Increasing Prevalence of Antimicrobial Resistance
Increasing Prevalence of Antimicrobial Resistance
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Arne C Rodloff
University of Leipzig
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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.
25
© 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).
26
Prevalence of antimicrobial resistance and in vitro comparison of activity
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-
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
D. Felmingham et al.
Table 2. Patient demographics and culture source of 3362 isolates of S. pneumoniae collected in the
PROTEKT study (1999–2000)
NR, not recorded; AECB, acute exacerbation of chronic bronchitis; COAD, chronic obstructive airways disease; BAL,
bronchoalveolar lavage; MEF, middle ear fluid.
28
Prevalence of antimicrobial resistance and in vitro comparison of activity
Table 3. Number (%) of S. pneumoniae strains by penicillin G and erythromycin A susceptibility interpretative category in each
continent and country
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.
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
D. Felmingham et al.
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
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
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
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
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
D. Felmingham et al.
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).
aFor susceptibility criteria see Table 1.
bInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).
Prevalence of antimicrobial resistance and in vitro comparison of activity
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)
Discussion
Erythromycin A resistant
Co-trimoxazole resistant
Levofloxacin resistant
Clindamycin resistant
Tetracycline resistant
33
D. Felmingham et al.
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
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
Prevalence of antimicrobial resistance and in vitro comparison of activity
35
D. Felmingham et al.
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
mycin and clindamycin, respectively. Furthermore, studies in
study. Antimicrobial Agents and Chemotherapy 40, 1208–13.
man have shown that telithromycin selects for resistance
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-
In conclusion, the 1999–2000 data from PROTEKT con- therapy 11, Suppl. 1, 5–21.
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.
national and international level, with the data being analysed 10. Felmingham, D. & Grüneberg R. N. (2000). The Alexander
and disseminated rapidly so that changes in susceptibility Project 1996–1997: latest susceptibility data from this international
patterns can be quickly detected allowing appropriate control study of bacterial pathogens from community-acquired lower respir-
atory tract infections. Journal of Antimicrobial Chemotherapy 45,
measures to be put in place. In this era of increasing pneumo-
191–203.
coccal resistance, the ketolide telithromycin has emerged as
a promising new candidate for the treatment of CARTIs, 11. Sahm, D. F., Jones, M. E., Hickey, M. L., Diakun, D. R., Mani,
S. V. & Thornsberry, C. (2000). Resistance surveillance of Strepto-
possessing potent anti-pneumococcal activity even against coccus pneumoniae, Haemophilus influenzae and Moraxella
strains with resistance to other commonly used antimicro- catarrhalis isolated in Asia and Europe, 1997–1998. Journal of Anti-
bials. microbial Chemotherapy 45, 457–66.
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12. Schito, G. C., Debbia, E. A. & Marchese, A. (2000). The pneumoniae, Haemophilus influenzae and Moraxella catarrhalis
evolving threat of antibiotic resistance in Europe: new data from the isolated in the United States, 1997–1998. Journal of Antimicrobial
Alexander Project. Journal of Antimicrobial Chemotherapy 46, Chemotherapy 44, 749–59.
Topic T1, 3–9.
26. Stratton, C., Barry, A. & Yee, Y. C. (2001). In vitro activity of
13. Chen, D. K., McGeer, A., de Azavedo, J. C. & Low, D. E. (1999). telithromycin against clinical isolates of Streptococcus pneumoniae
Decreased susceptibility of Streptococcus pneumoniae to fluoro- collected from 214 medical centers across the United States during
quinolones in Canada. Canadian Bacterial Surveillance Network. the winter of 2000/2001. In Program and Abstracts of the Forty-first
New England Journal of Medicine 341, 233–9. Interscience Conference on Antimicrobial Agents and Chemo-
14. Jones, R. N. (1999). The impact of antimicrobial resistance: therapy, Chicago, IL, 2001. Abstract 1018, p. 190. American Society
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15. Balfour, J. A. & Figgitt, D. P. (2001). Telithromycin. Drugs 61, among clinically significant respiratory tract isolates of Strepto-
815–29. coccus pneumoniae in the United States and Canada – 1997 results
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Antimicrobial Chemotherapy 48, Topic T1, 9–23. among Streptococcus pneumoniae and Streptococcus pyogenes
21. Edlund, C., Alvan, G., Barkholt, L., Vacheron, F. & Nord, C. E. isolated from the PROTEKT 1999–2000 study. Journal of Antimicro-
(2000). Pharmacokinetics and comparative effects of telithromycin bial Chemotherapy 50, Suppl. S1, 39–47.
(HMR 3647) and clarithromycin on the oropharyngeal and intestinal 32. Morrissey, I., Farrell, D. J., Enright, M. C. & Felmingham, D.
microflora. Journal of Antimicrobial Chemotherapy 46, 741–9.
(2001). Molecular characterization of fluoroquinolone-resistant
22. Felmingham, D. (2002). The need for antimicrobial resistance Streptococcus pneumoniae PROTEKT 2000 isolates from Hong
surveillance. Journal of Antimicrobial Chemotherapy 50, Suppl S1, Kong. In Program and Abstracts of the Forth-first Interscience Con-
1–7. ference on Antimicrobial Agents and Chemotherapy, Chicago, IL,
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24. Hoban, D. J., Doern, G. V., Fluit, A. C., Roussel-Delvallez, M. & (1998). Increased incidence of ciprofloxacin resistance in penicillin-
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Moraxella catarrhalis in the SENTRY Antimicrobial Surveillance 34. Davies, T. A., Dewasse, B. E., Jacobs, M. R. & Appelbaum, P.
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J. & Sahm, D. F. (1999). Resistance surveillance of Streptococcus 414–7.
37
Journal of Antimicrobial Chemotherapy (2002) 50, Suppl. S1, 25–37
DOI: 10.1093/jac/dkf808
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.
25
© 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).
26
Prevalence of antimicrobial resistance and in vitro comparison of activity
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-
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
D. Felmingham et al.
Table 2. Patient demographics and culture source of 3362 isolates of S. pneumoniae collected in the
PROTEKT study (1999–2000)
NR, not recorded; AECB, acute exacerbation of chronic bronchitis; COAD, chronic obstructive airways disease; BAL,
bronchoalveolar lavage; MEF, middle ear fluid.
28
Prevalence of antimicrobial resistance and in vitro comparison of activity
Table 3. Number (%) of S. pneumoniae strains by penicillin G and erythromycin A susceptibility interpretative category in each
continent and country
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.
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
D. Felmingham et al.
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
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
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
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
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
D. Felmingham et al.
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).
aFor susceptibility criteria see Table 1.
bInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).
Prevalence of antimicrobial resistance and in vitro comparison of activity
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)
Discussion
Erythromycin A resistant
Co-trimoxazole resistant
Levofloxacin resistant
Clindamycin resistant
Tetracycline resistant
33
D. Felmingham et al.
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
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
Prevalence of antimicrobial resistance and in vitro comparison of activity
35
D. Felmingham et al.
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
mycin and clindamycin, respectively. Furthermore, studies in
study. Antimicrobial Agents and Chemotherapy 40, 1208–13.
man have shown that telithromycin selects for resistance
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-
In conclusion, the 1999–2000 data from PROTEKT con- therapy 11, Suppl. 1, 5–21.
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.
national and international level, with the data being analysed 10. Felmingham, D. & Grüneberg R. N. (2000). The Alexander
and disseminated rapidly so that changes in susceptibility Project 1996–1997: latest susceptibility data from this international
patterns can be quickly detected allowing appropriate control study of bacterial pathogens from community-acquired lower respir-
atory tract infections. Journal of Antimicrobial Chemotherapy 45,
measures to be put in place. In this era of increasing pneumo-
191–203.
coccal resistance, the ketolide telithromycin has emerged as
a promising new candidate for the treatment of CARTIs, 11. Sahm, D. F., Jones, M. E., Hickey, M. L., Diakun, D. R., Mani,
S. V. & Thornsberry, C. (2000). Resistance surveillance of Strepto-
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strains with resistance to other commonly used antimicro- catarrhalis isolated in Asia and Europe, 1997–1998. Journal of Anti-
bials. microbial Chemotherapy 45, 457–66.
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12. Schito, G. C., Debbia, E. A. & Marchese, A. (2000). The pneumoniae, Haemophilus influenzae and Moraxella catarrhalis
evolving threat of antibiotic resistance in Europe: new data from the isolated in the United States, 1997–1998. Journal of Antimicrobial
Alexander Project. Journal of Antimicrobial Chemotherapy 46, Chemotherapy 44, 749–59.
Topic T1, 3–9.
26. Stratton, C., Barry, A. & Yee, Y. C. (2001). In vitro activity of
13. Chen, D. K., McGeer, A., de Azavedo, J. C. & Low, D. E. (1999). telithromycin against clinical isolates of Streptococcus pneumoniae
Decreased susceptibility of Streptococcus pneumoniae to fluoro- collected from 214 medical centers across the United States during
quinolones in Canada. Canadian Bacterial Surveillance Network. the winter of 2000/2001. In Program and Abstracts of the Forty-first
New England Journal of Medicine 341, 233–9. Interscience Conference on Antimicrobial Agents and Chemo-
14. Jones, R. N. (1999). The impact of antimicrobial resistance: therapy, Chicago, IL, 2001. Abstract 1018, p. 190. American Society
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& Jones, R. N. (1998). The prevalence of fluoroquinolone resistance
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(2000). Pharmacokinetics and comparative effects of telithromycin bial Chemotherapy 50, Suppl. S1, 39–47.
(HMR 3647) and clarithromycin on the oropharyngeal and intestinal 32. Morrissey, I., Farrell, D. J., Enright, M. C. & Felmingham, D.
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(2001). Molecular characterization of fluoroquinolone-resistant
22. Felmingham, D. (2002). The need for antimicrobial resistance Streptococcus pneumoniae PROTEKT 2000 isolates from Hong
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24. Hoban, D. J., Doern, G. V., Fluit, A. C., Roussel-Delvallez, M. & (1998). Increased incidence of ciprofloxacin resistance in penicillin-
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J. & Sahm, D. F. (1999). Resistance surveillance of Streptococcus 414–7.
37
Journal of Antimicrobial Chemotherapy (2002) 50, Suppl. S1, 25–37
DOI: 10.1093/jac/dkf808
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.
25
© 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).
26
Prevalence of antimicrobial resistance and in vitro comparison of activity
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-
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
D. Felmingham et al.
Table 2. Patient demographics and culture source of 3362 isolates of S. pneumoniae collected in the
PROTEKT study (1999–2000)
NR, not recorded; AECB, acute exacerbation of chronic bronchitis; COAD, chronic obstructive airways disease; BAL,
bronchoalveolar lavage; MEF, middle ear fluid.
28
Prevalence of antimicrobial resistance and in vitro comparison of activity
Table 3. Number (%) of S. pneumoniae strains by penicillin G and erythromycin A susceptibility interpretative category in each
continent and country
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.
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
D. Felmingham et al.
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
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
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
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
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
D. Felmingham et al.
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).
aFor susceptibility criteria see Table 1.
bInhibited by ≤1 mg/L (tentative NCCLS susceptibility breakpoint).
Prevalence of antimicrobial resistance and in vitro comparison of activity
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)
Discussion
Erythromycin A resistant
Co-trimoxazole resistant
Levofloxacin resistant
Clindamycin resistant
Tetracycline resistant
33
D. Felmingham et al.
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
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
Prevalence of antimicrobial resistance and in vitro comparison of activity
35
D. Felmingham et al.
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
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