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Dkf503.fmJournal of Antimicrobial Chemotherapy (2002) 50, Suppl. S2, 21–26
Susceptibility patterns of bacteria causing community-acquired
respiratory infections in Spain: the SAUCE project
Juan García-de-Lomas1,2*, César García-Rey3 and Lorena López1, Concepción Gimeno1,2 and
the Spanish Surveillance Group for Respiratory Pathogens†
1Instituto Valenciano de Microbiología, 2Department of Microbiology, School of Medicine and University Hospital, Valencia; 3Medical Department, GlaxoSmithKline, Tres Cantos, Madrid, Spain Multicentre surveillance is essential in order to monitor the prevalence of certain resistance
phenotypes and to identify rapidly the emergence of new ones. However, many surveillance
studies are based either on a relatively small number of isolates from a single country, or on a
large number of isolates from many different countries and so are not equally meaningful.
Extensive national multicentre surveillance would provide a more reliable strategy for
assessing the extent of antimicrobial resistance in individual countries. This article describes
Spanish experience with the surveillance network SAUCE, and summarizes the main results on
antimicrobial resistance in the three key bacterial pathogens involved in community-acquired
respiratory tract infections in Spain: Streptococcus pneumoniae, Haemophilus influenzae and
streptococci, Haemophilus influenzae and Moraxella catar-rhalis.
Valid assessments of antimicrobial resistance patterns withinspecified areas are difficult to achieve. Until recently only Materials and methods
local, small-scale studies of resistance were used to assess theextent of resistance for a given country. However, the general- In 1996 a national ‘joint-venture’ was set up involving public ization of those results to the whole country was of question- hospitals and universities, the National Institute of Health Carlos III and private initiative with the sponsorship of Smith- To address this issue, there are a number of important Kline Beecham (currently GlaxoSmithKline) and the par- considerations to be taken into account. First, it is necessary to ticipation of the Valencian Institute for Microbiology. This determine a geographical setting and the most suitable spatial project came to be called SAUCE, an acronym standing for granularity from which conclusions can be drawn and ‘Susceptibility to the Antimicrobials Used in the Community applied. Sentinel centres working as a network, ideally with a in España’, which is also the Spanish word for willow tree.
single central laboratory to standardize tests, would be the The project was conducted under the auspices of the Spanish most appropriate framework. Spain, with one of the highest Surveillance Group for Respiratory Pathogens, which con- rates of resistance to many drugs in many different species, sisted of representatives of each centre and co-workers, who was the subject of this surveillance project.
share the authorship of any publication generated by the It is essential to define the infections and potential pathogens to be studied. This report focuses on community- Over a continuous 365 day period non-duplicate isolates acquired respiratory tract infections, namely acute pharyngitis, were collected from patients with the conditions listed above.
acute otitis media, acute exacerbations of chronic bronchitis Only those isolates that would have been considered diag- and pneumonias, and their potential pathogens Streptococcus nostically relevant would be further processed and reported, pneumoniae, Streptococcus pyogenes and other β-haemolytic in order to estimate the prevalence of resistance to antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
*Correspondence address. Department of Microbiology, University Hospital and School of Medicine, Avda Blasco Ibañez 17, 46010 Valencia, Spain. Fax: +34-96-356-19-86; E-mail: firstname.lastname@example.org †Other members of the Spanish Surveillance Group for Respiratory Pathogens are listed in the Acknowledgements.
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2002 The British Society for Antimicrobial Chemotherapy J. García-de-Lomas et al.
commonly used in the treatment of community-acquired res- different bacteria for different antibiotics. These databases piratory tract infections in Spain. The 1 year project was can also be used to link with demographic variables or anti- intended to take into account possible seasonal variations that might influence overall isolation or resistance rates for indi- The value of the SAUCE project has been endorsed by a number of publications in important peer-reviewed jour- Since 1996, two SAUCE studies have been completed nals.2–11 At present, this initiative is considered to provide the (SAUCE 1: May 1996–April 1997; and SAUCE 2: November most reliable, up-to-date and comprehensive information on 1998–October 1999), and another one is presently underway antimicrobial resistance in respiratory pathogens in Spain.
(SAUCE 3: November 2001–October 2002). The number of Accurate data on resistance rates in respiratory pathogens are hospitals participating increased from 14 in SAUCE 1 to 25 in essential to an evidence-based approach to empirical therapy SAUCE 3, and the number of S. pneumoniae, S. pyogenes and H. influenzae isolates increased from 3444 (SAUCE 1) to5666 (SAUCE 2), with ∼8000 strains predicted in SAUCE 3.
Results and discussion
The central laboratory performs the susceptibility testing bysemi-automated microdilution in customized microplates Since detailed results have already been published, the (Sensititre; Trek Diagnostics, Westlake, OH, USA) following present article will focus on the most important data for NCCLS recommendations. To ensure consistency we have S. pneumoniae, H. influenzae and S. pyogenes, giving a applied the same breakpoints (namely, those issued by the general comparative overview of the findings from the first NCCLS in 20001) to all surveillance.
two studies, and paediatric and adult isolates of S. pneumo- In Spain all microbiology laboratory investigations are niae. Results for S. pneumoniae are summarized in Tables 1 undertaken in larger secondary or tertiary hospitals. Only and 2, whereas Tables 3 and 4 show the results for S. pyogenes local differences in the frequency with which microbiological and H. influenzae, respectively.
investigation is considered worthwhile for an individual It is plain that for S. pneumoniae (Table 1) a decrease in patient and/or differences in laboratory procedure could the frequency of resistance to all oral β-lactams took place (except for co-amoxiclav, which had a very low resistance Other objectives of the SAUCE project are the rapid identi- level in 1996–1997), averaging 21.7% for penicillin, 5.1% for fication and tracking of rare phenotypes, and the acquisition co-amoxiclav, 41.6% for cefaclor and 31.4% for cefuroxime of a defined collection of isolates for more detailed studies axetil. This is also consistent with a decrease in the MIC of (molecular epidemiology, in vitro or animal models) that penicillin. As regards macrolides, the prevalence of resist- would be readily available on request to any member of the ance did not change, with a small trend towards increase group. Consequently, huge databases were created that allow (prevalence of resistance 35%), and intrinsic activity (MIC) for comparisons between different provinces, age groups, that was confirmed to be ≥64 mg/L of the three drugs tested.
type of sample and time-point estimates of resistance rates in Resistance to ciprofloxacin (as defined by an arbitrary break- Table 1. In vitro activity of antimicrobial agents against S. pneumoniae isolates obtained from SAUCE studies3,10
aBreakpoints used are ≥2 mg/L (resistant) for penicillin and azithromycin; ≥8 mg/L (resistant) for co-amoxiclav; ≥4 mg/L (resistant) for cefaclor andcefuroxime axetil; ≥1 mg/L (resistant) for erythromycin and clarithromycin.
bCo-amoxiclav, amoxicillin–clavulanate (2:1). The concentration listed is for amoxicillin.
cNo NCCLS breakpoints have been established. Arbitrary ciprofloxacin breakpoint for resistance, ≥4 mg/L.
Susceptibility of bacteria causing RTI
point of ≥4 mg/L) also seemed to grow over time (from 5.3% ≥4 mg/L. A study is currently underway to address the likely clonal relatedness of these isolates, as seems to be the case Macrolide resistance is due almost exclusively to MLS (E. Pérez-Trallero, San Sebastián, personal communication).
mechanisms10 (in contrast to American reports), and is there- Co-resistance could also be assessed. Results from fore linked with resistance to 16-membered macrolides and SAUCE 2 indicate that for strains showing intermediate resistance to penicillin, both amoxicillin and cefuroxime In the SAUCE 2 surveillance, 5% of pneumococcal iso- axetil are suitable oral therapy alternatives (1% and 36%, lates showed an MIC of amoxicillin of ≥8 mg/L, and therefore respectively, were resistant). Only amoxicillin may be suit- were categorized as highly resistant. Interestingly, serotype able for highly penicillin-resistant strains (of which 23% 14 accounted for 46% of these isolates, in contrast to 9% in the were amoxicillin resistant); of these, 9% were resistant to overall study. More than two-thirds came from northern ciprofloxacin and so newer fluoroquinolones could be a valid centres compared with only 6% from southern Spain. Peni- option. Particularly concerning is the increase in resistance to cillin MICs for these strains were two or three two-fold dilu- erythromycin (and therefore to clarithromycin and azithro- tions lower than those of amoxicillin, as reported elsewhere12.
mycin) among penicillin-susceptible isolates, with a current Multiresistance was the rule, since non-susceptibility of 11% resistance (and ∼60% for both intermediate and high- these strains was total for penicillin, co-amoxiclav, cefaclor, level penicillin resistance). No less worrying is the associa- cefuroxime, and even cefotaxime; up to 65% were also tion of resistance to ciprofloxacin and erythromycin on one resistant to macrolides and 12% had a ciprofloxacin MIC of hand, and penicillin non-susceptibility on the other. Resist- Table 2. In vitro activity of antimicrobial agents against S. pneumoniae paediatric isolates obtained from SAUCE
aSee Table 1, footnote a.
bSee Table 1, footnote b.
Table 3. In vitro activity of antimicrobial agents against S. pyogenes isolates obtained from SAUCE studies2,10
aBreakpoints used are ≥4 mg/L (resistant) for penicillin; ≥1 mg/L (resistant) for erythromycin and clarithromycin; ≥2 mg/L (resistant) forazithromycin.
bIn accordance with NCCLS, a streptococcal isolate that is susceptible to penicillin is considered susceptible to the remaining β-lactams.
J. García-de-Lomas et al.
Table 4. In vitro activity of antimicrobial agents against H. influenzae isolates obtained from SAUCE studies4,9
aBreakpoints used are: penicillin, NT (not tested, no NCCLS breakpoint criteria); amoxicillin, NT; ampicillin, ≥4 mg/L (resistant); co-amoxiclav, ≥8/4 mg/L(resistant); cefaclor, ≥32 mg/L (resistant); cefuroxime, ≥16 mg/L (resistant); erythromycin, NT; clarithromycin, ≥32 mg/L (resistant); azithromycin, ≤4 mg/L(susceptible); ciprofloxacin, NT.
b,cβ-lac+ and β-lac–, β-lactamase positive and β-lactamase negative, respectively.
dAmox/Amp; amoxicillin/ampicillin. Ampicillin was not tested in SAUCE 1. Data from SAUCE 1 refer to amoxicillin and data from SAUCE 2 to ampicillin.
eSee Table 1, footnote b.
ance to ciprofloxacin might therefore increase even in the resistant to penicillin (50.4%), cefaclor (68%) and cefuroxime absence of selective pressure by quinolones, driven by co- axetil (54%), ∼40% were resistant to macrolides, but only 5.6% were highly resistant to co-amoxiclav (MIC 4 mg/L).
Analysis of the pulsed-field gel electrophoretic profiles of The apparent decrease in resistance in the SAUCE 2 surveil- pneumococcal isolates with reduced susceptibility to cipro- lance was also mirrored in isolates from children: prevalence floxacin and of co-occurring susceptible isolates indicates a of high-level resistance of 28% for penicillin, 50% for considerable genetic diversity among the former isolates and cefaclor and macrolides, 40% for cefuroxime axetil and only points to a close relationship between the two groups. This suggests that strains with reduced susceptibility to ciprofloxacin As far as S. pyogenes is concerned (Table 3), the main find- emerge through independent mutational events. However, ing is an apparent decrease in the raw estimation of resistance up to 30% of the isolates belonged to two internationally to erythromycin from 25% in SAUCE 1 to 20% in SAUCE 2.
spread multidrug-resistant epidemic clones: Spain23F-1 This reduction is probably an underestimate due to a greater and Spain9V-3, implying that dissemination of ciprofloxacin contribution of isolates from northern centres with a low resistance through these isolates may be likely to occur in resistance rate in the latter survey. By assigning the same relative weight to every province, regardless of the number of Another interesting ecological association that has been isolates provided, a prevalence of erythromycin resistance consistently found in the two surveys performed so far is the correlation between the prevalence of erythromycin The M phenotype (efflux pump) accounts for 90% of this resistance by site in S. pneumoniae and S. pyogenes.5,10 Since resistance, in contrast to S. pneumoniae. Erythromycin resist- these two species are epidemiologically unrelated, and their ance is mainly due to a few M types, predominantly M4.13 mechanisms of resistance are distinct, there must be some This association between resistance to erythromycin and force driving this co-selection of resistance.
ciprofloxacin in S. pneumoniae also occurs with S. pyogenes Paediatric isolates represented 11% and 17% of the (6.1% compared with 2.7% ciprofloxacin resistance for SAUCE 1 and SAUCE 2 pneumococcal strains. As has been erythromycin-resistant and -susceptible isolates, respect- widely reported, rates of resistance in this subpopulation ively) in the last survey, paving the way for further increases (Table 2) also tended to be higher than in the whole popula- in resistance to ciprofloxacin driven by macrolides.
tion. Particularly striking was the fact that in the SAUCE 1 Regarding H. influenzae (Table 4), β-lactamase was found surveillance, more than half of these isolates were highly in 25% of isolates (no apparent change over time), which is Susceptibility of bacteria causing RTI
lower than the 30–35% reported by others.14,15 The β-lactam- Riestra, B. Regueiro, A. Jato and M. Prieto, Hospital Clínico ase production status influenced only the susceptibility to Universitario, Santiago de Compostela; C. Rubio and ampicillin and cefaclor, but not that to cefuroxime. Of C. García, Hospital Clínico Universitario, Zaragoza; M. de la H. influenzae isolates from SAUCE 2, 9% were of the Rosa, Hospital Virgen de las Nieves, Granada; A. M. Martín- β-lactamase-negative ampicillin-resistant (BLNAR) pheno- Sánchez and F. Cañas, Hospital Insular, Las Palmas;type, since they were neither fully susceptible to ampicillin, D. Romero and M. González, Hospital Nuestra Señora de nor producers of β-lactamase. Differences in the intrinsic Alarcos, Ciudad Real; J. M. Nogueira, Hospital Dr Peset, potency of macrolides were also seen, with clarithromycin Valencia; M. Casal and A. Ibarra, Hospital Reina Sofía, being less active than azithromycin.
Córdoba; M. Gobernado and N. Diosdado, Hospital La Fe, The data presented in the tables are average estimates of the Valencia; G. Prats and F. Sánchez, Hospital Santa Creu i Sant results obtained by each hospital, and may lead to the mis- Pau, Barcelona; R. Cisterna and A. Morla, Hospital de leading image that prevalence of resistance is homogeneous Basurto, Bilbao; A. C. Gómez-García and F. J. Blanco- within the country. But the reality is very different since Palenciano, Hospital Infanta Cristina, Badajoz; A. Fenoll and resistance showed wide variations between provinces. It J. Casal, Instituto Carlos III, Madrid; J. J. Granizo, Fundación ranges from 6% to 41% for penicillin and from 22% to 61% Jiménez Díaz, Madrid; L. Aguilar, J. E. Martín and R. Dal-Ré, for erythromycin in S. pneumoniae; from 11% to 49% for GlaxoSmithKline, Tres Cantos, Madrid.
erythromycin in S. pyogenes and from 16% to 30% for
β-lactamase production in H. influenzae (not statistically References
significant in this latter case) in the SAUCE 2 survey.
In conclusion, it can be affirmed that the Spanish experi- 1. National Committee for Clinical Laboratory Standards. (2000).
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has become an essential reference, offering the most reliable and comprehensive data on resistance in key respiratory bac-teria in Spain. It is expected that the ongoing third SAUCE 2. Baquero, F., García-Rodriguez, J. A., García-de-Lomas, J.,
Aguilar, L. & the Spanish Surveillance Group for Respiratory Patho- survey will update even more accurately the information gen- gens. (1999). Antimicrobial resistance of 914 beta-hemolytic erated so far, and at the same time more profound studies on streptococci isolated from pharyngeal swabs in Spain: Results of a molecular mechanisms of resistance and epidemiology of the 1-year (1996–1997) multicenter surveillance study. Antimicrobial isolates obtained will clarify the complexity of antimicrobial Agents and Chemotherapy 43, 178–80.
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are likely to be more valuable, efficient, feasible and less Aguilar, L. & the Spanish Surveillance Group for Respiratory Patho- costly than huge multinational surveillance studies.
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obtained without the sincere interest and help of SmithKlineBeecham S.A. Spain (presently GlaxoSmithKline Spain). 5. Gómez-Lus, R., Granizo, J. J., Aguilar, L., Bouza, E., Gutierrez,
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