Journal of Antimicrobial Chemotherapy (2004) 53, 1033–1038
DOI: 10.1093/jac/dkh214
Advance Access publication 5 May 2004
Antibiotic resistance in 3113 blood isolates of Staphylococcus aureus in
40 Spanish hospitals participating in the European Antimicrobial
Resistance Surveillance System (2000–2002)
Jesús Oteo1, Fernando Baquero2, Ana Vindel1 and José Campos1* on behalf of the Spanish members
of The European Antimicrobial Resistance Surveillance System (EARSS)†
1Centro
Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid; 2Servicio de
Microbiología, H. Ramón y Cajal, Madrid, Spain
Received 17 December 2003; returned 21 January 2004; revised 24 February 2004; accepted 28 February 2004
Objectives: Since 1998 the European Commission has funded EARSS. We present the antibiotic susceptibility results of invasive Staphylococcus aureus obtained in Spain (2000–2002).
Material and methods: Forty hospitals participated in this study, covering nearly 30% of the Spanish population. All blood isolates of S. aureus were included. Laboratories used their usual methods to perform
microbiological studies. Annual external quality controls were carried out. A questionnaire with hospital,
patient and specimen data was completed for each isolate. Results were included in a database and analysed with WHONET 5 software.
Results: Invasive S. aureus was isolated in 3113 patients. Resistance was 24.5% to oxacillin, 25.4% to ciprofloxacin, 25.2% to erythromycin and 12.1% to gentamicin. Gentamicin resistance decreased from 16.6%
(2000) to 9.7% (2002). Multiresistance was observed in 68.1% of oxacillin-resistant isolates. More prevalent
multiresistance profiles consisted of oxacillin–ciprofloxacin–erythromycin–gentamicin (7.4%) and oxacillin–
ciprofloxacin–erythromycin (7.1%). Oxacillin resistance was significantly higher in nosocomial isolates
than in those implicated in community-onset infections (26.7% versus 14.2%), in isolates from adults than in
those from children (27.3% versus 4.7%), in hospitals with >500 beds than in those with <500 beds (31.1%
versus 18.3%) and in isolates from Intensive Care Units than in those from other departments (39.3% versus
24%). Decreased susceptibility to vancomycin was not detected.
Conclusions: In Spain, S. aureus blood isolates present a high prevalence of resistance to oxacillin, ciprofloxacin and erythromycin, as well as a high prevalence of multiresistance. Oxacillin resistance remains
stable but varies in relation to hospital size, patient age, hospital department and place of infection acquisition.
Keywords: invasive pathogens, staphylococcal infections, antimicrobial susceptibility
Introduction
The increasing prevalence of antibiotic resistance is a cause of serious
concern, requiring an international approach to its management. The
World Health Organization (WHO) and the European Commission
have recognized the importance of studying the emergence and determinants of resistance and the need for control strategies.1,2 In Europe,
antimicrobial resistance of invasive pathogens has been monitored
since 1998 by the European Antimicrobial Resistance Surveillance
System (EARSS). Funded by the European Commission, EARSS is
an international network of national surveillance systems that
attempts to collect reliable and comparable data. The purpose of
EARSS is to document variations in antimicrobial resistance over
time and space to provide the basis for, and assess the effectiveness
of, prevention programmes and policy decisions.
One of the indicator organisms in EARSS is Staphylococcus
aureus, which is a pathogen of major clinical importance for nosocomial infections. Since the introduction of antibiotics in clinical
practice, S. aureus has progressively developed resistance to many of
the antibiotics more frequently used. The most notable example of
this phenomenon is methicillin-resistant S. aureus (MRSA), the first
..................................................................................................................................................................................................................................................................
*Correspondence. Tel: +34-91-822-36-50; Fax: +34-91-509-79-66; E-mail: [email protected]
†The Spanish Group of the European Antimicrobial Resistance Surveillance System are listed in the Acknowledgements.
...................................................................................................................................................................................................................................................................
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JAC vol.53 no.6 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
J. Oteo et al.
clinical isolate of which was reported as early as 1961, just 1 year
after the launch of methicillin.3 Since then, MRSA has become a
major threat worldwide, and its incidence is increasing despite the
institution of infection-control programmes in many countries.4–7
The goal of this study was to describe and analyse S. aureus antibiotic resistance data collected by the Spanish hospitals participating
in the EARSS network in 2000–2002.
Materials and methods
The protocol for S. aureus susceptibility testing included oxacillin
and vancomycin. A specific guideline for detection of S. aureus with
reduced susceptibility to glycopeptides was recommended by EARSS to
all hospital participants based on published data.8 In addition, data on
antimicrobial susceptibility to other antibiotics were also considered, in
case a participating laboratory routinely tested them. Multidrug resistance
was defined as resistance to three or more of the antimicrobials tested.
The number of strains studied, by antibiotic and method, was not always
equal to the total number of strains.
Selection of participating hospitals
Quality control
To fulfil the goal of obtaining representative data, participating hospitals
were chosen to meet the following criteria: (i) coverage of at least 20% of
the Spanish population; (ii) different areas of the country covered; and
(iii) different kinds of hospitals (size and category) represented.
To assess the comparability of susceptibility test results, a quality assurance exercise was performed each year among the 40 laboratories participating in the Spanish EARSS. The UK National External Quality
Assessment Scheme designed this quality control. Altogether, 18 wellcharacterized control invasive strains, including four S. aureus and one
Staphylococcus haemolyticus with different resistance phenotypes, were
tested; S. haemolyticus had an MIC to vancomycin of 2–4 mg/L. The
inclusion of all these external quality control strains into the regular internal
quality control procedures carried out by each laboratory was recommended. Data on susceptibility to oxacillin, vancomycin, gentamicin and
erythromycin were required.
In addition, each laboratory completed a questionnaire concerning the
methods used for determining susceptibility and applying interpretation
criteria.
Strains studied
All clinical isolates of S. aureus obtained from blood in Spanish laboratories participating in the EARSS during 2000–2002 were included.
Only the first invasive isolate per patient was reported.
Data collection
A questionnaire concerning some hospital characteristics (coverage,
hospital type, number of beds, number of patients admitted/year, hospital
departments), methods of antimicrobial susceptibility study and interpretation criteria was submitted to each participating centre. One isolate
record form per patient was completed. This form included patient’s
personal data (code, age, sex), hospital and departmental data and antibiotic susceptibility data.
Hospitals sent standardized results to the Centro Nacional de Microbiología of the Instituto de Salud Carlos III, where results were analysed
and validated using the laboratory-based WHONET 5 program (WHO
Collaborating Centre for the Surveillance of Antibiotic Resistance). All
records were carefully analysed by a clinical microbiologist.
Duplicated isolates, more than one isolate per patient, were identified
and deleted. Discrepancies and atypical results were resolved by telephone and the corresponding database records updated if necessary. At
the end of each year, an annual report of all the data stored in the central
database was sent to each participating laboratory to avoid possible
disagreements.
Strain identification and antimicrobial susceptibility studies
Each laboratory—using its own routine methods and breakpoints—
identified the strains and tested their susceptibility. Thirty-three laboratories used commercial microdilution systems: 18 MicroScan (DadeBehring, Illinois, USA); seven Vitek (bioMérieux, France); six Wider
(Fco. Soria Melguizo S.A., Madrid, Spain); and two Sensititre (Radiometer/Copenhagen Company, Denmark). In five laboratories, both discdiffusion and Etest methods (AB-Biodisk, Solna, Sweden) were used and
two laboratories used a disc-diffusion susceptibility method. Among the
seven laboratories using a disc-diffusion method, NCCLS methodology
was used by six laboratories and the Neosensitab system (Rosco,
Sweden; user’s guide available at the website http://www.rosco.dk/uk/
userguides/neo-sensitabs_o.pdf) was used by one.
Results were scored as susceptible, intermediate or resistant according
to NCCLS criteria in 39 laboratories. One laboratory used the Neosensitab system. No significant differences in susceptibility results were
found between the laboratory using the Neosensitab system criteria and
the laboratories using NCCLS criteria. Quality-control results of this
laboratory also agreed with those obtained by reference laboratories.
Statistical analyses
Differences in the prevalence of antibiotic resistance between different
groups were assessed by the Fisher exact test. Association was determined by calculation of odds ratios (OR) with 95% confidence intervals
(CI). The null hypothesis was rejected for values of P < 0.05. Statistical
analyses were performed using EPI-Info version 6.04.
Results
Characteristics of participating laboratories
During 2000–2002, 40 laboratories reported data on invasive S. aureus
isolates. The estimated average coverage of the Spanish population
was 30%, corresponding to ∼12 000 000 persons. Twenty-seven
laboratories participated in the 3 years studied. The annual median
number of hospital beds and patients admitted were ∼17 500 and
∼721 300, respectively. Four hospitals (10%) had >1000 beds,
12 (30%) 500–1000, 17 (42.5%) 250–500 and seven (17.5%) <250
beds. Sixteen (40%) were university/tertiary care hospitals and 24
(60%) were general/secondary-care hospitals.
Quality control results
Among participating laboratories, the overall concordance of antimicrobial susceptibility in the four S. aureus and one S. haemolyticus
control isolates tested in the 3 years was 90%–100% for oxacillin,
86%–100% for vancomycin, 100% for gentamicin and 97%–100%
for erythromycin.
In the few cases of disagreement between the quality control
expected results and performance of individual laboratories, each
case was analysed and discussed with the participants; measures to
improve the laboratory procedures were proposed when necessary,
including the dispatch of the isolates to the Spanish S. aureus reference laboratory.
1034
Antibiotic resistance in blood isolates of Staphylococcus aureus
Table 1. Frequency of antimicrobial susceptibility in invasive
S. aureus in Spain (2000–2002)
Antibiotic
Oxacillin
Ciprofloxacin
Erythromycin
Gentamicin
Vancomycin
n
R (%)
I (%)
S (%)
3113
2859
3071
3035
3113
762 (24.5)
726 (25.4)
773 (25.2)
368 (12.1)
0
–
24 (0.8)
209 (6.8)
29 (0.9)
0
2351 (75.5)
2109 (73.8)
2089 (68)
2638 (87)
3113 (100)
Figure 1. Frequency by age of oxacillin resistance in invasive S. aureus.
n, number of strains; R, resistant; I, intermediate susceptibility; S, susceptible.
Table 2. Prevalence of antibiotic resistance in invasive S. aureus
isolated in EARSS-Spain laboratories (2000–2002)
Antibiotic
Oxacillin
Ciprofloxacin
Erythromycin
Gentamicin
Year 2000 R (%) Year 2001 R (%) Year 2002 R (%)
253 (28.1)
240 (26.6)
215 (23.8)
150 (16.6)
233 (23)
223 (24.7)
258 (26.2)
104 (10.8)
276 (23)
263 (24.9)
300 (25.4)
114 (9.7)
R, resistant.
Patient data and incidence of nosocomial bacteraemia
Over the study period, the 40 participant hospitals reported data on
3113 invasive isolates of S. aureus, corresponding to the same
number of patients: 903 in 2000, 1011 in 2001, and 1199 in 2002. Of
these, 2008 strains (64.5%) were isolated from males and 1105
(35.5%) from females. Two hundred and thirty-three (7.5%) of the
strains were isolated from children ≤14 years of age. Nosocomial
infections (defined as infections acquired at least 48 h after admission) accounted for 2853 (91.6%) cases, and community-onset infections, 260 (8.4%). The incidence of invasive S. aureus nosocomial
infections was 1.3 cases/1000 admitted patients.
A total of 725 nosocomial oxacillin-resistant S. aureus (MRSA)
isolates were identified: 253 in 2000, 221 in 2001 and 251 in 2002.
The incidence of MRSA nosocomial bacteraemia was 0.41/1000
patients admitted in 2000, 0.30 in 2001 and 0.33 in 2002.
Antimicrobial susceptibility
The antibiotic susceptibility of the 3113 S. aureus isolates is provided
in Table 1. Oxacillin resistance was detected in 762 strains (24.5%;
CI 95%: 23%–26%). Resistance to ciprofloxacin, erythromycin,
gentamicin and vancomycin was detected in 25.4% (95% CI: 23.8%–
27%), 25.2% (95 CI%: 23.9%–26.9%), 12.1% (95% CI: 10.9%–
13.3%) and 0% of the isolates studied, respectively. No statistical
differences were observed between the antimicrobial resistance figures
obtained by the 27 laboratories that participated in the 3 years of
study, in comparison with the antimicrobial resistance data provided
by the total number of 40 laboratories.
In comparison with other European countries participating in
EARSS with susceptibility results from at least 1000 isolates in the
studied period, Spain, which was equal to Belgium, was the fifth
country in oxacillin resistance behind the UK (42.7%), Ireland
(41.4%), Italy (40.1%) and France (33.1%).9
Trends of antimicrobial resistance during the 3 years of study are
detailed in Table 2. Oxacillin resistance decreased from 28.1% in
2000 to 23% in 2002 and 2003. A continuous decrease in resistance
to gentamicin was observed from 2000 (16.6%) to 2002 (9.7%)
(P < 0.0001; OR: 1.87; 95% CI: 1.43–2.45). No significant antibiotic
susceptibility differences to ciprofloxacin or erythromycin were
detected over the period of study.
Paediatric (≤14 years old) isolates were significantly less resistant
to oxacillin than those from adults, 4.7% versus 27.3% (P < 0.0001,
OR: 7.5; 95% CI: 4–14.7) (Figure 1). Comparative oxacillin resistance between isolates from males (26.1%) and females (23.3%) was
not statistically significant.
Resistance to ciprofloxacin, erythromycin and gentamicin was
more prevalent in oxacillin-resistant S. aureus (92.4%, 65.3% and
40.3%, respectively) than in oxacillin-susceptible strains (4.4%,
12.4% and 3.8%, respectively) (P < 0.001) (Table 3).
Resistance to oxacillin was more prevalent in isolates from hospitals
of tertiary care (31.1%) than in those of secondary care (18.3%)
(P < 0.00001; OR: 2, 95% CI: 1.7–2.4) In Figure 2, resistance to oxacillin is detailed according to the number of hospital beds.
Of 2859 strains tested for susceptibility to oxacillin, ciprofloxacin,
erythromycin and gentamicin, multidrug resistance was present in
464 (16.2%) strains. Of the oxacillin-resistant isolates, 68.1%
showed multiresistance. The most prevalent multiresistance phenotypes were oxacillin–ciprofloxacin–erythromycin–gentamicin, which
was detected in 211 isolates, representing 45.5% of multiresistant
strains and 7.4% of strains overall, and oxacillin–ciprofloxacin–
erythromycin, which was detected in 203 strains, 43.7% of multiresistant strains and 7.1% of strains overall. The oxacillin–ciprofloxacin–erythromycin–gentamicin pattern was more prevalent in
Intensive Care Units (ICUs) than in other hospital departments: 12%
versus 4.6% (P < 0.0001; OR: 2.8, 95% CI: 2–4.1). In contrast, this
difference was not detected in the oxacillin–ciprofloxacin–erythromycin resistance pattern: 7% versus 6.5% (P = 0.7). Figure 3 shows
the prevalence of these two multiresistance patterns.
Resistance to oxacillin was more prevalent in nosocomial than in
community-acquired isolates: 26.7% and 14.2% (P < 0.0001;
OR: 2.1, 95% CI: 1.5–3.1), respectively (Figure 4). Prevalence of
multidrug resistance in nosocomial oxacillin-resistant strains was
65.1%, in comparison with 57.6% in those implicated in communityonset infections (statistically not significant). ICUs were the hospital
1035
J. Oteo et al.
Table 3. Antibiotic resistance to ciprofloxacin, erythromycin, and gentamicin of invasive S. aureus
according to its oxacillin susceptibility
Antibiotic
Ciprofloxacin R
Erythromycin R
Gentamicin R
Oxacillin R
Oxacillin S
Odds ratio
95% CI
P
605/655 (92.4%)
451/691 (65.3%)
273/677 (40.3%)
77/1896 (4.1%)
251/2030 (12.4%)
76/2013 (3.8%)
285.8
13.3
17.2
194.8–420.5
10.8–16.4
13–22.9
<0.00001
<0.00001
<0.00001
R, resistant; S, susceptible.
Figure 2. Resistance to oxacillin in S. aureus isolated from blood according to the
number of hospital beds.
Figure 4. Oxacillin-resistant invasive S. aureus in relation to hospital departments in Spain.
Figure 3. Evolution of multiresistance patterns in invasive S. aureus in Spain
(2000–2002).
departments with the highest oxacillin resistance (39.3%) followed
by Surgery departments (34.5%) (Figure 4).
Discussion
Antimicrobial resistance is a growing problem worldwide, requiring
international approaches. To address this important issue, it is necessary
to improve surveillance methods based on large database sets and
long-term surveys.
Funded in 1998 by the European Commission, EARSS is currently
considered the official European network of national surveillance
systems intended to collect comparable and reliable antimicrobial
resistance data (EARSS website; published by RIVM at http://
www.earss.rivm.nl).
The main sources of EARSS information are the results of routine
antimicrobial susceptibility testing performed by primary clinical
microbiology laboratories. The major disadvantages of the use of
routine results include the different methods of antimicrobial susceptibility testing performed in each laboratory, although in our experience, most laboratories used NCCLS-recommended methodologies.
Nevertheless, exploitation of routine susceptibility data may be an
important source of information for targeting and evaluating interventions to reduce antimicrobial resistance. To resolve this matter,
external cross-validation of routine data gathering and centralized
surveys have been carried out.10
Overall, oxacillin resistance found in invasive isolates from this
study is similar to the 25% described among 3051 European strain
isolates from 25 university hospitals that were studied in a single
reference laboratory4 and to the numbers reported in other Spanish
studies.11–13 The 27.2% of 311 bacteraemias studied in a single Spanish
hospital were due to MRSA.11 In a multicentre study carried out in 38
Spanish hospitals in 2001 with isolates from different samples,
oxacillin resistance was found in 24% of S. aureus.12 Preliminary
data on Spanish isolates showed 28% oxacillin resistance for the year
2000.13
In contrast with the high antimicrobial resistance levels found in
Spanish isolates of Escherichia coli14 and Streptococcus pneumoniae,15
1036
Antibiotic resistance in blood isolates of Staphylococcus aureus
the prevalence of oxacillin-resistant S. aureus is lower in Spain than
in other European countries such as the UK and Ireland. As we have
shown, oxacillin resistance in invasive Spanish strains has not
increased in recent years. However, an increase in oxacillin resistance
in blood isolates of S. aureus has been described in the USA between
1997 (23.4%) and 2002 (34.4%).5
Multidrug resistance in MRSA is frequently due to the successive
acquisition of plasmids and transposons with resistance determinants,16 or to the spread of a few clonal resistant lineages. The
majority of oxacillin-resistant S. aureus isolates in EARSS–Spain
were also resistant to erythromycin and ciprofloxacin, whereas
resistance to other antibiotics in oxacillin-susceptible strains was rare
(Table 3), as described previously.4,7,17,18
During 2000–2002, the genetic relatedness of >1500 MRSA
isolated from Spanish hospitals was analysed by the cluster analysis
of PFGE patterns and the determination of the staphylococcal
cassette mec type19,20 at the Spanish reference laboratory located at
the Centro Nacional de Microbiología, Mahadahonda, Madrid. The
results obtained showed that >60% of the MRSA were genetically
closely related and belonged to two similar clones (manuscript in
preparation). Both clones carried the staphylococcal cassette
chromosome mec type IV. No major differences were found between
blood isolates and isolates from other anatomical sources.
Frequently, gentamicin and oxacillin multiresistance has been
associated in strains in Spanish hospitals and worldwide. In the last
3 years, the resistance phenotype pattern, including oxacillin–
ciprofloxacin–erythromycin but not gentamicin, has progressively
replaced the resistance phenotype oxacillin–ciprofloxacin–erythromycin–gentamicin in Spain, according to data described in this study.
This tendency has also been described in other countries21,22 and in a
Spanish study of a single hospital.23 This change has been attributed
to a significant fitness benefit of some new gentamicin-susceptible
clones22 and has been associated with an aminoglycoside consumption
decrease.23 This trend has been noted in the EPINE project in Spain in
which overall gentamicin consumption in a large number of Spanish
hospitals decreased from 8.75% (1990) to 4.98% (1999), a 56.9%
reduction.24
Strains of MRSA with reduced susceptibility to vancomycin have
been isolated in several countries in the world.25 Recently, the first
documented case of infection caused by vancomycin-resistant S. aureus
has been described in the USA.26 In Spain, strains with decreased
vancomycin susceptibility have not been described previously, and
in our study no isolates with this profile were detected.
Recently, community-acquired MRSA infections have increased
in children without risk factors.27,28 In contrast with nosocomial
MRSA isolates, the majority of these strains do not have resistance
associated with other antibiotic classes27–29 and are clearly distinguishable from hospital-associated MRSA by PFGE and spa typing.29
In our study, 9.2% of strains isolated from community-onset infections came from children, and all were oxacillin susceptible. In
addition, we found that the isolates involved in community-onset
infections were also multiresistant, as was the case for nosocomial
isolates. Although we do not have enough risk-factor data, these
cases could be healthcare associated.
Differences in oxacillin resistance relating to the number of beds
in each hospital or hospital department probably reflect the different
kinds of patients and pathologies treated by each one. Bigger hospitals
and ICUs are probably more likely to have patients with chronic
pathologies and longer admissions that make antibiotic treatments
more necessary.
In summary, antibiotic multiresistance S. aureus was frequent in
invasive S. aureus in Spain, with phenotypes changing over time.
However, resistance was not uniform and varied according to several
parameters, such as hospital size, patient age and hospital department. Therefore, properly designed and conducted surveillance
systems will continue to be essential in providing safe and effective
empirical therapies. Moreover, results obtained from these surveillance systems must be used to implement prevention programmes
and policy decisions to prevent emergence and spread of antimicrobial resistance.
Acknowledgements
EARSS is funded by the European Commission, DG Sanco (Agreement SI2.123794). J. Oteo is the EARSS data manager for Spain.
José Lite and Javier Garau (H. Mutua de Terrassa, Terrassa), Dionisia
Fontanals (Corporació Parc Taulí, Barcelona), Pilar Berdonces and
M. José L. De Goicoetxea (H. Galdakao, Galdakao), Oscar del ValleOrtiz (H.Vall d’Hebron, Barcelona), Isabel Wilhemi (H. Severo
Ochoa, Leganés), Francisco J. Vasallo-Vidal (H. do Meixoeiro,
Vigo), Elena Loza (H. Ramón y Cajal, Madrid), Pilar Peña y Avelino
Gutiérrez-Altés (H. La Paz, Madrid), Gregoria Megías-Lobón and
Eva Ojeda (H. General Yagüe, Burgos), Carmina Martí (H.G. de
Granollers, Granollers), María José Castañares (H. San Millán,
Logroño), Mercedes Menéndez-Rivas (H. Infantil del Niño Jesús,
Madrid), Pilar Bermudez and Marta García-Campello (Complejo
Hospitalario de Pontevedra, Pontevedra), Rosario Moreno and
Alfonso García-del Busto (H.G. de Castellón, Castellón), María del
Mar Pérez-Moreno and Ignacio Buj (H. Verge de la Cinta, Tortosa),
Matilde Elia (H.G.U. de Elche, Elche), Francisco Merino y Ángel
María Campos (H. de Soria, Soria), María Teresa Pérez-Pomata
(H.G.U. de Guadalajara, Guadalajara), Almudena Tinajas (H.G. Cristal
Piñor, Orense), Consuelo Miranda and María Dolores Pérez (H.U.
Virgen de la Nieves, Granada), Ana Fleites (H.G. de Asturias,
Oviedo), Carmen Amores (H. San Agustín, Linares), Pilar Teno
(H. San Pedro de Alcántara, Cáceres), A. Gimeno and Ramona
Jimenez (H. Infanta Cristina, Badajoz), Carmen Raya (H. del Bierzo,
Ponferrada), Begoña Fernandez (H. Sta. María Nai, Orense), María
Fe Brezmes (H. Virgen de la Concha, Zamora), María Teresa Cabezas
(H. de Poniente, El Ejido), Rafael Carranza (H.G. La ManchaCentro, Ciudad Real), Jose Luis Hernández (H. de Cruces, Baracaldo), Concepción Segura (Laboratori de Referencia de Catalunya,
Barcelona), Ricardo Fernández-Roblas and Francisco Soriano
(Fundación Jiménez Díaz, Madrid), Alberto Yagüe (H. Vega Baja,
Orihuela), Natalia Montiel (H. Costa del Sol, Marbella), Alfonso
Pinedo (H. Virgen de la Victoria, Málaga), José Antonio Lepe
(H. Río Tinto, Huelva), Juan Carlos Alados (H. de Jerez, Cadiz),
Manuel Rodriguez (H. Puerto Real, Cadiz), Estrella Martín (H. Valme,
Sevilla), Inocente Cuesta (H. Ciudad de Jaén, Jaén), Virtudes
Gallardo (Consejeria de Salud de la Junta de Andalucia, Sevilla).
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