1 Clinical Institute of Hygiene and Medical Microbiology, Division of Hospital Hygiene, Vienna University Hospital, Währinger Gürtel 1820, A-1090 Vienna; 2 Clinical Institute of Hygiene and Medical Microbiology, Division of Clinical Microbiology, University of Vienna, Vienna, Austria
Received 27 February 2004; returned 1 April 2004; revised 6 April 2004; accepted 13 April 2004
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Materials and methods: All S. aureus isolates from patients in the Vienna University Hospital (2140 beds), isolated between 1/1996 and 12/2002, were stratified by patient status (ICU patient, regular inpatient, outpatient). Four kinds of specimen [blood, respiratory tract (RT), wounds and urine] were defined for analysis. Oxacillin and eight other compounds were considered.
Results: In total, 10 575 first isolates per patient were detected, derived from ICU patients (n=1464), inpatients (n=4152), and outpatients (n=4959). From blood, wounds, RT and urine, 610, 1464, 2716 and 3370 first isolates per patient, respectively, were available. The blood-MRSA-rate (19.93%) was similar to the MRSA-rate of RT- (OR: 0.98, 95% CI: 0.761.25), wound- (OR: 0.89, 95% CI: 0.711.12), and urine-isolates (OR: 0.91, 95% CI: 0.721.14). Isolates from inpatients (OR: 0.59, 95% CI: 0.470.74) and outpatients (OR: 0.16, 95% CI: 0.130.21), regardless of the specimen, showed lower MRSA-rates than blood-isolates, in contrast to isolates from ICU patients (OR: 1.12, 95% CI: 0.871.44). For other compounds, the resistance rates of blood-isolates were not always representative for RT- (six of eight rates similar), wound- (7/8), or urine-isolates (5/8). Most importantly, RT-, wound- and urine-isolates were significantly more often resistant to ciprofloxacin. Resistance rates of blood-isolates were more representative for isolates from inpatients (five of eight rates similar) than from ICU patients or outpatients (each 3/8).
Conclusions: The resistance rates of blood culture isolates enable a good overall assessment of the resistance of other clinically significant isolates. However, resistance data derived from selected specimens must not be equated with the overall resistance situation in the hospital.
Keywords: MRSA , S. aureus , blood culture isolates , antibiotic resistance , surveillance
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The Vienna University Hospital is a 2140 bed tertiary care teaching hospital, which has 1924 normal care beds, and 216 ICU (or intermediate care) beds. Per year, the hospital provides medical services for an average of 95 000 inpatients (of these, 4000 are ICU patients) and 430 000 outpatients. All microbiological specimens are processed at the Division for Clinical Microbiology.
Identification and in vitro susceptibility testing of S. aureus
All S. aureus isolates obtained between January 1996 and December 2002 in patients of the Vienna University Hospital were subject to analysis. S. aureus was cultured and identified according to standard procedures. Antimicrobial susceptibility testing for penicillin, oxacillin, erythromycin, clindamycin, gentamicin, amikacin, trimethoprim and ciprofloxacin was routinely carried out by the KirbyBauer disc diffusion method on MuellerHinton agar according to NCCLS guidelines.5,6 For fusidic acid, where the NCCLS does not provide disc susceptibility breakpoints, the required diameters for susceptibility, intermediate susceptibility, and resistance were 14 mm, 1521 mm, and
22 mm, respectively (10 µg disc).
Definitions and data stratification
Eighty different types of specimen were sent for microbiological analysis. For the purpose of this study, four classes of specimen were defined for further analysis: blood (all isolates from peripheral and central blood specimens), respiratory tract (RT; sputum and specimens collected by bronchoscopy), wounds (specimens designated as wound swab, wound secretion, or pus), and urine (both spontaneous and catheter urine). All patients were classified according to their patient status [ICU patients, regular inpatients (referred to as inpatients) and outpatients].
By this stratification procedure, seven subgroups of isolates were defined. Four subgroups comprised isolates from defined clinical specimens (blood, RT, wounds and urine), and three comprised isolates from defined patient categories (ICU, inpatients and outpatients). In order to assess the resistance rates of S. aureus isolates from ICU patients, inpatients and outpatients, the first isolate from each patient within the study period (regardless of the type of specimen) was subject to analysis. With regard to the defined clinical specimens, the first isolate per patient from the defined type of specimen was considered. In addition to these subgroups of isolates, all first isolates per patient within the study period (referred to as first patient isolates, including all S. aureus isolates regardless the type of specimen) were analysed. The resistance rates of blood culture isolates and of first patient isolates were compared with the resistance rates in the other subgroups. In vitro resistant and intermediate susceptible isolates were uniformly referred to as non-susceptible isolates.
In addition, the effect of inclusion of all S. aureus isolates (per specimen or patient category) instead of the first isolates per patient on the MRSA-rate was assessed. The MRSA-rate in the first patient isolates was compared to the MRSA-rate in all available isolates (all patients and all types of specimens including repeat isolates).
Statistics
Calculation of statistical significance (2 test with Yates correction; a P value of <0.05 was considered significant) and odds ratios with Cornfield 95% confidence intervals (CI) was carried out using EpiInfo 2002 (CDC, Atlanta, GA, USA).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
From 1/1996 to 12/2002, 29 611 isolates of S. aureus were detected. These isolates were derived from 10 575 patients in Vienna University Hospital (ICU: 1464; inpatients: 4152; outpatients: 4959). The number of isolates in the categories blood, RT, wounds and urine are shown in Table 1.
|
The MRSA-rates in each subgroup are shown in Table 2. The comparison of the MRSA-rate in the first patient isolates with the MRSA-rate in the other subgroups is shown in Table 3.
|
|
Inclusion of all S. aureus isolates (regardless of the type of specimen) instead of the first patient isolates gave a significantly higher MRSA-rate (P<0.0001; OR: 4.33, 95% CI: 4.054.64). This was also observed for outpatients (10.4% versus 3.9%, P<0.0001; OR: 2.82, 95% CI: 2.393.33), inpatients (38.8% versus 12.8%, P<0.0001; OR: 4.31, 95% CI: 3.94.77), and ICU patients (51.3% versus 18.1%, P<0.0001; OR: 4.75, 95% CI: 4.15.5). Analogously, the inclusion of all S. aureus isolates per specimen instead of the first isolate per patient and specimen resulted in a higher MRSA-rate for isolates from the RT (31.5% versus 19.6%, P<0.0001; OR: 1.89, 95% CI: 1.632.2), wounds (30.7% versus 18.1%, P<0.0001; OR: 2.0, 95% CI: 1.782.25), and urine (31.3% versus 9.5%, P<0.0001; OR: 2.07, 95% CI: 1.872.29), but not for blood culture isolates (20.7% versus 19.9%, P=0.8; OR: 1.05, 95% CI: 0.811.36).
Resistance to other antimicrobial agents
The resistance rates of the isolates in each subgroup are shown in Table 2.
The resistance rates of blood-isolates were not throughout representative for RT (six of eight rates similar), wound- (7/8), or urine-isolates (5/8). Most importantly, RT- (P<0.0001; OR: 1.66, 95% CI: 1.32.12), wound- (P<0.0001; OR: 1.62, 95% CI: 1.292.02), and urine-isolates (P=0.0006; OR: 1.55, 95% CI: 1.251.93) were more often resistant to ciprofloxacin. The resistance rates to fusidic acid were higher in blood-isolates than in isolates from the RT (P=0.009; OR: 2.59, 95% CI: 1.245.44) and from urine (P=0.03; OR: 1.9, 95% CI: 1.053.42). Blood culture isolates were significantly more often resistant to clindamycin than urine isolates (P=0.01, OR: 1.33, 95% CI: 1.071.65).
The resistance rates of blood-isolates were more representative for isolates from inpatients (five of eight rates similar) than from ICU-patients or outpatients (each 3/8).
The comparison of the resistance rates of the first patient isolates to the resistance rates of the other subgroups is shown in Table 3.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The study especially focused on the question of whether blood culture-based resistance rates are representative for isolates from other specimens, which may also be considered clinically significant. For this study, samples from the respiratory tract (excluding throat swabs, which are occasionally taken for screening purposes), wounds (if the specimens were definitely designated as material from a wound and not just as swab), and urine (from patients with microbiologically significant bacteriuria) were chosen for comparison.
With regard to the MRSA-rate, blood culture isolates were representative for isolates from the respiratory tract, wounds and urine. The inclusion of all (i.e. first and repeat) isolates instead of the first isolates per patient gave a significantly higher MRSA-rate in all subgroups with the exception of blood culture isolates. A possible explanation for this finding is that the frequency of taking control cultures is probably higher in patients with MRSA than in patients with MSSA. In contrast, in patients with bacteraemia or sepsis due to S. aureus, the number of control cultures is rather determined by the clinical course of the patient than by the in vitro resistance pattern of the pathogen. Resistance of S. aureus to oxacillin (or methicillin) is essentially determined by the mecA gene, which encodes an altered penicillin-binding protein (PBP 2a), a membrane-bound enzyme.7,8 As the mutations leading to the expression of PBP 2a are complex, acquisition of resistance to oxacillin due to antibiotic pressure is nearly impossible. Therefore, it is biologically plausible that the MRSA-rate in the specimens considered clinically significant is essentially similar. In contrast, inpatient and outpatient isolates (not regarding the specimen) showed significantly lower MRSA-rates than clinically significant isolates, whereas the MRSA-rate of isolates from the ICU patient population was similar to the MRSA-rate of the clinically significant isolates. Obviously, screening samples, which are occasionally obtained without clinical evidence of infection (from nose, skin, and throat) have decreased the MRSA-rate significantly. The fact that infections with MRSA (compared with infections with MSSA) are more likely to occur in seriously ill patients has been described previously.9 The accumulation of MRSA strains in clinically significant sites and ICU patients may be explained by a higher virulence of MRSA compared to MSSA.3
With regard to compounds other than oxacillin, the resistance rates were higher in inpatients than in outpatients, and highest in ICU patients. This is predictable given the expected antibiotic exposure. The resistance rates of blood culture isolates were poorly representative for these groups of patients. The overall agreement between blood culture isolates and other clinically significant isolates was good, with the important exception of ciprofloxacin. Ciprofloxacin resistance in S. aureus is acquired more easily than resistance to most other (non-quinolone) compounds, due to a stepwise acquisition of chromosomal mutations.7 With regard to patients with chronic respiratory tract infections (e.g. COPD), chronic wounds (e.g. diabetic patients), or recurrent urinary tract infection, a higher resistance of such isolates to quinolones is biologically plausible.
In addition to ciprofloxacin, significant differences between blood culture isolates and other clinically significant isolates were observed for fusidic acid, which had lower resistance rates in isolates from the respiratory tract and from urine. Natural mutants resistant to fusidic acid are present in normal populations of S. aureus with a frequency of 1 in 106 to 1 in 108. Although it may not occur in a high frequency in clinical practice, selection of resistant mutants during therapy has been recognized in vivo.10 Fusidic acid is a second-line compound, which is notably used for treatment of patients with skin and soft tissue infections. Wounds are an important source of S. aureus bacteraemia.11 Therefore it may be speculated that the higher resistance of blood and wound isolates is directly attributable to the acquisition of secondary resistance.
It should be noted that the significant differences in fusidic acid resistance between blood culture isolates (2.8%) and isolates from urine (1.5%) or respiratory tract (1.1%) are primarily of epidemiological interest, while they may have little clinical impact. The differences in clindamycin (blood versus urine: 21.8% versus 17.3%) and ciprofloxacin resistance (blood versus respiratory tract: 25.7% versus 36.4%) were more pronounced. However, it should be noted that ciprofloxacin is not a first-line compound for the treatment of S. aureus infections.
It is a limitation of this study that the presented resistance rates, notably for compounds which enable the acquisition of secondary resistance by S. aureus, are influenced by local antibiotic policy. The number of isolates tested against the investigated antimicrobial agents varied, because for some classes of antibiotics (e.g. quinolones), different reference compounds were used, and because some second-line compounds (e.g. trimethoprim) were not tested routinely.
In recent years, increasing interest has focused on the occurrence of community-acquired MRSA strains. These strains have been reported to cause infections in healthy community-dwelling persons without established risk factors for MRSA acquisition, and may be primarily identified by their unusual susceptibility to non-ß-lactam antibiotics. It has been shown that community-acquired MRSA strains are genotypically distinct from hospital-acquired MRSA strains, which can be confirmed by multi-locus sequence typing. The emergence of these strains will have to be considered in resistance surveillance in the future; however, it is difficult to assess the proportion of these strains in a retrospective format (i.e. on the basis of the in vitro susceptibility pattern) without the availability of molecular markers.12,13
In conclusion, the present data indicate that the resistance of blood culture isolates enables a good overall assessment of the resistance of other clinically significant isolates. This is notably true with regard to the MRSA-rate. Nevertheless, the definition of additional types of specimens for routine resistance surveillance may enable a more detailed assessment of the local resistance epidemiology. In addition, pooling of isolates from blood, respiratory tract (excluding throat swabs if they are taken for screening purposes), wounds and urine increases the number of samples available for analysis, which may be especially important for small hospitals with low numbers of blood culture isolates. However, resistance data derived from clinically significant isolates must not be equated with the overall resistance situation in the hospital.
![]() |
Acknowledgements |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 . Fritsche, T. R., Sader, H. S. & Jones, R. N. (2003). Comparative activity and spectrum of broad-spectrum beta-lactams (cefepime, ceftazidime, ceftriaxone, piperacillin/tazobactam) tested against 12, 295 staphylococci and streptococci: report from the SENTRY antimicrobial surveillance program (North America: 20012002). Diagnostic Microbiology and Infectious Disease 47, 43540.[CrossRef][ISI][Medline]
3 . Melzer, M., Eykyn, S. J., Gransden, W. R. et al. (2003). Is methicillin-resistant Staphylococcus aureus more virulent than methicillin-susceptible S. aureus? A comparative cohort study of British patients with nosocomial infection and bacteremia. Clinical Infectious Diseases 37, 145360.[CrossRef][ISI][Medline]
4 . Cordova, S. P., Heath, C. H., McGechie, D. B. et al. (2004). Methicillin-resistant Staphylococcus aureus bacteraemia in Western Australian teaching hospitals, 19971999: risk factors, outcomes and implications for management. Journal of Hospital Infection 56, 228.[CrossRef][ISI][Medline]
5 . National Committee for Clinical Laboratory Standards (1993). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyThird Edition: Approved Standard M7-A3. NCCLS, Villanova, PA, USA.
6 . National Committee for Clinical Laboratory Standards (1994). Performance Standards for Antimicrobial Susceptibility Tests. Fifth Informational Supplement M100S5. NCCLS, Villanova, PA, USA.
7 . Hartman, B. & Tomasz, A. (1981). Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 19, 72635.[ISI][Medline]
8
.
Lowy, F. D. (2003). Antimicrobial resistance: the example of Staphylococcus aureus. Journal of Clinical Investigation 111, 126573.
9
.
Archer, G. L. & Climo, M. W. (2001). Staphylococcus aureus bacteremiaconsider the source. New England Journal of Medicine 344, 556.
10 . Turnidge, J. & Collignon, P. (1999). Resistance to fusidic acid. International Journal of Antimicrobial Agents 12, Suppl. 2, S3544.[CrossRef][ISI][Medline]
11 . Lautenschlager, S., Herzog, C. & Zimmerli, W. (1993). Course and outcome of bacteremia due to Staphylococcus aureus: evaluation of different clinical case definitions. Clinical Infectious Diseases 16, 56773.[ISI][Medline]
12 . Vandenesch, F., Naimi, T., Enright, M. C. et al. (2003). Community-acquired methicillin-resistant Staphylococcus aureus carrying PantonValentine leukocidin genes: worldwide emergence. Emerging Infectious Diseases 9, 97884.[ISI][Medline]
13
.
Okuma, K., Iwakawa, K., Turnidge, J. D. et al. (2002). Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community. Journal of Clinical Microbiology 40, 428994.
|