Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
In Vitro Activity of Commonly Used Oral Antimicrobial Agents Against Community Isolates of Respiratorypathogens M.J. Struelens, C. Nonhoft, M. Lontie, P. Delannoy, G. Lanis, H. Van Pelt & E. Serruys To cite this article: M.J. Struelens, C. Nonhoft, M. Lontie, P. Delannoy, G. Lanis, H. Van Pelt & E. Serruys (1991) In Vitro Activity of Commonly Used Oral Antimicrobial Agents Against Community Isolates of Respiratorypathogens, Acta Clinica Belgica, 46:5, 283-289, DOI: 10.1080/17843286.1991.11718178 To link to this article: http://dx.doi.org/10.1080/17843286.1991.11718178
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
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M. J. Struelens 1·, C. Nonhoft1, M. Lontie 2, P. Delannoy3, G. Lanis 3, H. Van Pelt4, E. Serruys 1
' SUMMARY
The in vitro activity of ampicillin, amoxicillin/ clavulanate, cefadroxil, cefaclor, cefuroxime (axetil), co-trimoxazole, doxycycline, 1 ciprofloxacin, ofloxacin, erythromycin, and :oxithromycin was tested against unselected isolates of S. pneumoniae (70), H . influenzae (93), and M. catarrhalis (46), cultured from clinically significant sputum samples of general Practice patients. All isolates of S. pneumoniae Were highly susceptible to ampicillin; cefadroxil and cefaclor were markedly less active on a , Weight basis; resistance was only observed with co-trimoxazole (4.3%), doxycycline (5.7%), and erythromycin (2.9% ); however, ciprofloxacin and ofloxacin showed median MICs (MIC50), that ) Were only one dilution below breakpoint. 13Iactamase was detected in 14.0% of H. influenzae isolates; all isolates were susceptible to amoxicil lin/clavulanate, cefaclor, and cefuroxime (axetil), although MICs were generally higher forcefaclor; the highest activity was exhibited by ciprofloxacin and ofloxacin; apart from
1
Department of Microbiology, Hopital Universitaire Erasme, 1070 Bruxelles. 1 Medisch Centrum Huisartsen, 3000 Leuven. 3 Laboratoire de B iologie Cl inique et Horrnonale, 60 I 0 Couillet. 4 Centraal Laboratorium, 3500 Hassell.
cefadroxil, erythromycin, and roxithromycin , that showed only marginal activity, resistance was observed with co-trimoxazole (4.3%) and doxycycline (1.1%). All (including 71.7 % ofl3lactamase producing) isolates of M . catarrhafis were susceptible to amoxicillin/clavulanate, cefaclor and cefuroxime (axetil), although M!Cs were markedly lower for amoxicillin/clavu lanate; ciprofloxacin and ofloxacin showed the lowest MICs; resistance was only observed with cefadroxil (2.2%). In conclusion, the antimicrobial agents showing the most uniformely high in vitro activity against the 3 common community respiratory pathogens tested in the present study, were amoxici llin/clavu lanate and, to a lesser extent, cefuroxime (axetil). Acta Clinica Belg. 46,5: 283-9. INTRODUCTION
Strepto coccus pneumoniae, Haemophilus influenzae, and Moraxeffa (Branhameffa) catarrhalis are the major pathogens responsible for bacterial infections of the lower respiratory tract in the community ( I ) . Several oral antibiotics, including various 13-lactams, co-trimoxazo le, tetracyclines, quinolones, and macrolides, are used by general practitioners to treat these infection s. The aim of this study was to test these commonly used antibiotics for their in vitro activity against unselected isolates of the above pathogens, cultured from clinically significant sputum samples, taken from general practice patients. Acta Clinica Belgica 46.5 ( 1991)
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
MATERIALS AND METHODS
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Isolates A total of 209 unselected isolates (70 S. pneumoniae, 93 H. influenzae, and 46 M. catarrhalis), identified according to standard methods, were tested. They were collected from October 1989 to March 1990 in three community clinical laboratories in Belgium. All isolates were cultured from clinically significant sputum samples (pus/epithelial cell ratio: ~ I 0/ 1), taken from general practice patients. Antibiotics Laboratory-grade powders of the antimicrobial agents were kindly provided by the following manufacturers: ampicillin, amoxicillin and clavulanic acid : Beecham; cefadroxil: Bristol; cefaclor: Lilly; cefuroxime : Glaxo; cotrimoxazole: Roche; doxycycline: Pfizer; ciprotloxacin : Bayer; otloxacin : Hoechst; erythromycin Abbott; roxithromycin : Roussel. Susceptibility testing Minimal inhibitory concentrations (MIC) were determined by agar dilution as described in the NCCLS approved standard for dilution antimicrobial susceptibility testing of aerobic bacteria (2). Mueller-Hinton agar(ll, Gold Label, BBL) was used. The agar was supplemented with 5% sheep blood for S. pneumoniae, and with 15 µg/ml of purified bovine haematin (Sigma), 15 µg/ml of B-NAD (Sigma), and 5 mg/ml of yeast extract (G18CO) yielding HTM (Haemophilus Test Medium) for H. injluenzae (3). The inoculum size was lO~ CFU perspot. lnoculum suspensions of H. influenzae were prepared from 16-18 h chocolate agar cultures. S. pneumoniae and M . catarrhalis were incubated in normal atmosphere, and H. influen ::ae in 5 % C0.2, except for erythromycin and roxithromycin, where both , . normal and 5% C02 atmosphere, were used. A growth control plate containing no antimicrobial agent was included with each series. £ . coli A TCC 25922, £ . coli ATCC 35218, S. aureus Acta Clinica Belgica 46.5 ( 1991 J
ATCC 29213, and S. aureus NCTC 11561 were used as quality control organisms. When testing Haemophilus, H. influenzae ATCC 10211, H. influenzaeTD-4,andH. influenzae NEMC l were used as additional q~ality control organisms. Breakpoints The NCCLS recommended breakpoints for Haemophilus species were used, unless separate breakpoints were available for S pneumoniae and M. catarrhalis. Where specific breakpoint recommendations for Haemophilus species were ' lacking (cefadroxil, erythromycin), those recommended for other organisms than Haemophilus were used. However, for Haemophilus, these should be considered tentative. The MICs of cefadroxil and erythromycin for Haemophi/us are distributed around the breakpoint concentrations. Slight methodological variations may cause these distributions to shift, either to lower or to higher MICs, yielding, susceptibility rates that should be interpreted with caution. For roxithromycin, the same breakpoints were used as for erythromycin. 13-lactamase testing All isolates of H. influenzae and M . catarrha/is were tested for B-lactamase production with a nitrocefin-based paper disk test (Cefinase, BBL).
~
RESULTS The MIC data (MIC range, MIC 50 , MIC 90 ) of all antibiotics tested, and the percentages of isolates susceptible and resistant at breakpoint, are shown in Tables I (S. pneumoniae), 2 (H . influenzae) and 3 (M. catarrhalis) . S. pneumoniae was fully susceptible to ampicillin, hence to amoxicillin/clavulanate, at ~0 . 06 µg/ml. Although resistance was not observed with any of the cephalosporins tested, cefadroxil and cefaclor were conspicuously less active on a weight basis than cefuroxime (axetil). Co- · trimoxazole, doxycycline and erythromycin showed .broader MIC ranges; 3 isolates (4.3%)
IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
were resistant to co-trimoxazole (MI Cs: 4, 4, and 32 µg/ml), 4 (5.7%) to doxycycline (MICs: 8, 8, 8, and 16 µg/ml) , and 2 (2.9%) to erythromycin (MICs: 8 and 64 µg/ml); combined resistance to 2 or all 3 of these antibiotics did not occur. All isolates were inhibited at 2 µg/ml of ciprotloxa-
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cin and ofloxacin. However, in both cases, the median MIC (MIC50) was only 1 dilution below breakpoint, with 77.1 and 74.3% of isolates requiring 0.5-2 µg/ml of ciprotloxacin and 1-2 µg/ml of otloxacin, respectively, to be inhibited. The rate of B-lactamase production in H.
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Table 1: Comparative in vitro activ ity against 70 isolates of S. pneumoniae
MIC (µg/m l) Antibiotic
Range
Arnpicillin Arnoxicillin/clavulanate (2/ 1) Cefadroxil Cefaclor Cefuroxime (axetil) Trimethoprim/sulfamethoxazole ( 1/19) Doxycycline Ciprofloxacin Ofloxacin Erythromycin
$;0.06 $;0.06 $0.06-8 $;0.06-2 $0.06-1 $0.06-32 $0.06-16 $0.06-2 $0.06-2 $0.06-64
%S at breakpoint
%R at breakpoint
50%
90%
%S
µg/ml
%R
$;0.06 $0.06 0.5 0.25 $;0.06 $;0.06 $;0.06 0.5 I $0.06
$;0.06 $0.06 1 0 .5 $0.06 0.5 2 I I 0.25
100.0 100.0 100.0 100.0 100.0 91.4 90.0 97 . l 100.0 94.3
$0. 12 $0.12/0.06 $8 $8 $4 $0.5/9.5 $2 $1 $2 $0.5
0.0 0.0 0.0 0.0 0.0 4.3 5.7 0.0 0.0 2.9
µg/ml ~4
~4/2 ~32 ~32 ~16 ~4/76 ~8 ~4
~8 ~8
Table 2: Comparative in vitro activity against 93, including 13 B-Iactamase producing isolates of H. injluenzae. MIC (µg/m l) %S at breakpoint %R at breakpoint Antibiotic Arnpicillin Arnoxicillin/clavulanate (2/1) Cefadroxil Ce factor Cefuroxime (axetil) Trirnethoprim/sulfamethoxazole ( 1/19) Doxycycline Ciprofloxacin Ofloxacin Erythromycin - 0 2 Erythromycin - C0 2 Roxithromycin - 0 2 Roxithromycin - C0 2
50'%
90%
%S
$0.06-128 0.25 0.5 $0.06-4 16 1-128 2 0.25-8 0.5 0 . 12-2 0.12 $0.06-8 0.25 $0.06-8 $;0.06 $0.06 $0.06 $0.06 4 $0.06-16 4 $0.06-32 8 0 . 12-32 0. 12-32 16
16 0.5 64 4 I 0.25 0 .5 $0.06 $0.06 8 32 16 32
86.0* 100.0
Range
20.4 100.0 100.0 94.6 98.9 100.0 100.0 12.9 2.2 2.2 I. I
µg/ml
% R
µg/ml
14.0* 0.0 46.2 0 .0 0.0 4.3 I. I 0.0 0.0 29.0 49.5 83.9 95.7
-
$4/2 $8** $8 $4 $0.5/9.5 $2 $1 $2 $0.5** $0.5** $0.5** $0.5**
-
~8/4 ~32** ~32 ~ 16
~4/76
~8 ~4 ~8
~8** ~8**
~8** ~8**
* According to B-lactamase production. **Tentative breakpoints (see materials and methods). · Acta Clinica Belgica 46.5 ( 199 1)
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
Table 3: Comparative in vitro activity against 46, including 33 B-lactamase producing isolates of M. catarrhalis
MIC (µg/ml)
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Antibiotic Ampicillin Amoxicillin/clavulanate (2/1 ) Cefadroxil Cefaclor Cefuroxime (axetil) Trimethoprirn/sulfamethoxazole (1/19) Doxycycline Ciprofloxacin Ofloxacin Erythromycin
%S at breakpoint
%R at breakpoint
50%
90%
%S
.µg/ml
%R
µg/ml
:50.06-2 0.25 :50.06-0.25 0.12 0.5-32 2 0.12-4 0.5 :50.06-4 0.5 :50.06-2 :50.06 :50.06-4 0.12 :50.06 :50.06 :50.06 :50.06 :50.06-0.5 0.25
2 0.25 4 1 2 0.25 0.12 :50.06 :50.06 0.25
28.3* 100.0 97 .8 100.0 100.0 95.7 97.8 100.0 100.0 100.0
-
71.7 * 0.0 2.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-
Range
:54/2 :58 :58 :54 :50.5/9.5 :52 :51 :52 :50.5
~8/4 ~32 ~32 ~16
~4/76 ~8
~4
~8 ~8
* According to B-Iactamase production.
influenzae was 14.0%. None of the B-lactamase negative isolates was resistant to ampicill in, while, on the other hand, 2 B-lactamase positive isolates were inhibited at concentrations below breakpoint for resistance to ampicillin (MICs: 0.5 and 2 µg/ ml). All, including the B-lactamase producing isolates, were susceptibl e to amoxicillin/ clavulanate, cefaclor, and cefuroxime (axetil); however, cefaclor generally showed higher MI Cs. In contrast, only 20.4% of isolates proved susceptible to cefadroxil. The highest activity against H . influenzae was exhibited by ciprofloxacin and ofloxacin, with all isolates inhibited at :50.06 µg/ ml. Co-trimoxazole and doxycycline showed resistance in 4 (4.3 %, MI Cs: 4, 8, 8, and 8 µg/ml) and 1 isolate (l.l %; MIC: 8 µg/ml), respectively. The doxycycline and co-trimoxazole resistant isolates were higly resistant to ampicillin (MICs: 128 µg/ml); resistance to co-trimoxazole and doxycycline was not -combinect. Erythromycin and roxithromycin were tested under normal and 5% C0 2 atmosphere. As expected, both macrolides were more active when tested under normal atmosphere. However, even then the
majority of isolates proved of intermediate susceptibility to erythromycin (58. I%), and resistant to roxithromycin (83.9% ). B-lactamase was detected in 71.7% of M. catarr ha/is isolates, while only 32.6% of isolates were resistant to ampicil lin at the NCCLS , recommended breakpoint of >0.5 µg/ml. All, including the B-lactamase producing isolates, were susceptible to amoxicillin/cl avulanate, cefaclor and cefurox ime (axetil); however, , cefaclor and cefuroxime (axetil) were markedly less active on a weight basis, with MICs very similar to those of ampicillin. The highest activity against M . catarrhalis was exhibited by ciprofloxacin and ofloxacin, with all isolates inhibited at :50.06 µg/ml. Apart from ampici llin, resistance was only observed with cefadroxil in 1 isolate (2.2%; MIC: 32 µg/ml).
DISCUSSION This survey of community respiratory isolates of S. pn eumoniae , H . influ enzae, and M .
Acta Clinica Belgica 46.5 (1991) ,l...._
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
catarrhalis from different areas in Belgium allowed to compare their in vitro susceptibility to antimicrobials that are currently available for oral therapy of respiratory tract infections. Ampicillin showed excellent activity against S. Pneumoniae, but is amenable to inactivation by B-lactamase producing isolates of H . influenzae and M. catarrha/is, which, in all, accounted for 22% of the pathogens tested in this study. The apparent susceptibility to ampicillin of some of these B-lactamase producing organisms is probably related to the low inoculum that was used, as shown previously (4, 5). In 1989, national reference laboratories reported higher resistance rates in invasive isolates of S. pneumoniae (3% to penicillin) and H. influenzae (39% B-lactamase Production) (6). The difference for H . influenzae may be due to the fact that different populations were sampled; it is well-known, for instance, that invasive isolates of H. influenzae, most of which are of type b, more frequently harbour the TEM -1 B-lactamase than non-encapsulated isolates (7-9). The combination of amoxicillin and clavulanate was active against all isolates tested: this was not unexpected, inasmuch as clavulanate is a potent inhibitor of both H . influenzae and M. catarrha/is 13-lactamases (I 0).
Cefadroxil was the least active among the oral cephalosporins tested, especially against H. influ enzae, as shown previously (I I). Ce factor had a better overall activity; however, its MI Cs for S. Pneumoniae and H. influenzae were markedly higher than tho se of cefuroxime (axetil). Furthermore, susce ptibility to cefaclor of 13-lactamase producing isolates of M . catarrhalis should be interpreted with caution, si nce the concerned 13-lactamases (BRO-I and BR0-2) have been shown to hydrolyse cefaclor more rapidly than benzylpenicillin and ampicillin ( 12). Cefuroxime axetil is a second ge nera tion cephalosporin available for oral administration. We con finned its excellent in vitro activity against the pathogens tested. Apart from M. catarrhalis, that was inhibited at higher concentrations,
287
cefuroxime (axetil) compared favourably with amoxicillin/clavulanate. However, there remain some questions about the bioavailability of this cefuroxime ester. ( 13). Co-trimoxazole and doxycycline, for decades, have been used extensively in the treatment of bacterial respiratory tract infections. Both drugs showed activity against >90% of the various pathogens tested in the present study, although 16.7% resistance to tetracycline is currently reported for invasive isolates of S. pneumoniae (6). Tetracycline resistance in M . catarrhalis, which is very rare, was not observed. Ciprofloxacin and ofloxacin were extremely active against the Gram-negative respiratory pathogens tested (MI Cs~ 0.06 µg/ml) , but only poorly against S. pneumoniae. Pneumococci have been involved in failures, super- and reinfections upon treatment of respiratory tract infections with these agents ( 14-17); therefore, the use of the currently available quinolones in the empiric therapy of respiratory tract infections remai ns controversial (I). Resi stance of M. catarrhalis to macrolides has been described, but is rare (9, 18); the mechanism of resistance is unknown. None of th e M . catarrhalis isolates was resistant to erythromycin in the present study, while resistance was found in 2.9% of th e pneumococcal isolates . A prevalence of 13% erythromycin resistance has recently been reported in Belgium for invasive pneumococcal isolates (6). Erythromycin and roxithromycin were only marginally active against H . inj711e11zae, even when tested in normal atmosphere to ensure optimal medium pH; these results are in agreement with other data (79, 19). In summary, the antimicrobial agents showing the most unifonnely hi gh in vitro activity again st the common commun ity respiratory pathogens tested in the present study, were amox icillin/ clavulanate and , to a lesser extent, cefuroxime (axetil). Acta Clinica Belgica 46.5 ( 199 1J
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
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RESUME L'activite in vitro de l'ampicilline, de l'amoxicilline/clavulanate, du cefadroxil, du cefaclor, du cefuroxime (axetil), du co-trimoxazole, de la doxycycline, de la ciprofloxacine, de l'ofloxacine, de l'erythromycine, et de la roxithromycine a ete testee sur des souches non selectionnees de S. pneumoniae (70), d' H. influenzae (93), et de M. catarrhalis (46), isolees en pratique generate a partir d'expectorations cliniquement significatives. Toutes les souches de S. pneumoniae etaient fort sensibles a l'ampicilline; le cefadroxil et le cefaclor etaient beaucoup moins actifs sur base ponderale; des resistances ont ete observees uniquement au cotrimoxazole (4.3%), a ladoxycycline (5 .7%), eta J' erythromycine (2.9% ); toutefois, la ciprofloxacine et l'ofloxacine montraient des CMI medianes (CMI50), situees a peine une dilution en-dessous du seuil critique. Des 8-lactamases ont ete detectees dans 14.0% des souches d'H. influenzae; toutes Jes souches etaient sensibles a l'amoxicilline/ c~avulanate, au cefaclor, et au cefuroxime (axetil), b1en que Jes CMis fussent plus elevees pour le cefaclor; la ciprofloxacine et l'ofloxacine etaient les antibiotiques Jes plus actifs; hormis le cefadroxil, l'erythromycine, et la roxithromycine, qui n 'avaient qu 'une activite marginale, des resistances ont ete observees au'co-trimoxazole (4.3%) et a la doxycycline (I. I %). Toutes les souches de M . catarrhalis, y compris celles produisant des 8-lactamases (71.7%), etaient sensibles a 1'amoxicilline/clavulanate, au cefaclor, et au cefuroxime (axetil), bien que les CMis fussent inferieures pour l'amoxicilline/clavulanate; la ciprofloxacine et l'ofloxacine avaient les CM!s Jes plus basses; des resistances ont ete observees uniquement au cefadroxil (2.2%). En conclusion, l'amoxicilline/ clavulanate et, a un moindre degre, le cefuroxime (axetil), etaient Jes antibiotiques dont l'activite in vitro etait la plus uniformement elevee sur les pathogenes respiratoires testes dans Ia presente etude. SAMENV ATTING De in vitroactiviteitvan ampicilline, amoxicilline/
clavulanaat, cefadroxil, cefaclor, cefuroxime
Acta Clinica Belgica 46.5 ( 1991)
(axetil), co-trimoxazol, doxycycline, ciprofloxacine, ofloxacine, erythromycine, en roxithromycine werd getest op niet geselecteerde stammen van S. pneumoniae (70), H. inf/uenzae (93), en M. catarrhalis (46), ge-isoleerd uit klinisch significante sputummonsters van patienten uit de huisartsenpraktijk. Alie S. pneumoniae stammen waren erg gevoelig voor ampicilline; cefadroxil en cefaclor waren merkelijk minder actief op gewichtsbasis; resistentie werd enkel waargenomen tegen cotrimoxazol (4.3%), doxycycline (5.7%), en erythromycine (2. 9% ); ciprotloxacine en otloxacine toonden evenwel mediane MICS (MIC50), die nauwelijks I dilutie beneden breekpunt lagen. BLactamasen werden gedetecteerd in 14.0% van de H . influenzae stammen; alle stammen waren gevoelig voor amoxicilline/clavulanaat, cefaclor, en cefuroxime (axetil), alhoewel de MICs over het algemeen hoger waren voor cefaclor; ciprofloxacine en ofloxacine vertoonden de hoogste activiteit; afgezien van cefadroxil, erythromycine en roxithromycine, die slechts marginaal actief waren, werd resistentie waargenomen voor co-trimoxazol (4.3%)endoxycycline (I. I%). Alle(inclusief71.7% B-Iactamase producerende) stammen van M . catarrha/is waren gevoelig voor amoxicilline/clavulanaat, cefaclor, en cefuroxime (axetil), alhoewel de MICs merkelijk lager waren voor amoxicilline/ /clavulanaat; ciprofloxacine en ofloxacine hadden de laagste MICs; resistentie werd enkel waargenomen voor cefadroxil (2..2%). Tot besluit waren amoxicilline/clavulanaat en, in mindere mate, cefuroxime (axetil), de antibiotica met de meest gelijkmatig hoge in vitro activiteit tegen de respiratoire pathogenen, die in deze studie werden getest.
ACKNOWLEDGMENTS This work was supported by a grant from SmithKline Beecham, Belgium.
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Acta Clinica Belgica 46.5 ( 1991)
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
In Vitro Activity of Commonly Used Oral Antimicrobial Agents Against Community Isolates of Respiratorypathogens M.J. Struelens, C. Nonhoft, M. Lontie, P. Delannoy, G. Lanis, H. Van Pelt & E. Serruys To cite this article: M.J. Struelens, C. Nonhoft, M. Lontie, P. Delannoy, G. Lanis, H. Van Pelt & E. Serruys (1991) In Vitro Activity of Commonly Used Oral Antimicrobial Agents Against Community Isolates of Respiratorypathogens, Acta Clinica Belgica, 46:5, 283-289, DOI: 10.1080/17843286.1991.11718178 To link to this article: http://dx.doi.org/10.1080/17843286.1991.11718178
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
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M. J. Struelens 1·, C. Nonhoft1, M. Lontie 2, P. Delannoy3, G. Lanis 3, H. Van Pelt4, E. Serruys 1
' SUMMARY
The in vitro activity of ampicillin, amoxicillin/ clavulanate, cefadroxil, cefaclor, cefuroxime (axetil), co-trimoxazole, doxycycline, 1 ciprofloxacin, ofloxacin, erythromycin, and :oxithromycin was tested against unselected isolates of S. pneumoniae (70), H . influenzae (93), and M. catarrhalis (46), cultured from clinically significant sputum samples of general Practice patients. All isolates of S. pneumoniae Were highly susceptible to ampicillin; cefadroxil and cefaclor were markedly less active on a , Weight basis; resistance was only observed with co-trimoxazole (4.3%), doxycycline (5.7%), and erythromycin (2.9% ); however, ciprofloxacin and ofloxacin showed median MICs (MIC50), that ) Were only one dilution below breakpoint. 13Iactamase was detected in 14.0% of H. influenzae isolates; all isolates were susceptible to amoxicil lin/clavulanate, cefaclor, and cefuroxime (axetil), although MICs were generally higher forcefaclor; the highest activity was exhibited by ciprofloxacin and ofloxacin; apart from
1
Department of Microbiology, Hopital Universitaire Erasme, 1070 Bruxelles. 1 Medisch Centrum Huisartsen, 3000 Leuven. 3 Laboratoire de B iologie Cl inique et Horrnonale, 60 I 0 Couillet. 4 Centraal Laboratorium, 3500 Hassell.
cefadroxil, erythromycin, and roxithromycin , that showed only marginal activity, resistance was observed with co-trimoxazole (4.3%) and doxycycline (1.1%). All (including 71.7 % ofl3lactamase producing) isolates of M . catarrhafis were susceptible to amoxicillin/clavulanate, cefaclor and cefuroxime (axetil), although M!Cs were markedly lower for amoxicillin/clavu lanate; ciprofloxacin and ofloxacin showed the lowest MICs; resistance was only observed with cefadroxil (2.2%). In conclusion, the antimicrobial agents showing the most uniformely high in vitro activity against the 3 common community respiratory pathogens tested in the present study, were amoxici llin/clavu lanate and, to a lesser extent, cefuroxime (axetil). Acta Clinica Belg. 46,5: 283-9. INTRODUCTION
Strepto coccus pneumoniae, Haemophilus influenzae, and Moraxeffa (Branhameffa) catarrhalis are the major pathogens responsible for bacterial infections of the lower respiratory tract in the community ( I ) . Several oral antibiotics, including various 13-lactams, co-trimoxazo le, tetracyclines, quinolones, and macrolides, are used by general practitioners to treat these infection s. The aim of this study was to test these commonly used antibiotics for their in vitro activity against unselected isolates of the above pathogens, cultured from clinically significant sputum samples, taken from general practice patients. Acta Clinica Belgica 46.5 ( 1991)
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
MATERIALS AND METHODS
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Isolates A total of 209 unselected isolates (70 S. pneumoniae, 93 H. influenzae, and 46 M. catarrhalis), identified according to standard methods, were tested. They were collected from October 1989 to March 1990 in three community clinical laboratories in Belgium. All isolates were cultured from clinically significant sputum samples (pus/epithelial cell ratio: ~ I 0/ 1), taken from general practice patients. Antibiotics Laboratory-grade powders of the antimicrobial agents were kindly provided by the following manufacturers: ampicillin, amoxicillin and clavulanic acid : Beecham; cefadroxil: Bristol; cefaclor: Lilly; cefuroxime : Glaxo; cotrimoxazole: Roche; doxycycline: Pfizer; ciprotloxacin : Bayer; otloxacin : Hoechst; erythromycin Abbott; roxithromycin : Roussel. Susceptibility testing Minimal inhibitory concentrations (MIC) were determined by agar dilution as described in the NCCLS approved standard for dilution antimicrobial susceptibility testing of aerobic bacteria (2). Mueller-Hinton agar(ll, Gold Label, BBL) was used. The agar was supplemented with 5% sheep blood for S. pneumoniae, and with 15 µg/ml of purified bovine haematin (Sigma), 15 µg/ml of B-NAD (Sigma), and 5 mg/ml of yeast extract (G18CO) yielding HTM (Haemophilus Test Medium) for H. injluenzae (3). The inoculum size was lO~ CFU perspot. lnoculum suspensions of H. influenzae were prepared from 16-18 h chocolate agar cultures. S. pneumoniae and M . catarrhalis were incubated in normal atmosphere, and H. influen ::ae in 5 % C0.2, except for erythromycin and roxithromycin, where both , . normal and 5% C02 atmosphere, were used. A growth control plate containing no antimicrobial agent was included with each series. £ . coli A TCC 25922, £ . coli ATCC 35218, S. aureus Acta Clinica Belgica 46.5 ( 1991 J
ATCC 29213, and S. aureus NCTC 11561 were used as quality control organisms. When testing Haemophilus, H. influenzae ATCC 10211, H. influenzaeTD-4,andH. influenzae NEMC l were used as additional q~ality control organisms. Breakpoints The NCCLS recommended breakpoints for Haemophilus species were used, unless separate breakpoints were available for S pneumoniae and M. catarrhalis. Where specific breakpoint recommendations for Haemophilus species were ' lacking (cefadroxil, erythromycin), those recommended for other organisms than Haemophilus were used. However, for Haemophilus, these should be considered tentative. The MICs of cefadroxil and erythromycin for Haemophi/us are distributed around the breakpoint concentrations. Slight methodological variations may cause these distributions to shift, either to lower or to higher MICs, yielding, susceptibility rates that should be interpreted with caution. For roxithromycin, the same breakpoints were used as for erythromycin. 13-lactamase testing All isolates of H. influenzae and M . catarrha/is were tested for B-lactamase production with a nitrocefin-based paper disk test (Cefinase, BBL).
~
RESULTS The MIC data (MIC range, MIC 50 , MIC 90 ) of all antibiotics tested, and the percentages of isolates susceptible and resistant at breakpoint, are shown in Tables I (S. pneumoniae), 2 (H . influenzae) and 3 (M. catarrhalis) . S. pneumoniae was fully susceptible to ampicillin, hence to amoxicillin/clavulanate, at ~0 . 06 µg/ml. Although resistance was not observed with any of the cephalosporins tested, cefadroxil and cefaclor were conspicuously less active on a weight basis than cefuroxime (axetil). Co- · trimoxazole, doxycycline and erythromycin showed .broader MIC ranges; 3 isolates (4.3%)
IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
were resistant to co-trimoxazole (MI Cs: 4, 4, and 32 µg/ml), 4 (5.7%) to doxycycline (MICs: 8, 8, 8, and 16 µg/ml) , and 2 (2.9%) to erythromycin (MICs: 8 and 64 µg/ml); combined resistance to 2 or all 3 of these antibiotics did not occur. All isolates were inhibited at 2 µg/ml of ciprotloxa-
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cin and ofloxacin. However, in both cases, the median MIC (MIC50) was only 1 dilution below breakpoint, with 77.1 and 74.3% of isolates requiring 0.5-2 µg/ml of ciprotloxacin and 1-2 µg/ml of otloxacin, respectively, to be inhibited. The rate of B-lactamase production in H.
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Table 1: Comparative in vitro activ ity against 70 isolates of S. pneumoniae
MIC (µg/m l) Antibiotic
Range
Arnpicillin Arnoxicillin/clavulanate (2/ 1) Cefadroxil Cefaclor Cefuroxime (axetil) Trimethoprim/sulfamethoxazole ( 1/19) Doxycycline Ciprofloxacin Ofloxacin Erythromycin
$;0.06 $;0.06 $0.06-8 $;0.06-2 $0.06-1 $0.06-32 $0.06-16 $0.06-2 $0.06-2 $0.06-64
%S at breakpoint
%R at breakpoint
50%
90%
%S
µg/ml
%R
$;0.06 $0.06 0.5 0.25 $;0.06 $;0.06 $;0.06 0.5 I $0.06
$;0.06 $0.06 1 0 .5 $0.06 0.5 2 I I 0.25
100.0 100.0 100.0 100.0 100.0 91.4 90.0 97 . l 100.0 94.3
$0. 12 $0.12/0.06 $8 $8 $4 $0.5/9.5 $2 $1 $2 $0.5
0.0 0.0 0.0 0.0 0.0 4.3 5.7 0.0 0.0 2.9
µg/ml ~4
~4/2 ~32 ~32 ~16 ~4/76 ~8 ~4
~8 ~8
Table 2: Comparative in vitro activity against 93, including 13 B-Iactamase producing isolates of H. injluenzae. MIC (µg/m l) %S at breakpoint %R at breakpoint Antibiotic Arnpicillin Arnoxicillin/clavulanate (2/1) Cefadroxil Ce factor Cefuroxime (axetil) Trirnethoprim/sulfamethoxazole ( 1/19) Doxycycline Ciprofloxacin Ofloxacin Erythromycin - 0 2 Erythromycin - C0 2 Roxithromycin - 0 2 Roxithromycin - C0 2
50'%
90%
%S
$0.06-128 0.25 0.5 $0.06-4 16 1-128 2 0.25-8 0.5 0 . 12-2 0.12 $0.06-8 0.25 $0.06-8 $;0.06 $0.06 $0.06 $0.06 4 $0.06-16 4 $0.06-32 8 0 . 12-32 0. 12-32 16
16 0.5 64 4 I 0.25 0 .5 $0.06 $0.06 8 32 16 32
86.0* 100.0
Range
20.4 100.0 100.0 94.6 98.9 100.0 100.0 12.9 2.2 2.2 I. I
µg/ml
% R
µg/ml
14.0* 0.0 46.2 0 .0 0.0 4.3 I. I 0.0 0.0 29.0 49.5 83.9 95.7
-
$4/2 $8** $8 $4 $0.5/9.5 $2 $1 $2 $0.5** $0.5** $0.5** $0.5**
-
~8/4 ~32** ~32 ~ 16
~4/76
~8 ~4 ~8
~8** ~8**
~8** ~8**
* According to B-lactamase production. **Tentative breakpoints (see materials and methods). · Acta Clinica Belgica 46.5 ( 199 1)
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
Table 3: Comparative in vitro activity against 46, including 33 B-lactamase producing isolates of M. catarrhalis
MIC (µg/ml)
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Antibiotic Ampicillin Amoxicillin/clavulanate (2/1 ) Cefadroxil Cefaclor Cefuroxime (axetil) Trimethoprirn/sulfamethoxazole (1/19) Doxycycline Ciprofloxacin Ofloxacin Erythromycin
%S at breakpoint
%R at breakpoint
50%
90%
%S
.µg/ml
%R
µg/ml
:50.06-2 0.25 :50.06-0.25 0.12 0.5-32 2 0.12-4 0.5 :50.06-4 0.5 :50.06-2 :50.06 :50.06-4 0.12 :50.06 :50.06 :50.06 :50.06 :50.06-0.5 0.25
2 0.25 4 1 2 0.25 0.12 :50.06 :50.06 0.25
28.3* 100.0 97 .8 100.0 100.0 95.7 97.8 100.0 100.0 100.0
-
71.7 * 0.0 2.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-
Range
:54/2 :58 :58 :54 :50.5/9.5 :52 :51 :52 :50.5
~8/4 ~32 ~32 ~16
~4/76 ~8
~4
~8 ~8
* According to B-Iactamase production.
influenzae was 14.0%. None of the B-lactamase negative isolates was resistant to ampicill in, while, on the other hand, 2 B-lactamase positive isolates were inhibited at concentrations below breakpoint for resistance to ampicillin (MICs: 0.5 and 2 µg/ ml). All, including the B-lactamase producing isolates, were susceptibl e to amoxicillin/ clavulanate, cefaclor, and cefuroxime (axetil); however, cefaclor generally showed higher MI Cs. In contrast, only 20.4% of isolates proved susceptible to cefadroxil. The highest activity against H . influenzae was exhibited by ciprofloxacin and ofloxacin, with all isolates inhibited at :50.06 µg/ ml. Co-trimoxazole and doxycycline showed resistance in 4 (4.3 %, MI Cs: 4, 8, 8, and 8 µg/ml) and 1 isolate (l.l %; MIC: 8 µg/ml), respectively. The doxycycline and co-trimoxazole resistant isolates were higly resistant to ampicillin (MICs: 128 µg/ml); resistance to co-trimoxazole and doxycycline was not -combinect. Erythromycin and roxithromycin were tested under normal and 5% C0 2 atmosphere. As expected, both macrolides were more active when tested under normal atmosphere. However, even then the
majority of isolates proved of intermediate susceptibility to erythromycin (58. I%), and resistant to roxithromycin (83.9% ). B-lactamase was detected in 71.7% of M. catarr ha/is isolates, while only 32.6% of isolates were resistant to ampicil lin at the NCCLS , recommended breakpoint of >0.5 µg/ml. All, including the B-lactamase producing isolates, were susceptible to amoxicillin/cl avulanate, cefaclor and cefurox ime (axetil); however, , cefaclor and cefuroxime (axetil) were markedly less active on a weight basis, with MICs very similar to those of ampicillin. The highest activity against M . catarrhalis was exhibited by ciprofloxacin and ofloxacin, with all isolates inhibited at :50.06 µg/ml. Apart from ampici llin, resistance was only observed with cefadroxil in 1 isolate (2.2%; MIC: 32 µg/ml).
DISCUSSION This survey of community respiratory isolates of S. pn eumoniae , H . influ enzae, and M .
Acta Clinica Belgica 46.5 (1991) ,l...._
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
catarrhalis from different areas in Belgium allowed to compare their in vitro susceptibility to antimicrobials that are currently available for oral therapy of respiratory tract infections. Ampicillin showed excellent activity against S. Pneumoniae, but is amenable to inactivation by B-lactamase producing isolates of H . influenzae and M. catarrha/is, which, in all, accounted for 22% of the pathogens tested in this study. The apparent susceptibility to ampicillin of some of these B-lactamase producing organisms is probably related to the low inoculum that was used, as shown previously (4, 5). In 1989, national reference laboratories reported higher resistance rates in invasive isolates of S. pneumoniae (3% to penicillin) and H. influenzae (39% B-lactamase Production) (6). The difference for H . influenzae may be due to the fact that different populations were sampled; it is well-known, for instance, that invasive isolates of H. influenzae, most of which are of type b, more frequently harbour the TEM -1 B-lactamase than non-encapsulated isolates (7-9). The combination of amoxicillin and clavulanate was active against all isolates tested: this was not unexpected, inasmuch as clavulanate is a potent inhibitor of both H . influenzae and M. catarrha/is 13-lactamases (I 0).
Cefadroxil was the least active among the oral cephalosporins tested, especially against H. influ enzae, as shown previously (I I). Ce factor had a better overall activity; however, its MI Cs for S. Pneumoniae and H. influenzae were markedly higher than tho se of cefuroxime (axetil). Furthermore, susce ptibility to cefaclor of 13-lactamase producing isolates of M . catarrhalis should be interpreted with caution, si nce the concerned 13-lactamases (BRO-I and BR0-2) have been shown to hydrolyse cefaclor more rapidly than benzylpenicillin and ampicillin ( 12). Cefuroxime axetil is a second ge nera tion cephalosporin available for oral administration. We con finned its excellent in vitro activity against the pathogens tested. Apart from M. catarrhalis, that was inhibited at higher concentrations,
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cefuroxime (axetil) compared favourably with amoxicillin/clavulanate. However, there remain some questions about the bioavailability of this cefuroxime ester. ( 13). Co-trimoxazole and doxycycline, for decades, have been used extensively in the treatment of bacterial respiratory tract infections. Both drugs showed activity against >90% of the various pathogens tested in the present study, although 16.7% resistance to tetracycline is currently reported for invasive isolates of S. pneumoniae (6). Tetracycline resistance in M . catarrhalis, which is very rare, was not observed. Ciprofloxacin and ofloxacin were extremely active against the Gram-negative respiratory pathogens tested (MI Cs~ 0.06 µg/ml) , but only poorly against S. pneumoniae. Pneumococci have been involved in failures, super- and reinfections upon treatment of respiratory tract infections with these agents ( 14-17); therefore, the use of the currently available quinolones in the empiric therapy of respiratory tract infections remai ns controversial (I). Resi stance of M. catarrhalis to macrolides has been described, but is rare (9, 18); the mechanism of resistance is unknown. None of th e M . catarrhalis isolates was resistant to erythromycin in the present study, while resistance was found in 2.9% of th e pneumococcal isolates . A prevalence of 13% erythromycin resistance has recently been reported in Belgium for invasive pneumococcal isolates (6). Erythromycin and roxithromycin were only marginally active against H . inj711e11zae, even when tested in normal atmosphere to ensure optimal medium pH; these results are in agreement with other data (79, 19). In summary, the antimicrobial agents showing the most unifonnely hi gh in vitro activity again st the common commun ity respiratory pathogens tested in the present study, were amox icillin/ clavulanate and , to a lesser extent, cefuroxime (axetil). Acta Clinica Belgica 46.5 ( 199 1J
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IN VITRO ACTIVITY OF COMMONLY USED ORAL ANTIMICROBIAL AGENTS AGAINST COMMUNITY ISOLATES OF RESPIRATORY PATHOGENS
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RESUME L'activite in vitro de l'ampicilline, de l'amoxicilline/clavulanate, du cefadroxil, du cefaclor, du cefuroxime (axetil), du co-trimoxazole, de la doxycycline, de la ciprofloxacine, de l'ofloxacine, de l'erythromycine, et de la roxithromycine a ete testee sur des souches non selectionnees de S. pneumoniae (70), d' H. influenzae (93), et de M. catarrhalis (46), isolees en pratique generate a partir d'expectorations cliniquement significatives. Toutes les souches de S. pneumoniae etaient fort sensibles a l'ampicilline; le cefadroxil et le cefaclor etaient beaucoup moins actifs sur base ponderale; des resistances ont ete observees uniquement au cotrimoxazole (4.3%), a ladoxycycline (5 .7%), eta J' erythromycine (2.9% ); toutefois, la ciprofloxacine et l'ofloxacine montraient des CMI medianes (CMI50), situees a peine une dilution en-dessous du seuil critique. Des 8-lactamases ont ete detectees dans 14.0% des souches d'H. influenzae; toutes Jes souches etaient sensibles a l'amoxicilline/ c~avulanate, au cefaclor, et au cefuroxime (axetil), b1en que Jes CMis fussent plus elevees pour le cefaclor; la ciprofloxacine et l'ofloxacine etaient les antibiotiques Jes plus actifs; hormis le cefadroxil, l'erythromycine, et la roxithromycine, qui n 'avaient qu 'une activite marginale, des resistances ont ete observees au'co-trimoxazole (4.3%) et a la doxycycline (I. I %). Toutes les souches de M . catarrhalis, y compris celles produisant des 8-lactamases (71.7%), etaient sensibles a 1'amoxicilline/clavulanate, au cefaclor, et au cefuroxime (axetil), bien que les CMis fussent inferieures pour l'amoxicilline/clavulanate; la ciprofloxacine et l'ofloxacine avaient les CM!s Jes plus basses; des resistances ont ete observees uniquement au cefadroxil (2.2%). En conclusion, l'amoxicilline/ clavulanate et, a un moindre degre, le cefuroxime (axetil), etaient Jes antibiotiques dont l'activite in vitro etait la plus uniformement elevee sur les pathogenes respiratoires testes dans Ia presente etude. SAMENV ATTING De in vitroactiviteitvan ampicilline, amoxicilline/
clavulanaat, cefadroxil, cefaclor, cefuroxime
Acta Clinica Belgica 46.5 ( 1991)
(axetil), co-trimoxazol, doxycycline, ciprofloxacine, ofloxacine, erythromycine, en roxithromycine werd getest op niet geselecteerde stammen van S. pneumoniae (70), H. inf/uenzae (93), en M. catarrhalis (46), ge-isoleerd uit klinisch significante sputummonsters van patienten uit de huisartsenpraktijk. Alie S. pneumoniae stammen waren erg gevoelig voor ampicilline; cefadroxil en cefaclor waren merkelijk minder actief op gewichtsbasis; resistentie werd enkel waargenomen tegen cotrimoxazol (4.3%), doxycycline (5.7%), en erythromycine (2. 9% ); ciprotloxacine en otloxacine toonden evenwel mediane MICS (MIC50), die nauwelijks I dilutie beneden breekpunt lagen. BLactamasen werden gedetecteerd in 14.0% van de H . influenzae stammen; alle stammen waren gevoelig voor amoxicilline/clavulanaat, cefaclor, en cefuroxime (axetil), alhoewel de MICs over het algemeen hoger waren voor cefaclor; ciprofloxacine en ofloxacine vertoonden de hoogste activiteit; afgezien van cefadroxil, erythromycine en roxithromycine, die slechts marginaal actief waren, werd resistentie waargenomen voor co-trimoxazol (4.3%)endoxycycline (I. I%). Alle(inclusief71.7% B-Iactamase producerende) stammen van M . catarrha/is waren gevoelig voor amoxicilline/clavulanaat, cefaclor, en cefuroxime (axetil), alhoewel de MICs merkelijk lager waren voor amoxicilline/ /clavulanaat; ciprofloxacine en ofloxacine hadden de laagste MICs; resistentie werd enkel waargenomen voor cefadroxil (2..2%). Tot besluit waren amoxicilline/clavulanaat en, in mindere mate, cefuroxime (axetil), de antibiotica met de meest gelijkmatig hoge in vitro activiteit tegen de respiratoire pathogenen, die in deze studie werden getest.
ACKNOWLEDGMENTS This work was supported by a grant from SmithKline Beecham, Belgium.
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Acta Clinica Belgica 46.5 ( 1991)
