Meticillin-resistant Staphylococcus aureus (MRSA) bacteraemia in Tampere University Hospital: a case- control study, Finland October 2002 to January 2010

Meticillin-resistant Staphylococcus aureus (MRSA) has emerged as a frequent pathogen in blood cultures in Pirkanmaa Hospital District (HD), Finland. To study risk factors for MRSA bacteraemia and the adequacy of empirical antimicrobial treatment, we retrospectively reviewed the hospital records of 102 patients, 51 with MRSA, and 51 with meticillin-sensitive Staphylococcus aureus (MSSA) bacteraemias respectively, who had been admitted to Tampere University Hospital in Pirkanmaa HD, from October 2002 to January 2010. For each patient with MRSA bacteraemia, one consecutively detected unmatched patient with MSSA bacteraemia was chosen as control. Patients with MRSA bacteraemias were significantly older (median age: 73 years vs 59 years, p=0.001), were more likely to have been transferred directly from another healthcare facility or were already in the hospital at the onset of bacteraemia (39/51 vs 26/51, p=0.007) and had a higher McCabe class than patients with MSSA bacteraemia (p=0.005). Patients with MRSA bacteraemia more seldom received adequate empirical antimicrobial therapy when compared to those with MSSA bacteraemia (13/51 vs 43/51, p<0.001). Of previously known MRSA carriers 10 of 29 received adequate empirical antimicrobial therapy for their condition. The percentage of MRSA bacteraemias among all S. aureus bacteraemias in Pirkanmaa HD is high compared to corresponding figures for the whole of Finland.


Introduction
Meticillin-resistant Staphyloccus aureus (MRSA) is a significant cause of both healthcare-and communityacquired infections [1].The spread of MRSA in hospitals and healthcare facilities is a major threat, mainly for patients with underlying conditions.Studies conducted in countries with endemic MRSA have shown that patients with MRSA bacteraemia have more comorbidities and are significantly older than those with meticillin-sensitive S. aureus (MSSA) bacteraemia [2][3][4].The worldwide emergence of MRSA-associated infections has prompted an Expert Panel of the Infectious Diseases Society of America to publish evidence-based guidelines for the management of patients with MRSA infections [1].
MRSA has emerged as a frequent pathogen isolated in severe infections such as bacteraemia, in regions previously reported to be low-prevalence areas, for example Sweden and Finland [5,6].From 1997 to 2003, the annual number of MRSA notifications to the National Infectious Disease Register in Finland rose over tenfold, and the proportion of MRSA among S. aureus blood isolates tripled, from less than 1% to 2.8% in 2004 [7].
In the Pirkanmaa Hospital District (HD), Finland, the number of new MRSA notifications has increased during the past 10 years and MRSA bacteraemia has emerged as a prevalent pathogen isolated in blood cultures.MRSA epidemics began in Pirkanmaa HD in 2001 [unpublished data].Since then, Pirkanmaa HD has conducted routine surveillance for MRSA.From 2001 to 2007, Pirkanmaa HD recommended that patients admitted in Tampere University Hospital (TAUH), the central hospital of the Pirkanmaa HD, should be screened for MRSA if they had been treated in long-term care facilities of Tampere or in high-MRSA-incidence wards in Tampere city hospitals.During recent years, from 2008 to July 2011, Pirkanmaa HD recommended that all patients admitted to hospitals/healthcare institutions should be screened for MRSA if they had been treated in any hospital, healthcare institution or long-term care unit of the Pirkanmaa HD after 2001.Since August 2011, universal screening of all patients admitted to hospitals/healthcare institutions of the Pirkanmaa HD is conducted.
We here carried out a retrospective case-control study in TAUH, Finland, to compare underlying patient characteristics and the adequacy of empirical therapy in MSSA and MRSA bacteraemias.

Pirkanmaa Hospital District
The Pirkanmaa HD is a joint municipal authority comprising 22 municipalities and responsible for healthcare services to about 477,600 inhabitants (population in year 2009).The overall population of Finland in 2009 was 5,351,427.Thus, Pirkanmaa HD provides healthcare for 9% of the total Finnish population [8].

Study population
The only central hospital in the Pirkanmaa HD area is TAUH.The present study comprised 51 patients with blood culture-confirmed MRSA bacteraemia and 51 unmatched control patients with MSSA confirmed bacteraemia admitted to TAUH, from October 2002 to January 2010.All MRSA bacteraemia patients ever treated in TAUH were included.Patients with polymicrobial bacteraemia were excluded (three cases) and only the first bacteraemia episode per patient, for those with multiple episodes was included.For each patient with MRSA bacteraemia a consecutively treated unmatched patient with MSSA bacteraemia was selected as control.Underlying diseases, clinical data and laboratory parameters were retrospectively reviewed from the hospital records.Patients were defined as previously known MRSA carriers, if their patient history indicated that MRSA had been detected by screening or in clinical samples prior to bacteraemia suspicion.Information regarding a previous MRSA finding was available in the patients` hospital records.Chronic diseases and sources of bacteraemia were registered.Alcohol-abuse was defined as a known social or medical problem due to alcohol use.Patients were defined as current smokers and non-smokers, i.e. those who had never smoked or had stopped smoking.
McCabe classification [9] was used to determine the severity of any underlying disease.

Diagnostics
In our hospital blood cultures are routinely taken in cases with symptoms or signs of systemic infection.To obtain blood for culture, two sequential samples of blood for anaerobic and aerobic culture (2 x (20+20ml)) were taken through venipuncture according to the manufacturer's instructions.The BACTEC 9240 (BD Diagnostic Systems, Sparks, MD, USA) blood culture system was used with standard media until November 2006, and the BactALERT (BacT/ALERT 3D (bioMérieux, Marcy l'Etoile, France) was used from December 2006.

Case fatality
The case fatality rate was studied within 30 days after a positive blood culture.

Antimicrobial treatment
Empirical antimicrobial treatment for MRSA was considered adequate when (i) the treatment was started or continued on the day or the day after (+1 day) the blood culture was taken, and (ii) when it was applied intravenously (with the exception of linezolid, which was considered adequate also when taken perorally) and (iii) contained at least one element with good activity against the MRSA strain in question (vancomycin, linezolid, daptomycin or teicoplanin).Intravenous clindamycin was only considered adequate when the S. aureus strain was susceptible to both clindamycin and erythromycin.Therapy against MSSA was considered adequate if it contained at least one intravenous regimen with good activity against MSSA.For one patient with MSSA bacteraemia receiving levofloxacin, which has a good bioavailability orally as an empiric regimen, the therapy was considered adequate.

Statistical analysis
An SPSS package (version 10.0) was used for statistical analyses and a two-sided p-value < 0.05 was taken as cut-off for statistical significance.Categorical data were analyzed by chi-square test or Fisher´s exact test when appropriate and nonparametric data by Mann-Whitney U-test.Odds ratios (ORs) were expressed with their 95% confidence intervals (CI).

Results
The total number of MRSA bacteraemias and the proportion of MRSA bacteraemias among all bacteraemias caused by S. aureus in Pirkanmaa HD and in TAUH have increased during the last decade (Table 1).The first  Disease severity did not differ between the two groups (Table 3).

Characteristics of patients
In 45 of 51 of MRSA bacteraemia cases, MRSA strain type was spa type t067 (FIN-16), which is the epidemic strain type in Pirkanmaa HD [unpublished data].Four of 51 were caused by spa type t172 (FIN-4) and two of 51 cases by t026/t4819 (FIN-10).
Nineteen of 51 MRSA bacteraemia patients and 22 of of MSSA bacteraemia patients were in TAUH when bacteraemia was detected.Twenty-five of 51 MSSA bacteraemia patients and 12 of 51 MRSA bacteraemia patients were admitted to hospital from home, none of the MSSA patient and six of 51 MRSA patients from a long-term care institution, four of 51 MSSA patients and three of 51 MRSA patients from a healthcare centre ward, two of 51 MSSA patients and two of 51 MRSA patients from a regional hospital and none of the MSSA patients and nine of 51 MRSA patients from Tampere city hospitals.

Antimicrobial treatment
MRSA bacteraemia patients more seldom received adequate empirical antimicrobial therapy than those with MSSA bacteraemia (13/51 vs 43/51, p<0.001).Altogether 10 of 29 of those previously known to be MRSA carriers received inadequate empirical antimicrobial therapy.Ninety-eight of 100 patients in the study eventually received adequate antimicrobial treatment after susceptibility testing became available (data for changes in antibiotic treatment were missing for two MRSA cases, these patients having been transferred to regional hospitals).The delay until adequate antimicrobial treatment had a median 0 days (range: 0-10) in MSSA bacteraemia patients and a median days (range: 0-5) in MRSA bacteraemia patients.Demographics or underlying diseases were not statistically significantly associated with the adequacy or inadequacy of antimicrobial treatment in MRSA bacteraemia (data not shown).The adequacy of treatment was not associated with the mode of admission (whether admission was direct from another hospital/healthcare facility or direct from home to hospital) (data not shown).Empirical antimicrobial therapy administered to patients is given in Table 4.

Discussion
The present study shows that in HD, a notable percentage (7-15% during recent years) of all S. aureus blood culture isolates are currently meticillin-resistant strains.The percentage of MRSA bacteraemias among all S. aureus bacteraemias in Pirkanmaa HD is high compared to corresponding figures for the whole of Finland.This may reflect the high rate of new MRSA notifications per year in our HD [7], or alternatively suggest that some regions in Finland, such as ours, are more affected by MRSA.Although Scandinavian countries including Finland have been considered low prevalence countries, substantial regional variations are common [7,10].
By retrospectively reviewing the hospital records of 102 patients with S. aureus bacteraemias, who had been admitted to TAUH from October 2002 to January 2010, we found that patients with MRSA bacteraemia were significantly older than those with MSSA and/or had higher McCabe class and/or had previous MRSA carrier status.In accordance with previous reports [2] comorbidities and healthcare facility stay were significant factors associated with the risk of MRSA bacteraemia.Interestingly, the risk factors for MRSA bacteraemia in our study did not differ from the risk factors reported in counties where MRSA is endemic [3,4].Most of MRSA bacteraemia cases in the present study were caused by the spa type t067 (FIN-16), which has caused a wide ongoing epidemic in Pirkanmaa HD since 2001.
MRSA bacteraemia was associated with an increased risk of inadequate empirical antimicrobial therapy.Inadequate empirical therapy was common also for patients previously known to be MRSA carriers.Despite a low statistical power due to a low number of patients, the present study is in line with the findings of a recent multicentre study in nine western European countries indicating that empirical antimicrobial treatment frequently fails in patients with MRSA bacteraemia [10].Cefuroxime, which is not effective in MRSA bacteraemia, has been a widely used empirical regimen among patients with community-acquired bacteraemia in Finland [11].It has been used to treat patients with common infections such as skin and soft tissue infections.Intravenous cefuroxime was by far the most common agent chosen as an empirical antibiotic therapy in S. aureus bacteraemia in this study.The present study indicates that local guidelines for empirical antimicrobial therapy should be updated for MRSA endemicity, guidelines should be made available on the internet and doctors should be widely informed on the new guidelines to be published.This may be done for example in the form of an electronic bulletin.MRSA is a potential cause of severe infections in MRSA carriers.Vancomycin is now recommended empirically for all previously known MRSA carriers with suspected or documented sepsis or other severe infection or infection potentially caused by S. aureus (i.e.osteomyelitis,  endocarditis, post-surgery infections) in Pirkanmaa HD.Moreover, although the importance of administering an antimicrobial agent with good activity against MRSA to MRSA carriers has been highlighted in hospital hygiene education of staff in our institution, this may not be sufficient.Information regarding a previous MRSA finding has appeared in patients' electronic hospital records for many years.This information has been made more conspicuous during the last years, as an electronic alert system for MRSA has been constructed for hospital records.
Novel molecular methods may offer some advance in reducing the time frame for detecting mecA gene, the major determinant for meticillin resistance in S. aureus, in patients with S. aureus bacteraemia.These methods may be used to guide empiric antimicrobial therapy before definite culture-based susceptibility testing is available [12].Also, in the case of bacteraemia in a MRSA carrier, molecular methods for the detection of mecA gene are now adapted for clinical use to speed up microbiological diagnosis.Some limitations must be conceded here.There were altogether 92 patients with MRSA bacteraemias in Pirkanmaa HD during the period 2001 to January 2010 (Table 1), most of these patients having been treated in TAUH.However, we did not study the hospital records of patients treated in other hospitals than TAUH.Only one bacteraemia episode (the first) per patient was included in the study and patients with polymicrobial bacteraemias were excluded.As the study was retrospective by design, the data regarding socioeconomic status and travel history were not acquirable.The data regarding the number of days of hospital prior to bacteraemia and data regarding a contact with a known MRSA carrier could not be obtained.Although not done in the present study, the use of total MSSA bacteraemia patients (2001-2010) as a control group would have increased the statistical power of this study.
The present study is a case-control study with regard to the assessment of risk factors for meticillin resistance.The study was not designed to assess comparative outcomes, effects of appropriate vs. inappropriate empirical treatment or risk factors for death.The risk factors for meticillin resistance were studied because the case-control patients here were not matched for age, sex or other characteristics.Some work indicates that advanced age would be a significant factor associated with the adequacy of empirical therapy in MRSA bacteraemia [13], but this was not confirmed in the present study.

Table 1
Meticillin-resistant Staphylococcus aureus bacteraemias relative to all Staphylococcus aureus bacteraemias, in Tampere University Hospital, Pirkanmaa hospital districtand Finland, Finland, 2001-2010 [7]A: meticillin-resistant Staphylococcus aureus; NR: Not reported.aAbacteraemiamay have been reported more than once if the time between the bacteraemia episodes in a patient was ≥ 3 months.bValuesforFinland are according to[7].patientwith MRSA bacteraemia in TAUH was diagnosed in October 2002.

Table 2
Characteristics and underlying conditions of patients with Staphylococcus aureus bacteraemia, Tampere University Hospital, Finland, October 2002-January 2010 (n=102) MSSA: meticillin-sensivite Staphylococcus aureus; MRSA: meticillin-resistant Staphylococcus aureus.a McCabe class≥2: rapidly or ultimately fatal underlying disease.b Coronary artery disease, valvular heart disease, cardiac myopathy or congestive heart failure.c Data available for 64 patients.d ≥5mg/day of systemic prednisolone (or equivalent dose of another corticosteroid) during the preceding 30 days.e Data available for 94 patients, 48 with MRSA and 46 with MSSA.f Data available for 80 patients, 47 with MRSA and 33 with MSSA.

Table 3
Case fatality, sources of bacteraemia and adequacy of treatment in patients with Staphylococcus aureus bacteraemia, Tampere University Hospital, Finland, October 2002-January 2010 (n=102) a The case fatality rate was studied within 30 days after a positive blood culture.