycin (MICs O-5-2 mg 1-l) was marginally more active than erythromycin (MICs B. fragilis sensu stricto. Mobiluncus spp. and 14mg 1-l) against peptostreptococci were equally susceptible, with P. anaerobius markedly more sensitive than other species. While clarithromycin was clearly the more active against the B. melaninogenicus group it was less active against

B. urealyticus. Discussion

Our results largely confirm those of others in demonstrating the similarity of the activity of clarithromycin and erythromycin for the species tested, although there are differences in detail. In accordance with Hardy et aZ.‘*2 and Fernandes et a1.,4 we found clarithromycin slightly more active against less active against coagulase-negative strains. S. aureus and slightly However, unlike these authors, but in accordance with Barry et al., ’ we did not encounter any advantage for clarithromycin against streptococci, except in relation to the enterococci. In agreement with the results presented here, most authors have recorded that clarithromycin is marginally less active than erythromycin against H. infEuenzae but the range of MICs reported has varied widely.‘*2~4~5 Results for clarithromycin are affected by the medium used, the presence of serum (which is associated with lower MICs) and inoculum size.6 It has further been shown that clarithromycin MICs are reduced in the presence of the active metabolite 14-hydroxyclarithromycin.7 Some of these factors are is operative in vivo.8 There is thus evidence to suggest that clarithromycin more active in viva against H. influenzae than our results imply. A number of other bacteria that we have not tested have also been shown to be sensitive to clarithromycin, including Mycoplasma pneumoniae,

Chlamydia pneumoniae, Legionella pneumophila, Bordetella pertussis, Listeria monocytogenes and corynebacteria,“” in some cases more so than to erythromycin. No macrolide is active against Mycoplasma hominis. Although clarithromycin is highly active against some strains of Ureaplasma urealyticum, resistance is common in this species.’ We conclude that clarithromycin is sometimes slightly more and sometimes slightly less active than erythromycin against a range of respiratory, skin and soft-tissue, and genital tract pathogens, and may have advantages over this agent for H. inyuenzae infections when interactions with its metaboiite and serum are taken into account.

In-vitro

activity

of clarithromycin

9

References 1 Hardy DJ, Hensey DM, Beyer JM, Vojtko C, McDonald EJ, Fernandes PB. Comparative in vitro activities of new 14-. 1 S- and 16-membered macrolides. Antimicrob Agents Chemother 1988; 32: 171&1719. 2 Hardy DJ, Swanson RN, Rode RA, Marsh K, Shipkowitz NL, Clement JJ. Enhancement of the in vitro and in vivo activities of clarithromvcin against Haemoahilus inflzlenzae by 14-hydroxyclarithromycin, its major metabolite in h:mans. Anti&rob Agents Chemother 1990; 34: 1407-1413. 3 King A, Warren C, Shannon K, Phillips I. The in vitro antibacterial activity of cefotaxime compared with that of cefuroxime and cefoxitin. J Antimicrob Chemother 1980: 6: 479-494. 4 Fernandes PB, Bailer R, Swanson R et al. In vitro and in vivo evaluation of A-56268 (TE-031). a new macrolide. Antimicrob Agents Chemother 1986: 30: 865-873. 5 Barry AL, Thornsberry C, Jones RN. Invitro activity of a new macrolide, A 56268, compared with that of roxithromycin, erythromycin and clindamycin. Antimicrob Agents Chemother 1987; 31: 343-345. 6 Barry AL, Fernandes PB, Jorgensen JH, Thornsberry C, Hardy DJ, Jones RN. Variability of clarithromycin and erythromycin susceptibility tests with Huemophilus influenzae in four different broth media and correlation with standard disk diffusion test. J Clin Microbial 1988; 26: 24152420. 7 Olsen-Liljequist B, Hoffman B-M. In vitro activity of clarithromycin combined with its 14-hydroxy metabolite A 62671 against Haemophilus influenzae. Antimicrob Chemother 1991; 27 (Suppl. A): 11-17. PB, Hardy D, Bailer R et al. Susceptibility testing of macrolide antibiotics 8 Fernandes against Huemophilus injluenzue and correlation of in vitro results and in vivo efficacy in a mouse septicemia model. Antimicrob Agents Chemother 1987; 31: 124331250. 9 Waites KB, Cassell CH, Canupp KC, Fernandes PB. In vitro susceptibilities of mycoplasmas and ureaplasmas to new macrolides and aryl-fluoroquinolones. Antimicrob Agents Chemother 1988; 32: 1500-l 502. K, Roblin PM, Hammerschlag MR. In vitro susceptibility of Chlamydia 10‘. Chirgwin pneumoniae (Chlamydiu sp. strain TWAR). Antimicrob Agents Chemother 1989; 33: 16341635.

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