Increasing Prevalence of Antimicrobial Resistance

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Increasing prevalence of antimicrobial resistance among isolates of

Streptococcus pneumoniae from the PROTEKT surveillance study, and
comparative in vitro activity of the ketolide,...
Article in Journal of Antimicrobial Chemotherapy · October 2002

DOI: 10.1093/jac/dkf808 · Source: PubMed
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Journal of Antimicrobial Chemotherapy (2002) 50, Suppl. S1, 25–37
DOI: 10.1093/jac/dkf808

Streptococcus pneumoniae from the PROTEKT surveillance study,
and comparative in vitro activity of the ketolide, telithromycin
David Felmingham1*, Ralf Rene Reinert2, Yoichi Hirakata3 and Arne Rodloff4
1GR Micro Ltd, 7–9 William Road, London NW1 3ER, UK; 2National Reference Centre for Streptococci, Aachen,
Germany; 3Nagasaki University School of Medicine, Nagasaki, Japan; 4University of Leipzig, Leipzig, Germany
The prevalence of resistance to a range of antimicrobials was determined for isolates of Strepto-
coccus pneumoniae examined in the PROTEKT (Prospective Resistant Organism Tracking and
Epidemiology for the Ketolide Telithromycin) surveillance study (1999–2000) using NCCLS
testing methods and interpretative criteria. Of 3362 pneumococcal isolates collected from
69 centres in 25 countries, 22.1% overall were resistant to penicillin G, with the highest rates of
resistance found among isolates from Asia (53.4%), France (46.2%) and Spain (42.1%). Erythro-
mycin A resistance occurred in 31.1% of isolates overall with the highest rates found in Asia
(79.6%), France (57.6%), Hungary (55.6%) and Italy (42.9%). Marked geographical differences in
the prevalence of both penicillin G (the Netherlands 0%; South Korea 71.5%) and erythromycin A
(Sweden 4.7%; South Korea 87.6%) resistance were observed. Asia was characterized by the
highest prevalence of resistance, overall, with only eight of 19 antimicrobials (co-amoxiclav,
linezolid, vancomycin, teicoplanin, quinupristin/dalfopristin, levofloxacin, moxifloxacin and
telithromycin) retaining high activity against isolates of S. pneumoniae from this region. Notable
rates of resistance to clarithromycin, azithromycin, co-trimoxazole and tetracycline were
observed in the majority of countries submitting isolates of S. pneumoniae to the PROTEKT
surveillance study. Fluoroquinolone resistance was low (1%), overall, although 14.3% of
70 isolates from Hong Kong were resistant to levofloxacin and moxifloxacin, all but one of these
isolates belonging to a single clone of the 23F serotype. Although, at present, apparently limited
to pockets of clonal spread, continued vigilance with regard to the evolution of fluoroquinolone
resistance is indicated. Telithromycin (MIC90 0.12 mg/L; 99.9% of isolates susceptible) and lin-
ezolid (MIC90 2 mg/L; 100% of isolates susceptible) were the two most active oral agents tested,
both compounds retaining activity against isolates of fluoroquinolone-resistant S. pneumoniae.
The results of the PROTEKT surveillance study 1999–2000 emphasize the widespread evolution
of resistance to a variety of antimicrobials amongst isolates of S. pneumoniae and demonstrate
the potential of telithromycin as a therapeutic option for the treatment of community-acquired
respiratory tract infections caused by this organism.
Introduction estimated that each year in the USA, S. pneumoniae infections

account for 500 000 cases of pneumonia, 55000 cases of
Although a common component of the normal human respir- bacteraemia and 6000 cases of meningitis. 4,5
atory flora, Streptococcus pneumoniae is also one of the most While β-lactams, most notably penicillin G, have been the
important bacterial pathogens. Infection with this organism is mainstay of antimicrobial treatment for CARTIs, resistance
among the most frequent causes of community-acquired to these agents has reached alarming levels in many regions.
respiratory tract infections (CARTIs), including community- Isolates of S. pneumoniae with reduced susceptibility to
acquired pneumonia (45% of cases), otitis media (30–40%) penicillin G were first reported during the 1960s in Australia
and sinusitis (20–35%), as well as being one of the leading and Papua New Guinea.3,6 By the early 1970s penicillin G-
causes of meningitis and bacteraemia.1–3 Indeed, it has been intermediate and -resistant strains had been detected in
..................................................................................................................................................................................................................................................................
*Corresponding author. Tel: +44-20-7388-7320; Fax: +44-20-7388-7324; E-mail: [email protected]

...................................................................................................................................................................................................................................................................
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© 2002 The British Society for Antimicrobial Chemotherapy
D. Felmingham et al.
Poland and Germany, with Japan, South Africa, Switzerland Netherlands (1), Sweden (1), UK (2), Eire (1), Belgium (1),
and the UK also reporting the presence of such strains during France (4), Portugal (2), Spain (2), Switzerland (2), Italy (2),
the mid to late 1970s.6 Subsequently, penicillin G-resistant Austria (1), Turkey (1), Hungary (1), Poland (1), Hong Kong
strains of S. pneumoniae have rapidly spread worldwide and (1), Japan (6), South Korea (2), Australia (2) and Indonesia
their prevalence continues to increase.7–12 Of even more con- (1).
cern is the degree to which these isolates are cross-resistant,
not only to other β-lactam drugs, such as the cephalosporins, Bacterial isolates
but also to non-β-lactam classes, e.g. the macrolides.10 Resist-
ance to fluoroquinolones is also emerging among S. pneumo- Each centre recruited into the PROTEKT study was requested
niae, albeit currently at relatively low levels.13 to collect a minimum of 60 isolates of S. pneumoniae from
In this era of increasing antimicrobial resistance, treatment patients with any of six types of community-acquired infec-
of CARTIs should ideally be pathogen directed, based on tion, namely sinusitis, otitis media, pharyngitis, pneumonia,
identification and susceptibility testing of the causative acute bacterial exacerbations of chronic bronchitis and acute
organism. In reality, however, an aetiologically specific diag- exacerbation of chronic obstructive airways disease. Sources
nosis, let alone susceptibility results, is rarely available to for isolation of RTI pathogens were cultures from blood,
assist in the selection of therapy, which is consequently sputum, bronchoalveolar lavage, middle ear fluid, naso-
largely empirical. In view of the importance of S. pneumoniae pharyngeal swab or aspirate, and sinus aspirate. Patients
in CARTIs and the traditionally empirical approach to the with nosocomial RTIs and those with cystic fibrosis were
treatment of these infections, knowledge of local anti- excluded, and duplicate strains or strains originating from
microbial resistance patterns is essential to ensure rational existing collections were not included in the study. Demo-
prescribing.14 These issues highlight the need for continuing graphic data collected included the age and sex of the patient,
surveillance of antimicrobial resistance at local, national and infection, culture source, in/outpatient status, specimen
international levels, as well as the need for research into new accession number and date of sample collection. Criteria for
antibacterial agents with the ability to overcome S. pneumo- isolate storage, transportation and identification, and con-
niae resistance mechanisms and which do not induce or select firmation of isolate identification have been described in
further resistance. detail previously.22
The ketolides are a new family of antibacterial agents
belonging to the macrolide–lincosamide–streptogramin Antimicrobial susceptibility testing
class.15,16 Telithromycin, the first ketolide antibacterial, has
MICs were determined at a central laboratory (GR Micro Ltd,
demonstrated clinical efficacy across a range of CARTIs,
London, UK) for a panel of existing and new antimicrobials,
and potent in vitro activity against the pathogens commonly
using previously described methods.22 In brief, we used the
implicated in these infections, including drug-resistant
NCCLS broth microdilution method with lyophilized micro-
S. pneumoniae.17–19 Data from both in vitro and human studies
titre plates (Sensititre system; Trek Diagnostics) and an inoc-
suggest that this agent also has a low potential for the selection
ulum of 3–7 × 104 cfu in 100 µL medium. MIC endpoints were
or induction of resistance, and has minimal effect on normal
read as the lowest concentration of antimicrobial that totally
human gut flora.20,21 In 1999, the PROTEKT (Prospective
inhibited macroscopically visible growth of the inoculum.
Resistant Organism Tracking and Epidemiology for the
Isolates were tested against the following antimicrobials:
Ketolide Telithromycin) surveillance study was established
penicillin G, co-amoxiclav (2:1 ratio), cefaclor, cefixime,
to track longitudinally the susceptibility of common respir-
cefpodoxime, cefuroxime, azithromycin, clarithromycin,
atory pathogens from patients with CARTIs to current and new
erythromycin A, telithromycin, clindamycin, levofloxacin,
antimicrobials, including the new ketolide, telithromycin.
ciprofloxacin, moxifloxacin, co-trimoxazole (1:19 ratio),
This paper describes the widespread prevalence of resistance
linezolid, quinupristin–dalfopristin (30:70 ratio), teicoplanin,
and the comparative activity of common and newly devel-
tetracycline and vancomycin. Percentage susceptibilities
oped antimicrobial agents against isolates of S. pneumoniae
were calculated based on NCCLS breakpoints, although it
collected during the first year (1999–2000) of the PROTEKT
should be noted that NCCLS breakpoints applied to telithro-
study.
mycin are tentative and not yet approved (Table 1).
Materials and methods

Results
Collecting centres
A total of 3362 isolates of S. pneumoniae were collected from
During the 1999–2000 respiratory season, 69 centres in 25 countries within Western Europe (n = 1322), North
25 countries participated in PROTEKT: Canada (7), USA (8), America (n = 687), Latin America (n = 518), Asia (n = 515),
Mexico (4), Brazil (7), Argentina (2), Germany (7), the Eastern Europe (n = 199) and Australasia (n = 121). Informa-
26
Prevalence of antimicrobial resistance and in vitro comparison of activity
Table 1. Interpretative categories for S. pneumoniaea
Interpretative categories (mg/L)
Antimicrobial agent susceptible intermediate resistant
Co-amoxiclav ≤2 4 ≥8
Azithromycin ≤0.5 1 ≥2
Cefaclor ≤1 2 ≥4
Cefixime susceptibility reported as for penicillin G
Cefpodoxime ≤0.5 1 ≥2
Cefuroxime ≤1 2 ≥4
Clarithromycin ≤0.25 0.5 ≥1
Clindamycin ≤0.25 0.5 ≥1
Co-trimoxazole ≤0.5 1–2 ≥4
Erythromycin A ≤0.25 0.5 ≥1
Levofloxacin ≤2 4 ≥8
Linezolid ≤2 ≥8
Moxifloxacin ≤1 2 ≥4
Penicillin G ≤0.06 0.12–1 ≥2
Quinupristin/dalfopristin ≤1 2 ≥4
Teicoplanin ≤8 16 ≥32
Telithromycin ≤1 2 ≥4
Tetracycline ≤2 4 ≥8
Vancomycin ≤1 – –
aAll breakpoints given are NCCLS, with the exception of telithromycin for which NCCLS-
approved breakpoints are not yet available (tentative breakpoints given).
tion on culture source, patient age and gender, and treatment Erythromyin A resistance rates were also very high (31.0%
setting were available for approximately 45–87% of the overall), and in most countries (19/25) they exceeded rates of
isolates collected, and this is summarized in Table 2. penicillin G resistance. Again, Asian countries had a very
high prevalence of erythromycin A resistance, averaging
Prevalence of antimicrobial resistance 79.6%, while for isolates collected from North America,
Western Europe, Latin America, Eastern Europe and Austral-
Susceptibility of S. pneumoniae to penicillin G and to erythro- asia, the prevalence of erythromycin A resistance ranged
mycin A is shown in Table 3 by region and by country. from 11.6 to 29.1%. Across Europe, rates of resistance of
Strains of S. pneumoniae with reduced susceptibility to S. pneumoniae isolates to erythromycin A reached 55.6% in
penicillin G were evident in all of the participating countries, Hungary and 57.6% in France. Other European countries with
at an overall prevalence of 36.2%. There was, however, high levels of resistance included Belgium (32.1%), Eire
marked variation between countries in the prevalence of such (26.4%), Italy (42.9%) and Spain (28.6%).
isolates, ranging from 3.9% in the Netherlands to 81% in Fluoroquinolone resistance (defined as levofloxacin MIC
South Korea. Of those isolates with reduced susceptibility to ≥ 8 mg/L) was detected in nine of the countries participating
penicillin G, the resistant phenotype was found to dominate in PROTEKT in 1999–2000, reaching rates of 14.3% in
over the intermediate phenotype in 12 of the 25 countries, Hong Kong (Figure 1). However, the overall prevalence of
with particularly high rates of penicillin G resistance being fluoroquinolone resistance was low, averaging 1.0%. Similar
reported in all three countries within Asia (44.5–71.5%), as resistance rates were noted for moxifloxacin.
well as in France (46.2%) and Spain (42.1%). The Nether-
lands and Indonesia were the only countries not to report any Comparative in vitro activity of the test agents
isolates with full resistance to penicillin G, although the
number of isolates submitted by the latter is too small to draw MIC and percentage susceptibility data for the 19 antimicro-
any meaningful conclusions. Overall, 22.1% of isolates were bials tested against S. pneumoniae are reported by region in
resistant to penicillin G, with 7.9% of isolates having a peni- Table 4. These data highlight striking differences between
cillin G MIC ≥ 4 mg/L. regions in terms of susceptibility of S. pneumoniae not only to
27
penicillin G and erythromycin A, but also to other commonly

used agents. In particular, Asian countries had a very high
prevalence of resistance to many of the antimicrobials tested,
with only eight of the 19 agents being active against >50%
of all 515 S. pneumoniae isolates: co-amoxiclav (87.6%),
linezolid (100%), teicoplanin (100%), vancomycin (100%),
quinupristin/dalfopristin (96.3%), moxifloxacin (96.7%), levo-
floxacin (95.3%) and telithromycin (100%).
The pattern of resistance to the cephalosporins tended to
parallel that to penicillin G, the highest and lowest suscept-
ibilities being recorded for isolates collected from Australasia
and Asia, respectively. Based on MIC and susceptibility data,
co-amoxiclav proved the most active of the β-lactams tested,
Figure 1. Prevalence of fluoroquinolone resistance among S.
pneumoniae (n = 3362) collected in the PROTEKT study (1999–2000). although susceptibility to this agent was reduced somewhat in
(Only those countries where fluoroquinolone-resistant isolates were both Asia and North America (87.6% and 90.5%, respect-
detected are shown.) ively) compared with the other regions (97.5–100%).
Table 2. Patient demographics and culture source of 3362 isolates of S. pneumoniae collected in the
PROTEKT study (1999–2000)
Percentage of total Percentage of

Parameter Group Number with data total collected
Age 0–2 440 15.30 13.09

3–14 362 12.60 10.77
>14–65 1261 43.90 37.51
>65 809 28.20 24.06
NR 490 – 14.57
Gender male 1831 63.10 54.46
female 1073 36.90 31.92
NR 458 – 13.62
Source blood 502 17.30 14.93
BAL 258 8.90 7.67
sputum 1482 51.10 44.08
sinus 137 4.70 4.07
ear 203 7.00 6.04
MEF 30 1.00 0.89
nasopharyngeal 234 8.10 6.96
throat 54 1.90 1.61
NR 462 – 13.74
Infection site AECB 448 24.40 13.33
COAD 141 7.70 4.19
pneumonia 742 40.40 22.07
sinusitis 158 8.60 4.70
otitis media 265 14.40 7.88
tonsillitis/pharyngitis 81 4.40 2.41
NR 1527 – 45.42
In/outpatient in 1514 51.50 45.03
out 1425 48.50 42.39
NR 423 – 12.58
NR, not recorded; AECB, acute exacerbation of chronic bronchitis; COAD, chronic obstructive airways disease; BAL,
bronchoalveolar lavage; MEF, middle ear fluid.
28
Table 3. Number (%) of S. pneumoniae strains by penicillin G and erythromycin A susceptibility interpretative category in each
continent and country
Penicillin G susceptibilitya Erythromycin A susceptibilityb

[no. (%) of isolates] [no. (%) of isolates]
Total no. of
Region/country isolates tested susceptible intermediate resistant susceptible intermediate resistant
Western Europe 1322 996 (75.3%) 115 (8.7) 211 (16.0) 998 (75.5) 2 (0.2) 322 (24.4)
Austria 57 53 (93.0%) 1 (1.8) 3 (5.3) 49 (86.0) 1 (1.8%) 7 (12.3)
Belgium 28 23 (82.1%) 1 (3.6) 4 (14.3) 19 (67.9) 0 (0) 9 (32.1)
Eire 53 31 (58.5) 4 (7.5) 18 (34.0) 39 (73.6) 0 (0) 14 (26.4)
France 184 70 (38.0) 29 (15.8) 85 (46.2) 77 (41.8) 1 (0.5) 106 (57.6)
Germany 325 298 (91.7) 20 (6.2) 7 (2.2) 274 (84.3) 0 (0) 51 (15.7)
Italy 119 101 (84.9) 6 (5.0) 12 (10.1) 68 (57.1) 0 (0) 51 (42.9)
The Netherlands 51 49 (96.1) 2 (3.9) 0 (0) 47 (92.2) 0 (0) 4 (7.8)
Portugal 106 76 (71.7) 19 (17.9) 11 (10.4) 89 (84.0) 0 (0) 17 (16.0)
Spain 133 62 (46.6) 15 (11.3) 56 (42.1) 95 (71.4) 0 (0) 38 (28.6)
Sweden 64 58 (90.6) 1 (1.6) 5 (7.8) 61 (95.3) 0 (0) 3 (4.7)
Switzerland 111 97 (87.4) 9 (8.1) 5 (4.5) 101 (91.0) 0 (0) 10 (9.0)
UK 91 78 (85.7) 8 (8.8) 5 (5.5) 79 (86.8) 0 (0) 12 (13.2)
Eastern Europe 199 118 (59.3) 54 (27.1) 27 (13.6) 141 (70.9) 0 (0) 58 (29.1)
Hungary 54 19 (35.2) 28 (51.9) 7 (13.0) 24 (44.4) 0 (0) 30 (55.6)
Poland 68 50 (73.5) 9 (13.2) 9 (13.2) 52 (76.5) 0 (0) 16 (23.5)
Turkey 77 49 (63.6) 17 (22.1) 11 (14.3) 65 (84.4) 0 (0) 12 (15.6)
North America 687 468 (68.1) 72 (10.5) 147 (21.4) 525 (76.4) 2 (0.3) 160 (23.3)
Canada 350 276 (78.9) 37 (10.6) 37 (10.6) 292 (83.4) 2 (0.6) 56 (16.0)
USA 337 192 (57.0) 35 (10.4) 110 (32.6) 233 (69.1) 0 (0) 104 (30.9)
Latin America 518 300 (57.9) 139 (26.8) 79 (15.3) 438 (84.6) 1 (0.2) 79 (15.3)
Argentina 55 40 (72.7) 6 (10.9) 9 (16.4) 49 (89.1) 0 (0) 6 (10.9)
Brazil 260 172 (66.2) 67 (25.8) 21 (8.1) 242 (93.1) 1 (0.4) 17 (6.5)
Mexico 203 88 (43.3) 66 (32.5) 49 (24.1) 147 (72.4) 0 (0) 56 (27.6)
Australasia 121 95 (78.5) 21 (17.4) 5 (4.1) 106 (87.6) 1 (0.8) 14 (11.6)
Australia 114 91 (79.8) 18 (15.8) 5 (4.4) 99 (86.8) 1 (0.9) 14 (12.3)
Indonesia 7 4 (57.1) 3 (42.9) 0 (0) 7 (100) 0 (0) 0 (0)
Asia 515 165 (32.0) 75 (14.6) 275 (53.4) 104 (20.2) 1 (0.2) 410 (79.6)
Hong Kong 70 29 (41.4) 1 (1.4) 40 (57.1) 20 (28.6) 0 (0) 50 (71.4)
Japan 308 110 (35.7) 61 (19.8) 137 (44.5) 67 (21.8) 1 (0.3) 240 (77.9)
South Korea 137 26 (19.0) 13 (9.5) 98 (71.5) 17 (12.4) 0 (0) 120 (87.6)
Total 3362 2142 (63.7) 476 (14.2) 744 (22.1) 2312 (68.8) 7 (0.2) 1043 (31.0)
aPenicillin G susceptibility interpretative criteria: susceptible, ≤0.06 mg/L; intermediate, 0.12–1 mg/L; resistant, ≥2 mg/L.
bErythromycin A susceptibility interpretative criteria: susceptible, ≤0.25 mg/L; intermediate, 0.5 mg/L; resistant, ≥1 mg/L.
Of the macrolide–lincosamide–streptogramin antimicro- high prevalence of resistance to co-trimoxazole, ranging from

bials, telithromycin proved the most active overall (99.9% 15.7% in Australasia to 45.6% in Latin America (28.6%
susceptibility). In contrast, high rates of resistance were overall). Overall, resistance to tetracycline averaged 29.7%,
reported for both clarithromycin (30.6%) and azithromycin the highest prevalence being reported in Asia (81.2%). All
(30.7%); the activity of these agents and patterns of resistance isolates collected were susceptible to linezolid, teicoplanin
being essentially equivalent to those of erythromycin A across and vancomycin.
the regions studied. Resistance to clindamycin averaged Of the oral agents tested, telithromycin and linezolid proved
19.7%. Clindamycin resistance was reported most frequently to have the most potent anti-pneumococcal activity, based on
for isolates collected from Asia and from Europe, where MIC and percentage susceptibilities. S. pneumoniae MIC
resistance rates were three-fold and seven-fold higher, distributions for telithromycin compared with β-lactams,
respectively, than for the other regions. All regions reported a macrolides and fluoroquinolones are shown in Figures 2–4.
29
Table 4. In vitro activity of 19 antimicrobial agents against 3362 isolates of S. pneumoniae collected from across five continents in the PROTEKT study
(1999–2000)a
Asia (n = 515) Australasia (n = 121) Europe (n = 1521) Latin America (n = 518) North America (n = 687)
Antimicrobial MIC50 MIC90 %S MIC50 MIC90 %S MIC50 MIC90 %S MIC50 MIC90 %S MIC50 MIC90 %S
Telithromycinb 0.06 0.5 100 0.008 0.015 100 0.015 0.06 99.9 0.008 0.06 100 0.015 0.25 100
Penicillin G 2 4 32.0 0.015 0.25 78.5 0.015 2 73.2 0.06 2 57.9 0.015 2 68.1
Co-amoxiclav 1 4 87.6 0.03 0.25 100 0.03 2 97.5 0.03 2 98.7 0.03 2 90.5
Cefaclor 64 >64 21.6 1 8 81.0 1 >64 70.2 1 64 63.7 1 >64 63.5
Cefixime 32 64 32.0 0.25 4 78.5 0.25 32 73.2 0.5 32 57.9 0.25 32 68.1
Cefpodoxime 2 4 36.3 0.12 0.25 93.4 0.12 2 80.6 0.12 v2 78.4 0.12 4 75.3
30
Cefuroxime 4 8 36.7 0.03 0.5 92.6 0.06 8 80.6 0.12 4 77.0 0.06 8 75.3
Azithromycin 64 >64 20.2 0.12 4 87.6 0.12 >64 75.1 0.12 8 84.8 0.12 16 76.4
Clarithromycin 32 >32 20.4 0.03 1 88.4 0.03 >32 75.0 0.03 4 84.8 0.06 8 76.4
Clindamycin 2 >4 49.5 0.06 0.12 94.2 0.06 >4 80.1 0.06 0.12 93.1 0.06 0.12 91.1
Erythromycin A 64 >64 20.2 0.06 2 87.6 0.06 >64 74.9 0.06 4 84.6 0.06 16 76.4
Levofloxacin 1 1 95.3 1 1 100 1 1 99.8 1 1 99.2 1 1 98.0
Moxifloxacin 0.12 0.25 96.7 0.12 0.25 100 0.12 0.25 99.9 0.12 0.25 99.2 0.12 0.25 98.7
Co-trimoxazole 1 16 35.0 0.25 4 70.2 48.8 11.2 66.3 2 16 36.5 0.5 16 61.6
Tetracycline >16 >16 18.4 0.25 >16 86.6 60.6 32 75.9 0.25 >16 75.1 0.25 >16 86.2
Quinupristin/dalfopristin 0.5 1 96.3 0.5 1 99.2 0.5 1 98.9 0.5 0.5 99.8 0.5 1 99.6
Linezolid 1 1 100 1 1 100 1 1 100 1 2 100 1 2 100
Teicoplanin 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100
Vancomycin 0.5 0.5 100 0.5 0.5 100 0.5 0.5 100 0.5 v0.5 100 0.5 0.5 100
aFor susceptibility criteria see Table 1.

bInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).
Figure 2. MIC distributions for telithromycin and β-lactams against Figure 3. MIC distributions for telithromycin and macrolides against
3362 isolates of S. pneumoniae collected in total in the PROTEKT study 3362 isolates of S. pneumoniae collected in the PROTEKT study (1999–
(1999–2000). Key: black bars, susceptible; shaded bars, intermediate; 2000). For key see Figure 2.
white bars, resistant
Cross- and parallel-resistance penicillin G-susceptible isolates. A similar cross-resistance

profile was observed between penicillin G and other β-
In total, 12.6% of penicillin G-susceptible S. pneumoniae
lactams, and between penicillin G and macrolides (data not
isolates were found to be resistant to erythromycin A, with
shown). Again there was marked geographical variation in
rates rising to 49.2% and 72.4% for penicillin G-intermediate
and -resistant isolates, respectively. Table 5 summarizes the the prevalence of antimicrobial resistance among the peni-
activity of representatives of the major groups of antimicro- cillin G resistance phenotypes.
bials against S. pneumoniae isolates collected in PROTEKT Table 6 shows the extent to which S. pneumoniae isolates
according to the penicillin G susceptibility phenotype, and by were multi-resistant to commonly used oral antimicrobials.
region. With the exception of levofloxacin and telithromycin, Approximately 50% of all erythromycin A-resistant strains
resistance to the drugs listed in Table 5 was notably higher were also resistant to penicillin G and co-trimoxazole, while
among penicillin G-non-susceptible isolates than among 63.2% and 76.5% of erythromycin A-resistant strains were
31
Table 5. In vitro activity of selected antimicrobial agents against 3362 isolates of S. pneumoniae collected in the PROTEKT study (1999–2000), according to
penicillin G susceptibility and continenta
Telithromycinb
Pen-S 0.03 0.25 100 0.008 0.015 100 0.008 0.015 100 0.008 0.015 100 0.008 0.015 100
Pen-I 0.06 0.5 100 0.008 0.015 100 0.015 0.06 100 0.015 0.25 100 0.015 0.12 100
Pen-R 0.06 0.5 100 0.015 0.03 100 0.015 0.5 99.2 0.008 0.12 100 0.06 0.5 100
Co-amoxiclav
Pen-S 0.03 0.06 100 0.03 0.03 100 0.03 0.03 100 0.03 0.03 100 0.03 0.03 100
Pen-I 0.25 1 98.7 0.25 0.5 100 0.12 1 100 0.12 1 100 0.25 2 100
Pen-R 2 4 77.0 2 2 100 2 8 84.0 2 2 91.4 2 >4 55.8
Cefpodoxime
Pen-S 0.12 0.5 95.2 0.12 0.12 100 0.12 0.12 100 0.12 0.12 100 0.12 0.12 99.4
Pen-I 2 4 40.0 0.25 1 85.7 0.25 2 67.4 0.25 2 76.3 0.25 2 72.2
Pen-R 4 8 0 2 4 0 4 4 0 4 4 0 4 8 0
32
Erythromycin A
Pen-S 4 >64 44.9 0.06 0.5 89.5 0.06 4 88.8 0.06 0.06 95.0 0.06 0.12 93.4
Pen-I 64 >64 14.7 0.06 0.06 90.4 >64 >64 43.8 0.06 >64 66.2 0.06 >64 58.3
Pen-R 64 >64 6.9 4 >64 40.0 >64 >64 31.9 0.06 8 77.2 4 >64 31.3
Levofloxacin
Pen-S 1 1 95.2 1 1 100 1 1 99.7 1 1 99.3 1 1 98.1
Pen-I 0.5 1 98.7 1 1 100 1 1 100 1 1 100 1 1 98.6
Pen-R 1 1 94.5 1 1 100 1 1 100 1 1 97.5 1 1 97.3
Co-trimoxazole
Pen-S 0.5 2 70.3 0.25 2 80 0.25 2 82.1 1 8 49.3 0.25 0.5 81.4
Pen-I 1 8 42.7 1 4 42.9 1 8 42.6 4 >16 25.2 1 16 45.8
Pen-R 4 >16 11.6 8 16 0 8 16 8.8 8 >16 7.6 8 >16 6.1
Tetracycline
Pen-S 16 >16 37.0 0.25 0.5 90.5 0.25 8 89.2 0.25 16 81.0 0.25 1 97.7
Pen-I >16 >16 14.7 0.25 >16 81.0 >16 >16 37.9 0.25 >16 71.2 0.25 >16 68.1
Pen-R >16 >16 8.4 >16 >16 40.0 >16 >16 40.3 0.5 >16 59.5 0.5 >16 58.5
Pen-S, penicillin G susceptible (MIC ≤ 0.06 mg/L); Pen-I, penicillin G intermediate (MIC 0.12–1 mg/L); Pen-R, penicillin G resistant (MIC ≥2 mg/L).
co-trimoxazole
552 (74.2%)
366 (55.4%)
527 (50.5%)
20 (57.1%)
491 (49.2%)
Table 6. Multiple resistance among 3362 isolates of S. pneumoniae collected in the PROTEKT study (1999–2000) (the percentages quoted in the table are the
486 (65.3%)
586 (88.7%)
798 (76.5%)
21 (60.0%)
491 (51.1%)
tetracycline
No. (%) of isolates also resistant to:
levofloxacin
18 (2.4%)
19 (2.9%)
27 (2.6%)
21 (2.1%)
20 (2.1%)
erythromycin A
539 (72.4%)
659 (99.7%)
27 (77.1%)
798 (80.0%)
527 (54.9%)
329 (44.2%)
659 (63.2%)
19 (54.2%)
586 (58.8%)
366 (38.1%)
Figure 4. MIC distributions for telithromycin and fluoroquinolones clindamycin
percentage of isolates resistant to Agent 1 that are also resistant to Agent 2)
against 3362 isolates of S. pneumoniae collected in total in the

PROTEKT study (1999–2000). For key see Figure 2.
329 (49.8%)
539 (51.7%)
18 (51.4%)
486 (48.7%)
552 (57.5%)
penicillin G
cross-resistant to clindamycin and tetracycline, respectively,

but they remained susceptible to levofloxacin, moxifloxacin,
telithromycin and linezolid (data not shown). Those isolates
that were resistant to levofloxacin (n = 35) were also highly
resistant to the other oral agents, with the exception of
telithromycin and linezolid (all fluoroquinolone-resistant
No. of isolates
S. pneumoniae remained fully susceptible to these two oral

744
661
1043
35
997
960
agents). The in vitro activity of telithromycin by penicillin G,

erythromycin A or fluoroquinolone susceptibility/resistance
phenotype is summarized in Table 7.
Discussion
Erythromycin A resistant
Co-trimoxazole resistant
Levofloxacin resistant
Clindamycin resistant
Tetracycline resistant
Over the last three decades, antimicrobial resistance among

Penicillin G resistant
isolates of S. pneumoniae has spread across the globe at an

alarming rate, and now threatens to compromise the clinical
usefulness of the current portfolio of agents for treating infec-
Phenotype
tions associated with this pathogen. International antimicro-

bial surveillance studies play a critical role in defining the
nature and extent of the resistance problem, as well as in
33
Table 7. In vitro activity of telithromycin against S. pneumoniae isolates collected in PROTEKT, by

antimicrobial resistance phenotype
MIC (mg/L)
Phenotype n Mode MIC50 MIC90 Range % susceptibilitya
Penicillin G
Susceptible 2142 0.008 0.008 0.03 0.002–0.5 100
Intermediate 476 0.008 0.015 0.12 0.004–1 100
Resistant 744 0.06 0.06 0.5 0.004–8 99.6
Erythromycin A
Susceptible 2312 0.008 0.008 0.015 0.002–0.12 100
Intermediate 7 0.015 0.015 0.03 0.008–0.03 100
Resistant 1043 0.06 0.06 0.5 0.008–8 99.7
Levofloxacin
Susceptible 3317 0.008 0.015 0.12 0.002–8 99.9
Intermediate 10 0.008 0.03 0.12 0.008–0.12 100
Resistant 35 0.03 0.03 0.12 0.008–0.5 100
Combined 3362 0.008 0.015 0.12 0.002–8 99.9
aInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).
guiding development of antimicrobial policies and usage.23 bouring countries of Germany and Switzerland, resistance to
Furthermore, by monitoring changes in resistance patterns this agent averaged 2.2% and 4.5%, respectively. The data
and the spread of significant resistance phenotypes across the also suggest that the prevalence of penicillin G resistance in
globe, these studies enable authorities to implement inter- the USA has risen substantially from the 9.5% reported in a
vention strategies to halt the spread of such strains. The 1994–1995 study by Doern et al.7 For 1997–1998 US isolates,
PROTEKT study was initiated in 1999 to monitor longitud- Thornsberry et al. found 13% penicillin G resistance,25 Hoban
inally the global spread of resistance among bacterial res- et al. reported 15% resistance among 1999 isolates,24 and in
piratory pathogens associated with CARTIs. Testing of all 1999–2000 isolates we have found 33% resistance. Although
isolates at a central laboratory using validated identification the penicillin G resistance prevalence in the USA seems
techniques and NCCLS-recommended methodologies has exceptionally high in this study, preliminary data from a sub-
helped to ensure the quality and consistency of the data sequent sister surveillance study, PROTEKT US, reported a
generated. rate of 26% among 10 103 isolates of S. pneumoniae, with
Consistent with previous international surveillance stud- individual rates as high as 36.5% being observed in the south-
ies,10,11,24 PROTEKT reported large differences between eastern region of the country.26
countries in the penicillin G resistance profile of S. pneumo- The increasing prevalence of penicillin G resistance
niae, the highest rates of resistance being noted in clinical among S. pneumoniae is a cause for concern, not only because
isolates from patients in the Asian region. In all three of the of the impact that it may have on the clinical usefulness of this
Asian countries studied, the resistant phenotype (44.5–71.6% agent, but also because resistance to penicillin G has been
of strains) dominated over the intermediate phenotype found to be associated with resistance to other β-lactams, such
(1.4–19.8%). For example, within Hong Kong, the preval- as the cephalosporins, as well as to several non-β-lactam
ence of penicillin G intermediate and penicillin G-resistant classes. In S. pneumoniae, reduced susceptibility to β-lactams,
strains was 1.4% and 57.1%, respectively, which is consistent such as penicillin, arises through alterations in the penicillin-
with that reported by Felmingham et al.10 Furthermore, our binding proteins (PBPs)—1A, 1B, 2A, 2B, 2X and 3—via
data suggest a large upward shift in the penicillin G MICs acquisition of genetic material from other Streptococcus spp
among S. pneumoniae from Japan: a multicentre study of coexisting in close proximity, e.g. S. mitis. The resistance
1997–1998 pneumococcal isolates reported penicillin G phenotype of the resulting strain depends upon which par-
intermediate and penicillin G resistant rates in Japan of 44% ticular PBP is modified. For example, while many of the
and 10%, respectively,11 while in the present 1999–2000 penicillin-resistant strains first identified remained susceptible
study, the percentages were 20% and 45%, respectively. to third-generation cephalosporins, resistance to these agents
Outside of Asia, penicillin G resistance rates in excess of is now well established among penicillin-resistant pneumo-
40% were recorded in France and Spain, while in the neigh- cocci, reflecting alterations in PBPs, particularly 1A and 2X.
34
As reported in other studies,7,24,25,27 co-resistance to erythro- in prevalence of erythromycin A-resistant pneumococci

mycin A, clindamycin, tetracycline and co-trimoxazole was observed in recent years.
higher among strains with intermediate susceptibility to Two major forms of macrolide resistance exist in Strepto-
penicillin G than among penicillin G-susceptible strains, with coccus spp: (i) modification of the 23S ribosomal RNA target
an even higher prevalence being noted among strains highly site by methylation (encoded by erm genes); and (ii) anti-
resistant to penicillin G. In the absence of any known common microbial efflux by proton-motive force or utilizing ATP
mechanism of resistance between penicillin G and these non- (encoded by mef genes).29,30 Modification of the ribosomal
β-lactam antimicrobials, this relationship most probably target site confers a high-level resistance not only to macro-
reflects increased selective pressure among S. pneumoniae lides, but also to lincosamides and streptograminB (so-called
created by broad-based antimicrobial usage.24 This hypo- MLSB phenotype), while the resistance conferred by efflux
thesis is supported by the fact that in some regions, elevated abnormality (M phenotype) is usually of a moderate level
resistance to these antimicrobials was also noted in the and confined to 14- and 15-membered ring macrolides only
penicillin G-susceptible population, particularly in Asia (clindamycin usually remains active). In a genotypic analysis
(macrolides, co-trimoxazole and tetracycline), Europe (macro- of the resistance mechanism in 1043 macrolide-resistant
lides) and Latin America (co-trimoxazole and tetracycline), pneumococcal isolates from the PROTEKT 1999–2000 study,
where these agents are widely prescribed. 56.2% of isolates expressed erm(B) (predominantly in Europe)
Overall, resistance to erythromycin A among S. pneumo- and 35.3% expressed mef(A) (predominantly in North
niae averaged 31%, and in many countries was more preval- America).31 In our study, 63% of erythromycin A-resistant
ent than resistance to penicillin G. There were no important pneumococci were also resistant to clindamycin, consistent
differences in the activity of the newer agents, e.g. clarithro- with erm (MLSB) resistance. Reduced susceptibility to
mycin and azithromycin, and pneumococci resistant to clindamycin was particularly prevalent in Asia and in Europe.
erythromycin A were invariably resistant to these second- Relative to mef-mediated resistance, these strains may be
generation macrolides. As reported in the 1996–1997 Alexan- more difficult to eradicate, with a subsequent risk of clinical
der Project,10 we found France, Belgium, Spain and Italy to be failure.
the foci of macrolide resistance in Western Europe. However, In the present study, the prevalence of resistance to the
the 58% and 43% macrolide resistance rates reported in our newer anti-pneumococcal fluoroquinolones, e.g. levofloxacin
study for 1999–2000 isolates from France and Italy, respect- and moxifloxacin, remained low (~1%). There were, how-
ively, are substantially higher than those reported by Felm- ever, pockets of resistance to these agents, particularly in
ingham et al. for 1997 isolates in the Alexander Project (46% Hong Kong (14%) and South Korea (3%). The situation in
and 30%, respectively).10 Within Western Europe, we also Hong Kong is particularly alarming since all fluoroquinolone-
found substantial increases in the prevalence of macrolide resistant pneumococci were also highly resistant to
resistance in Germany (16% versus 7%), Portugal (16% β-lactams, macrolides, co-trimoxazole, cephalosporins and
versus 4%) and Eire (26% versus 14%), compared with the tetracycline—the only two oral agents that retained full sus-
prevalences reported in the Alexander Project for 1997 iso- ceptibility against these isolates were the ketolide, telithro-
lates. Outside Western Europe, high rates of resistance were mycin and linezolid.32 Molecular characterization has shown
found in all Asian countries participating in the study, as well that the vast majority of the fluoroquinolone resistance de-
as in Hungary, Mexico and the USA. Hoban and colleagues tected in Hong Kong was due to the spread of the 23F Spanish
have recently reported a significant rise in macrolide resist- multidrug-resistant clone.32 Goldsmith et al. have reported an
ance among US pneumococci isolated in the SENTRY study, increased prevalence of fluoroquinolone resistance among
rising from 17% in 1998 to 23% in 1999.24 The 31% macrolide penicillin G-resistant pneumococci in Northern Ireland,33
resistance rate observed in our study for 1999–2000 S. pneu- although subsequent surveillance studies have not been able to
moniae US isolates, suggests that in the USA, resistance to confirm this relationship for other regions.11,24,25 In our study,
this class has risen from the 1999 data reported in SENTRY. levofloxacin-resistant and/or moxifloxacin-resistant strains
This is supported by the preliminary data from PROTEKT were isolates from countries with relatively low rates of peni-
US, which found that 31% of pneumococci collected during cillin G resistance (i.e. Germany, Switzerland and Canada), as
2000–2001 from 206 centres across the USA were resistant to well as from those countries in which reduced penicillin G
erythromycin A.26 A recent analysis conducted in Spain has susceptibility is more prevalent (e.g. Asia). Half of the
shown a clear correlation between erythromycin A resistance 35 levofloxacin-resistant pneumococci identified in this
and overall macrolide consumption, the relationship appear- study were also resistant to penicillin G, and approximately
ing to be due mainly to consumption of those macrolides three-quarters were co-resistant to erythromycin A. No glyco-
dosed once or twice daily.28 While this analysis is not able to peptide-resistant pneumococci were identified in the study.
demonstrate cause and effect, it does suggest that increased One of the objectives of the PROTEKT study was to pro-
use of long-acting macrolides may be linked to the increase vide current surveillance data for telithromycin at its time of
35
launch into clinical practice. The study has shown this new Acknowledgements
ketolide to be the most potent of the oral antimicrobials
currently available against S. pneumoniae. Moreover, the data We gratefully acknowledge the contribution of the scientific
confirm previously published findings that telithromycin staff of GR Micro Ltd, London, UK. Data management was
maintains its anti-pneumococcal activity against strains that undertaken by Micron Research Ltd, Upwell, Cambs, PE14
are resistant to β-lactams, macrolides and fluoroquinolones.18 9AR, UK. The PROTEKT surveillance study is funded by
Using the proposed NCCLS interpretative criteria of ≤1 mg/L Aventis.
to define susceptibility to telithromycin gives an overall
susceptibility of 99.9% for S. pneumoniae. Applying the References
slightly lower breakpoint (≤0.5 mg/L) adopted by the Euro-
pean authorities to the PROTEKT MIC data has negligible 1. Bartlett, J. G., Dowell, S. F., Mandell, L. A., File, T. M., Jr,
effect on the overall susceptibility to telithromycin, reducing Musher, D. M. & Fine, M. J. (2000). Practice guidelines for the man-
agement of community-acquired pneumonia in adults. Clinical
it to 99.3%. Results from subsequent years of the PROTEKT Infectious Diseases 31, 347–82.
study will help to establish the impact that the introduction of
2. Fang, G. D., Fine, M., Orloff, J., Arisumi, D., Yu, V. L., Kapoor, W.
telithromycin will have on susceptibility of S. pneumoniae
et al. (1990). New and emerging etiologies for community-acquired
not only to this agent, but also to non-ketolide antibacterials. pneumonia with implications for therapy. A prospective multicenter
In vitro studies and preliminary data from human studies study of 359 cases. Medicine (Baltimore) 69, 307–16.
suggest that telithromycin has a favourable ecological profile,
3. Musher D. M. (2000). Streptococcus pneumoniae. In Principles
with a low potential to select for resistant mutants, and, in con- and Practice of Infectious Disease, (Mandell, G. L., Bennett, J. E. &
trast to the macrolides, telithromycin does not induce MLS Dolin, R. Eds), pp. 2128–47. Churchill Livingstone, Edinburgh.
resistance in vitro.20 The low potential for telithromycin to 4. Campbell G. D., Jr & Silberman, R. (1998). Drug-resistant
select for pneumococcal resistance has been confirmed re- Streptococcus pneumoniae. Clinical Infectious Diseases 26, 1188–
cently by Davies and colleagues,34 who performed a series of 95.
in vitro serial passage experiments in which five macrolide- 5. Williams, W. W., Hickson, M. A., Kane, M. A., Kendal, A. P.,
susceptible and six macrolide-resistant [three erm(B), three Spika, J. S. & Hinman, A. R. (1988). Immunization policies and
mef(A)] strains of S. pneumoniae were repeatedly exposed to vaccine coverage among adults. The risk for missed opportunities.
sub-inhibitory concentrations of telithromycin or other MLSB Annals of Internal Medicine 108, 616–25.
antibacterials. They found that telithromycin selected for 6. Appelbaum, P. C. (1987). World-wide development of antibiotic
resistant mutants significantly less often than the other agents. resistance in pneumococci. European Journal of Clinical Micro-
Indeed, of the 54 mutants isolated with raised MICs of at least biology 6, 367–77.
one of the test agents, only three were resistant to telithro- 7. Doern, G. V., Brueggemann, A., Holley H. P., Jr & Rauch, A. M.
mycin compared with 36, 37, 36, 45 and 15 mutants resistant (1996). Antimicrobial resistance of Streptococcus pneumoniae
to azithromycin, clarithromycin, erythromycin A, roxithro- recovered from outpatients in the United States during the winter
months of 1994 to 1995: results of a 30-center national surveillance
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study. Antimicrobial Agents and Chemotherapy 40, 1208–13.
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among oropharyngeal and intestinal bacterial microflora 8. Felmingham, D. & Washington, J. (1999). Trends in the anti-
microbial susceptibility of bacterial respiratory tract pathogens–
significantly less than clarithromycin.21 findings of the Alexander Project 1992–1996. Journal of Chemo-
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firm the widespread and increasing prevalence of antimicro-
9. Felmingham, D. & Grüneberg, R. N. (1996). A multicentre
bial resistance among S. pneumoniae. The large intercountry collaborative study of the antimicrobial susceptibility of community-
variation reported in the prevalence of resistance, not only to acquired, lower respiratory tract pathogens 1992–1993: the Alex-
penicillin G but also to other antimicrobials, highlights the ander Project. Journal of Antimicrobial Chemotherapy 38, Suppl. A,
need for continuing surveillance of resistance at both the 1–57.
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and disseminated rapidly so that changes in susceptibility Project 1996–1997: latest susceptibility data from this international
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191–203.
coccal resistance, the ketolide telithromycin has emerged as
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S. V. & Thornsberry, C. (2000). Resistance surveillance of Strepto-
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Decreased susceptibility of Streptococcus pneumoniae to fluoro- collected from 214 medical centers across the United States during
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37
DOI: 10.1093/jac/dkf808


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...................................................................................................................................................................................................................................................................
25
study.

Results
Collecting centres
26
Linezolid ≤2 ≥8
Penicillin G ≤0.06 0.12–1 ≥2
27


Age 0–2 440 15.30 13.09

3–14 362 12.60 10.77
>14–65 1261 43.90 37.51
>65 809 28.20 24.06
NR 490 – 14.57
Gender male 1831 63.10 54.46
female 1073 36.90 31.92
NR 458 – 13.62
Source blood 502 17.30 14.93
BAL 258 8.90 7.67
sputum 1482 51.10 44.08
sinus 137 4.70 4.07
ear 203 7.00 6.04
MEF 30 1.00 0.89
throat 54 1.90 1.61
NR 462 – 13.74
COAD 141 7.70 4.19
pneumonia 742 40.40 22.07
sinusitis 158 8.60 4.70
NR 1527 – 45.42
out 1425 48.50 42.39
NR 423 – 12.58
28

Total no. of
Western Europe 1322 996 (75.3%) 115 (8.7) 211 (16.0) 998 (75.5) 2 (0.2) 322 (24.4)
Austria 57 53 (93.0%) 1 (1.8) 3 (5.3) 49 (86.0) 1 (1.8%) 7 (12.3)
Belgium 28 23 (82.1%) 1 (3.6) 4 (14.3) 19 (67.9) 0 (0) 9 (32.1)
Eire 53 31 (58.5) 4 (7.5) 18 (34.0) 39 (73.6) 0 (0) 14 (26.4)
France 184 70 (38.0) 29 (15.8) 85 (46.2) 77 (41.8) 1 (0.5) 106 (57.6)
Germany 325 298 (91.7) 20 (6.2) 7 (2.2) 274 (84.3) 0 (0) 51 (15.7)
Italy 119 101 (84.9) 6 (5.0) 12 (10.1) 68 (57.1) 0 (0) 51 (42.9)
The Netherlands 51 49 (96.1) 2 (3.9) 0 (0) 47 (92.2) 0 (0) 4 (7.8)
Portugal 106 76 (71.7) 19 (17.9) 11 (10.4) 89 (84.0) 0 (0) 17 (16.0)
Spain 133 62 (46.6) 15 (11.3) 56 (42.1) 95 (71.4) 0 (0) 38 (28.6)
Sweden 64 58 (90.6) 1 (1.6) 5 (7.8) 61 (95.3) 0 (0) 3 (4.7)
Switzerland 111 97 (87.4) 9 (8.1) 5 (4.5) 101 (91.0) 0 (0) 10 (9.0)
UK 91 78 (85.7) 8 (8.8) 5 (5.5) 79 (86.8) 0 (0) 12 (13.2)
Eastern Europe 199 118 (59.3) 54 (27.1) 27 (13.6) 141 (70.9) 0 (0) 58 (29.1)
Hungary 54 19 (35.2) 28 (51.9) 7 (13.0) 24 (44.4) 0 (0) 30 (55.6)
Poland 68 50 (73.5) 9 (13.2) 9 (13.2) 52 (76.5) 0 (0) 16 (23.5)
Turkey 77 49 (63.6) 17 (22.1) 11 (14.3) 65 (84.4) 0 (0) 12 (15.6)
North America 687 468 (68.1) 72 (10.5) 147 (21.4) 525 (76.4) 2 (0.3) 160 (23.3)
Canada 350 276 (78.9) 37 (10.6) 37 (10.6) 292 (83.4) 2 (0.6) 56 (16.0)
USA 337 192 (57.0) 35 (10.4) 110 (32.6) 233 (69.1) 0 (0) 104 (30.9)
Latin America 518 300 (57.9) 139 (26.8) 79 (15.3) 438 (84.6) 1 (0.2) 79 (15.3)
Argentina 55 40 (72.7) 6 (10.9) 9 (16.4) 49 (89.1) 0 (0) 6 (10.9)
Brazil 260 172 (66.2) 67 (25.8) 21 (8.1) 242 (93.1) 1 (0.4) 17 (6.5)
Mexico 203 88 (43.3) 66 (32.5) 49 (24.1) 147 (72.4) 0 (0) 56 (27.6)
Australasia 121 95 (78.5) 21 (17.4) 5 (4.1) 106 (87.6) 1 (0.8) 14 (11.6)
Australia 114 91 (79.8) 18 (15.8) 5 (4.4) 99 (86.8) 1 (0.9) 14 (12.3)
Indonesia 7 4 (57.1) 3 (42.9) 0 (0) 7 (100) 0 (0) 0 (0)
Asia 515 165 (32.0) 75 (14.6) 275 (53.4) 104 (20.2) 1 (0.2) 410 (79.6)
Hong Kong 70 29 (41.4) 1 (1.4) 40 (57.1) 20 (28.6) 0 (0) 50 (71.4)
Japan 308 110 (35.7) 61 (19.8) 137 (44.5) 67 (21.8) 1 (0.3) 240 (77.9)
South Korea 137 26 (19.0) 13 (9.5) 98 (71.5) 17 (12.4) 0 (0) 120 (87.6)
Total 3362 2142 (63.7) 476 (14.2) 744 (22.1) 2312 (68.8) 7 (0.2) 1043 (31.0)

29
(1999–2000)a
Telithromycinb 0.06 0.5 100 0.008 0.015 100 0.015 0.06 99.9 0.008 0.06 100 0.015 0.25 100
Penicillin G 2 4 32.0 0.015 0.25 78.5 0.015 2 73.2 0.06 2 57.9 0.015 2 68.1
Co-amoxiclav 1 4 87.6 0.03 0.25 100 0.03 2 97.5 0.03 2 98.7 0.03 2 90.5
Cefaclor 64 >64 21.6 1 8 81.0 1 >64 70.2 1 64 63.7 1 >64 63.5
Cefixime 32 64 32.0 0.25 4 78.5 0.25 32 73.2 0.5 32 57.9 0.25 32 68.1
Cefpodoxime 2 4 36.3 0.12 0.25 93.4 0.12 2 80.6 0.12 v2 78.4 0.12 4 75.3
30
Cefuroxime 4 8 36.7 0.03 0.5 92.6 0.06 8 80.6 0.12 4 77.0 0.06 8 75.3
Azithromycin 64 >64 20.2 0.12 4 87.6 0.12 >64 75.1 0.12 8 84.8 0.12 16 76.4
Clarithromycin 32 >32 20.4 0.03 1 88.4 0.03 >32 75.0 0.03 4 84.8 0.06 8 76.4
Clindamycin 2 >4 49.5 0.06 0.12 94.2 0.06 >4 80.1 0.06 0.12 93.1 0.06 0.12 91.1
Erythromycin A 64 >64 20.2 0.06 2 87.6 0.06 >64 74.9 0.06 4 84.6 0.06 16 76.4
Levofloxacin 1 1 95.3 1 1 100 1 1 99.8 1 1 99.2 1 1 98.0
Moxifloxacin 0.12 0.25 96.7 0.12 0.25 100 0.12 0.25 99.9 0.12 0.25 99.2 0.12 0.25 98.7
Co-trimoxazole 1 16 35.0 0.25 4 70.2 48.8 11.2 66.3 2 16 36.5 0.5 16 61.6
Tetracycline >16 >16 18.4 0.25 >16 86.6 60.6 32 75.9 0.25 >16 75.1 0.25 >16 86.2
Linezolid 1 1 100 1 1 100 1 1 100 1 2 100 1 2 100
Teicoplanin 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100
Vancomycin 0.5 0.5 100 0.5 0.5 100 0.5 0.5 100 0.5 v0.5 100 0.5 0.5 100


31
Telithromycinb
Pen-S 0.03 0.25 100 0.008 0.015 100 0.008 0.015 100 0.008 0.015 100 0.008 0.015 100
Pen-I 0.06 0.5 100 0.008 0.015 100 0.015 0.06 100 0.015 0.25 100 0.015 0.12 100
Pen-R 0.06 0.5 100 0.015 0.03 100 0.015 0.5 99.2 0.008 0.12 100 0.06 0.5 100
Co-amoxiclav
Pen-S 0.03 0.06 100 0.03 0.03 100 0.03 0.03 100 0.03 0.03 100 0.03 0.03 100
Pen-I 0.25 1 98.7 0.25 0.5 100 0.12 1 100 0.12 1 100 0.25 2 100
Pen-R 2 4 77.0 2 2 100 2 8 84.0 2 2 91.4 2 >4 55.8
Cefpodoxime
Pen-S 0.12 0.5 95.2 0.12 0.12 100 0.12 0.12 100 0.12 0.12 100 0.12 0.12 99.4
Pen-I 2 4 40.0 0.25 1 85.7 0.25 2 67.4 0.25 2 76.3 0.25 2 72.2
Pen-R 4 8 0 2 4 0 4 4 0 4 4 0 4 8 0
32
Erythromycin A
Pen-S 4 >64 44.9 0.06 0.5 89.5 0.06 4 88.8 0.06 0.06 95.0 0.06 0.12 93.4
Pen-I 64 >64 14.7 0.06 0.06 90.4 >64 >64 43.8 0.06 >64 66.2 0.06 >64 58.3
Pen-R 64 >64 6.9 4 >64 40.0 >64 >64 31.9 0.06 8 77.2 4 >64 31.3
Levofloxacin
Pen-S 1 1 95.2 1 1 100 1 1 99.7 1 1 99.3 1 1 98.1
Pen-I 0.5 1 98.7 1 1 100 1 1 100 1 1 100 1 1 98.6
Pen-R 1 1 94.5 1 1 100 1 1 100 1 1 97.5 1 1 97.3
Co-trimoxazole
Pen-S 0.5 2 70.3 0.25 2 80 0.25 2 82.1 1 8 49.3 0.25 0.5 81.4
Pen-I 1 8 42.7 1 4 42.9 1 8 42.6 4 >16 25.2 1 16 45.8
Pen-R 4 >16 11.6 8 16 0 8 16 8.8 8 >16 7.6 8 >16 6.1
Tetracycline
Pen-S 16 >16 37.0 0.25 0.5 90.5 0.25 8 89.2 0.25 16 81.0 0.25 1 97.7
Pen-I >16 >16 14.7 0.25 >16 81.0 >16 >16 37.9 0.25 >16 71.2 0.25 >16 68.1
Pen-R >16 >16 8.4 >16 >16 40.0 >16 >16 40.3 0.5 >16 59.5 0.5 >16 58.5
co-trimoxazole
552 (74.2%)
366 (55.4%)
527 (50.5%)
20 (57.1%)
491 (49.2%)
486 (65.3%)
586 (88.7%)
798 (76.5%)
21 (60.0%)
491 (51.1%)
tetracycline
levofloxacin
18 (2.4%)
19 (2.9%)
27 (2.6%)
21 (2.1%)
20 (2.1%)
erythromycin A
539 (72.4%)
659 (99.7%)
27 (77.1%)
798 (80.0%)
527 (54.9%)
329 (44.2%)
659 (63.2%)
19 (54.2%)
586 (58.8%)
366 (38.1%)

329 (49.8%)
539 (51.7%)
18 (51.4%)
486 (48.7%)
552 (57.5%)
penicillin G

No. of isolates

744
661
1043
35
997
960

Discussion


Phenotype

33

MIC (mg/L)
Penicillin G
Susceptible 2142 0.008 0.008 0.03 0.002–0.5 100
Intermediate 476 0.008 0.015 0.12 0.004–1 100
Resistant 744 0.06 0.06 0.5 0.004–8 99.6
Erythromycin A
Susceptible 2312 0.008 0.008 0.015 0.002–0.12 100
Intermediate 7 0.015 0.015 0.03 0.008–0.03 100
Resistant 1043 0.06 0.06 0.5 0.008–8 99.7
Levofloxacin
Susceptible 3317 0.008 0.015 0.12 0.002–8 99.9
Intermediate 10 0.008 0.03 0.12 0.008–0.12 100
Resistant 35 0.03 0.03 0.12 0.008–0.5 100
Combined 3362 0.008 0.015 0.12 0.002–8 99.9
34

35
191–203.
36
Topic T1, 3–9.
Suppl. 3, 4–11.
93.
37
DOI: 10.1093/jac/dkf808


..................................................................................................................................................................................................................................................................

...................................................................................................................................................................................................................................................................
25
study.

Results
Collecting centres
26
Linezolid ≤2 ≥8
Penicillin G ≤0.06 0.12–1 ≥2
27


Age 0–2 440 15.30 13.09

3–14 362 12.60 10.77
>14–65 1261 43.90 37.51
>65 809 28.20 24.06
NR 490 – 14.57
Gender male 1831 63.10 54.46
female 1073 36.90 31.92
NR 458 – 13.62
Source blood 502 17.30 14.93
BAL 258 8.90 7.67
sputum 1482 51.10 44.08
sinus 137 4.70 4.07
ear 203 7.00 6.04
MEF 30 1.00 0.89
throat 54 1.90 1.61
NR 462 – 13.74
COAD 141 7.70 4.19
pneumonia 742 40.40 22.07
sinusitis 158 8.60 4.70
NR 1527 – 45.42
out 1425 48.50 42.39
NR 423 – 12.58
28

Total no. of
Western Europe 1322 996 (75.3%) 115 (8.7) 211 (16.0) 998 (75.5) 2 (0.2) 322 (24.4)
Austria 57 53 (93.0%) 1 (1.8) 3 (5.3) 49 (86.0) 1 (1.8%) 7 (12.3)
Belgium 28 23 (82.1%) 1 (3.6) 4 (14.3) 19 (67.9) 0 (0) 9 (32.1)
Eire 53 31 (58.5) 4 (7.5) 18 (34.0) 39 (73.6) 0 (0) 14 (26.4)
France 184 70 (38.0) 29 (15.8) 85 (46.2) 77 (41.8) 1 (0.5) 106 (57.6)
Germany 325 298 (91.7) 20 (6.2) 7 (2.2) 274 (84.3) 0 (0) 51 (15.7)
Italy 119 101 (84.9) 6 (5.0) 12 (10.1) 68 (57.1) 0 (0) 51 (42.9)
The Netherlands 51 49 (96.1) 2 (3.9) 0 (0) 47 (92.2) 0 (0) 4 (7.8)
Portugal 106 76 (71.7) 19 (17.9) 11 (10.4) 89 (84.0) 0 (0) 17 (16.0)
Spain 133 62 (46.6) 15 (11.3) 56 (42.1) 95 (71.4) 0 (0) 38 (28.6)
Sweden 64 58 (90.6) 1 (1.6) 5 (7.8) 61 (95.3) 0 (0) 3 (4.7)
Switzerland 111 97 (87.4) 9 (8.1) 5 (4.5) 101 (91.0) 0 (0) 10 (9.0)
UK 91 78 (85.7) 8 (8.8) 5 (5.5) 79 (86.8) 0 (0) 12 (13.2)
Eastern Europe 199 118 (59.3) 54 (27.1) 27 (13.6) 141 (70.9) 0 (0) 58 (29.1)
Hungary 54 19 (35.2) 28 (51.9) 7 (13.0) 24 (44.4) 0 (0) 30 (55.6)
Poland 68 50 (73.5) 9 (13.2) 9 (13.2) 52 (76.5) 0 (0) 16 (23.5)
Turkey 77 49 (63.6) 17 (22.1) 11 (14.3) 65 (84.4) 0 (0) 12 (15.6)
North America 687 468 (68.1) 72 (10.5) 147 (21.4) 525 (76.4) 2 (0.3) 160 (23.3)
Canada 350 276 (78.9) 37 (10.6) 37 (10.6) 292 (83.4) 2 (0.6) 56 (16.0)
USA 337 192 (57.0) 35 (10.4) 110 (32.6) 233 (69.1) 0 (0) 104 (30.9)
Latin America 518 300 (57.9) 139 (26.8) 79 (15.3) 438 (84.6) 1 (0.2) 79 (15.3)
Argentina 55 40 (72.7) 6 (10.9) 9 (16.4) 49 (89.1) 0 (0) 6 (10.9)
Brazil 260 172 (66.2) 67 (25.8) 21 (8.1) 242 (93.1) 1 (0.4) 17 (6.5)
Mexico 203 88 (43.3) 66 (32.5) 49 (24.1) 147 (72.4) 0 (0) 56 (27.6)
Australasia 121 95 (78.5) 21 (17.4) 5 (4.1) 106 (87.6) 1 (0.8) 14 (11.6)
Australia 114 91 (79.8) 18 (15.8) 5 (4.4) 99 (86.8) 1 (0.9) 14 (12.3)
Indonesia 7 4 (57.1) 3 (42.9) 0 (0) 7 (100) 0 (0) 0 (0)
Asia 515 165 (32.0) 75 (14.6) 275 (53.4) 104 (20.2) 1 (0.2) 410 (79.6)
Hong Kong 70 29 (41.4) 1 (1.4) 40 (57.1) 20 (28.6) 0 (0) 50 (71.4)
Japan 308 110 (35.7) 61 (19.8) 137 (44.5) 67 (21.8) 1 (0.3) 240 (77.9)
South Korea 137 26 (19.0) 13 (9.5) 98 (71.5) 17 (12.4) 0 (0) 120 (87.6)
Total 3362 2142 (63.7) 476 (14.2) 744 (22.1) 2312 (68.8) 7 (0.2) 1043 (31.0)

29
(1999–2000)a
Telithromycinb 0.06 0.5 100 0.008 0.015 100 0.015 0.06 99.9 0.008 0.06 100 0.015 0.25 100
Penicillin G 2 4 32.0 0.015 0.25 78.5 0.015 2 73.2 0.06 2 57.9 0.015 2 68.1
Co-amoxiclav 1 4 87.6 0.03 0.25 100 0.03 2 97.5 0.03 2 98.7 0.03 2 90.5
Cefaclor 64 >64 21.6 1 8 81.0 1 >64 70.2 1 64 63.7 1 >64 63.5
Cefixime 32 64 32.0 0.25 4 78.5 0.25 32 73.2 0.5 32 57.9 0.25 32 68.1
Cefpodoxime 2 4 36.3 0.12 0.25 93.4 0.12 2 80.6 0.12 v2 78.4 0.12 4 75.3
30
Cefuroxime 4 8 36.7 0.03 0.5 92.6 0.06 8 80.6 0.12 4 77.0 0.06 8 75.3
Azithromycin 64 >64 20.2 0.12 4 87.6 0.12 >64 75.1 0.12 8 84.8 0.12 16 76.4
Clarithromycin 32 >32 20.4 0.03 1 88.4 0.03 >32 75.0 0.03 4 84.8 0.06 8 76.4
Clindamycin 2 >4 49.5 0.06 0.12 94.2 0.06 >4 80.1 0.06 0.12 93.1 0.06 0.12 91.1
Erythromycin A 64 >64 20.2 0.06 2 87.6 0.06 >64 74.9 0.06 4 84.6 0.06 16 76.4
Levofloxacin 1 1 95.3 1 1 100 1 1 99.8 1 1 99.2 1 1 98.0
Moxifloxacin 0.12 0.25 96.7 0.12 0.25 100 0.12 0.25 99.9 0.12 0.25 99.2 0.12 0.25 98.7
Co-trimoxazole 1 16 35.0 0.25 4 70.2 48.8 11.2 66.3 2 16 36.5 0.5 16 61.6
Tetracycline >16 >16 18.4 0.25 >16 86.6 60.6 32 75.9 0.25 >16 75.1 0.25 >16 86.2
Linezolid 1 1 100 1 1 100 1 1 100 1 2 100 1 2 100
Teicoplanin 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100 0.06 0.12 100
Vancomycin 0.5 0.5 100 0.5 0.5 100 0.5 0.5 100 0.5 v0.5 100 0.5 0.5 100


31
Telithromycinb
Pen-S 0.03 0.25 100 0.008 0.015 100 0.008 0.015 100 0.008 0.015 100 0.008 0.015 100
Pen-I 0.06 0.5 100 0.008 0.015 100 0.015 0.06 100 0.015 0.25 100 0.015 0.12 100
Pen-R 0.06 0.5 100 0.015 0.03 100 0.015 0.5 99.2 0.008 0.12 100 0.06 0.5 100
Co-amoxiclav
Pen-S 0.03 0.06 100 0.03 0.03 100 0.03 0.03 100 0.03 0.03 100 0.03 0.03 100
Pen-I 0.25 1 98.7 0.25 0.5 100 0.12 1 100 0.12 1 100 0.25 2 100
Pen-R 2 4 77.0 2 2 100 2 8 84.0 2 2 91.4 2 >4 55.8
Cefpodoxime
Pen-S 0.12 0.5 95.2 0.12 0.12 100 0.12 0.12 100 0.12 0.12 100 0.12 0.12 99.4
Pen-I 2 4 40.0 0.25 1 85.7 0.25 2 67.4 0.25 2 76.3 0.25 2 72.2
Pen-R 4 8 0 2 4 0 4 4 0 4 4 0 4 8 0
32
Erythromycin A
Pen-S 4 >64 44.9 0.06 0.5 89.5 0.06 4 88.8 0.06 0.06 95.0 0.06 0.12 93.4
Pen-I 64 >64 14.7 0.06 0.06 90.4 >64 >64 43.8 0.06 >64 66.2 0.06 >64 58.3
Pen-R 64 >64 6.9 4 >64 40.0 >64 >64 31.9 0.06 8 77.2 4 >64 31.3
Levofloxacin
Pen-S 1 1 95.2 1 1 100 1 1 99.7 1 1 99.3 1 1 98.1
Pen-I 0.5 1 98.7 1 1 100 1 1 100 1 1 100 1 1 98.6
Pen-R 1 1 94.5 1 1 100 1 1 100 1 1 97.5 1 1 97.3
Co-trimoxazole
Pen-S 0.5 2 70.3 0.25 2 80 0.25 2 82.1 1 8 49.3 0.25 0.5 81.4
Pen-I 1 8 42.7 1 4 42.9 1 8 42.6 4 >16 25.2 1 16 45.8
Pen-R 4 >16 11.6 8 16 0 8 16 8.8 8 >16 7.6 8 >16 6.1
Tetracycline
Pen-S 16 >16 37.0 0.25 0.5 90.5 0.25 8 89.2 0.25 16 81.0 0.25 1 97.7
Pen-I >16 >16 14.7 0.25 >16 81.0 >16 >16 37.9 0.25 >16 71.2 0.25 >16 68.1
Pen-R >16 >16 8.4 >16 >16 40.0 >16 >16 40.3 0.5 >16 59.5 0.5 >16 58.5
co-trimoxazole
552 (74.2%)
366 (55.4%)
527 (50.5%)
20 (57.1%)
491 (49.2%)
486 (65.3%)
586 (88.7%)
798 (76.5%)
21 (60.0%)
491 (51.1%)
tetracycline
levofloxacin
18 (2.4%)
19 (2.9%)
27 (2.6%)
21 (2.1%)
20 (2.1%)
erythromycin A
539 (72.4%)
659 (99.7%)
27 (77.1%)
798 (80.0%)
527 (54.9%)
329 (44.2%)
659 (63.2%)
19 (54.2%)
586 (58.8%)
366 (38.1%)

329 (49.8%)
539 (51.7%)
18 (51.4%)
486 (48.7%)
552 (57.5%)
penicillin G

No. of isolates

744
661
1043
35
997
960

Discussion


Phenotype

33

MIC (mg/L)
Penicillin G
Susceptible 2142 0.008 0.008 0.03 0.002–0.5 100
Intermediate 476 0.008 0.015 0.12 0.004–1 100
Resistant 744 0.06 0.06 0.5 0.004–8 99.6
Erythromycin A
Susceptible 2312 0.008 0.008 0.015 0.002–0.12 100
Intermediate 7 0.015 0.015 0.03 0.008–0.03 100
Resistant 1043 0.06 0.06 0.5 0.008–8 99.7
Levofloxacin
Susceptible 3317 0.008 0.015 0.12 0.002–8 99.9
Intermediate 10 0.008 0.03 0.12 0.008–0.12 100
Resistant 35 0.03 0.03 0.12 0.008–0.5 100
Combined 3362 0.008 0.015 0.12 0.002–8 99.9
34

35
191–203.
36
Topic T1, 3–9.
Suppl. 3, 4–11.
93.
37
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Increasing Prevalence of Antimicrobial Resistance

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Increasing prevalence of antimicrobial resistance among isolates of

Article in Journal of Antimicrobial Chemotherapy · October 2002

The user has requested enhancement of the downloaded file.

Increasing prevalence of antimicrobial resistance among isolates of

Introduction estimated that each year in the USA, S. pneumoniae infections

*Corresponding author. Tel: +44-20-7388-7320; Fax: +44-20-7388-7324; E-mail: [email protected]

Materials and methods

Table 1. Interpretative categories for S. pneumoniaea

Interpretative categories (mg/L)

Antimicrobial agent susceptible intermediate resistant

approved breakpoints are not yet available (tentative breakpoints given).

penicillin G and erythromycin A, but also to other commonly

Percentage of total Percentage of

Age 0–2 440 15.30 13.09

Penicillin G susceptibilitya Erythromycin A susceptibilityb

Of the macrolide–lincosamide–streptogramin antimicro- high prevalence of resistance to co-trimoxazole, ranging from

aFor susceptibility criteria see Table 1.

Cross- and parallel-resistance penicillin G-susceptible isolates. A similar cross-resistance

against 3362 isolates of S. pneumoniae collected in total in the

cross-resistant to clindamycin and tetracycline, respectively,

S. pneumoniae remained fully susceptible to these two oral

agents). The in vitro activity of telithromycin by penicillin G,

Over the last three decades, antimicrobial resistance among

isolates of S. pneumoniae has spread across the globe at an

tions associated with this pathogen. International antimicro-

Table 7. In vitro activity of telithromycin against S. pneumoniae isolates collected in PROTEKT, by

Phenotype n Mode MIC50 MIC90 Range % susceptibilitya

aInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).

As reported in other studies,7,24,25,27 co-resistance to erythro- in prevalence of erythromycin A-resistant pneumococci

Increasing prevalence of antimicrobial resistance among isolates of

Introduction estimated that each year in the USA, S. pneumoniae infections

*Corresponding author. Tel: +44-20-7388-7320; Fax: +44-20-7388-7324; E-mail: [email protected]

Materials and methods

Table 1. Interpretative categories for S. pneumoniaea

Interpretative categories (mg/L)

Antimicrobial agent susceptible intermediate resistant

approved breakpoints are not yet available (tentative breakpoints given).

penicillin G and erythromycin A, but also to other commonly

Percentage of total Percentage of

Age 0–2 440 15.30 13.09

Penicillin G susceptibilitya Erythromycin A susceptibilityb

Of the macrolide–lincosamide–streptogramin antimicro- high prevalence of resistance to co-trimoxazole, ranging from

aFor susceptibility criteria see Table 1.

Cross- and parallel-resistance penicillin G-susceptible isolates. A similar cross-resistance

against 3362 isolates of S. pneumoniae collected in total in the

cross-resistant to clindamycin and tetracycline, respectively,

S. pneumoniae remained fully susceptible to these two oral

agents). The in vitro activity of telithromycin by penicillin G,

Over the last three decades, antimicrobial resistance among

isolates of S. pneumoniae has spread across the globe at an

tions associated with this pathogen. International antimicro-

Table 7. In vitro activity of telithromycin against S. pneumoniae isolates collected in PROTEKT, by

Phenotype n Mode MIC50 MIC90 Range % susceptibilitya

aInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).

As reported in other studies,7,24,25,27 co-resistance to erythro- in prevalence of erythromycin A-resistant pneumococci

Increasing prevalence of antimicrobial resistance among isolates of

Introduction estimated that each year in the USA, S. pneumoniae infections

*Corresponding author. Tel: +44-20-7388-7320; Fax: +44-20-7388-7324; E-mail: [email protected]

Materials and methods

Table 1. Interpretative categories for S. pneumoniaea

Interpretative categories (mg/L)

Antimicrobial agent susceptible intermediate resistant