Methicillin-sensitive Staphylococcus aureus bacteremia in aged patients: the importance of formal infectious specialist consultation

Methicillin-sensitive Staphylococcus aureus bacteremia in aged patients: the importance of formal... Background Infectious specialist consultations (ISC) provide ever more evidence for improved outcome in Staphylococcus aureus bacteremia (SAB). Most ISC are formal (bedside). However, the impact of ISC on clinical management and prognosis lacks evaluation in aged patients with SAB. Methods Multicenter retrospective analysis of methicillin-sensitive (MS) SAB. Patients were stratified according to age ≥ 60 years (sub-analyses for ≥ 75 years and females) and formal (bedside) ISC given within 7 days of SAB diagnosis. The impact on management and outcome of formal ISC was explored. Statistics were performed with univariate analysis, Cox proportional hazards regression model analysis, including propensity-score adjustment, and graphic Kaplan–Meier interpretation. Results Altogether 617 patients were identified and 520 (84%) had formal ISC. Presence of formal ISC resulted in equiva - lent clinical management regardless of age over or under 60 years: localization and eradication of infection foci (80 vs. 82% and 34 vs. 36%) and use of anti-staphylococcal antibiotics (65 vs. 61%). Patients aged ≥ 60 years managed without formal ISC, compared to those with formal ISC, had less infection foci diagnosed (53 vs. 80%, p < 0.001). Lack of formal ISC in patients aged ≥ 60 years resulted in no infection eradication and absence of first-line anti-staphylococcal antibiotics. Formal ISC, compared to absence of formal ISC, lowered mortality at 90 days in patients aged ≥ 60 years (24 vs. 47%, p = 0.004). In Cox proportional regression, before and after propensity-score adjustment, formal ISC was a strong positive prognostic parameter in patients aged ≥ 60 years (HR 0.45; p = 0.004 and HR 0.44; p = 0.021), in patients aged ≥ 75 years (HR 0.18; p = 0.001 and HR 0.11; p = 0.003) and in female patients aged ≥ 75 years (HR 0.13; p = 0.005). Conclusion Formal ISC ensures proper active clinical management irrespective of age and improve prognosis in aged patients with MS-SAB. Keywords S. aureus bacteremia · High age · Infectious specialist consultation · Deep infection Introduction improved clinical management of SAB. ISC enhances choice and duration of antibiotic treatment [6] and accelerate radio- Staphylococcus aureus causes severe community- and logical diagnostics [7], localization [8] and eradication [9] healthcare-acquired bacteremia (SAB) [1, 2]. Despite anti- of infection foci. Most ISC are given formal (bedside) and staphylococcal agents, new potent antimicrobials, and identi- the superiority of formal ISC over other forms, e.g. informal fication and eradication of infection foci [ 3, 4], the mortality (telephone) ISC, has been demonstrated [10]. However, most in SAB remains high and ranges up to 30% [5]. Consul- important, ISC improve outcome of SAB [7–10]. tation by infectious specialist (ISC) provides evidence for There is a rapid expansion of the geriatric population in the Western countries [11] with rising incidences of SAB among older persons [12, 13]. Specific characteristics have * E. Forsblom been identified: aged SAB patients are comorbid, bactere - erik.forsblom@helsinki.fi mia often hospital-acquired and the mortality high [14, 15]. However, few studies have compared clinical management Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Central and prognosis of aged versus young SAB patients and in Hospital, Aurora Hospital, Nordenskiöldinkatu 26, Building many reports parameters that may influence prognosis, e.g. 5, P.O. Box 348, 00029 HUS Helsinki, Finland Vol.:(0123456789) 1 3 356 European Geriatric Medicine (2018) 9:355–363 essential diagnostics, are unreported or performed rarely [21]. Formal ISC was defined as bedside consultation within and deep infection foci documented scarcely or not iden- 1 week of SAB diagnosis by infectious specialist including: tified [16– 19]. The presence of ISC has been recorded in review of patient records and physical investigation with only three studies on aged patients with SAB reporting that comprehensive written directives into patient records on patients were managed in conjunction with an ISC or that clinical management. an ISC assisted in evaluating the source of SAB [14, 18], whereas one report concluded that aged patients were less Antibiotic therapy likely to receive ISC guidance [19]. However, despite certi- fication that ISC improve prognosis, the nature of ISC and The standard antibiotic therapy was anti-staphylococcal the impact of ISC on clinical management and outcome have penicillin cloxacillin. Patients with penicillin contradictions been neglected in previous reports on aged patients with received cephalosporin, either cefuroxime of ceftriaxone, SAB [14–19]. as a first-line alternative therapy, or vancomycin, clindamy - The objective was to explore how formal ISC impacts cin or a carbapenem as second-line choice. Rifampicin and/ clinical management and prognosis of aged patients with or fluoroquinolone were provided as an adjunctive therapy. methicillin-sensitive (MS) SAB. Main analyses were per- Antibiotic therapy was regarded correct when given intra- formed with patients aged  ≥  60  years and sub-analyses venously for at least 28 days for a deep infection focus and with patients aged ≥ 75 years and aged female patients. The 14 days in the absence of deep infection. Detailed informa- inclusion of MS-SAB only enabled a setting where each tion on indications, dosages and administration routes for patient received appropriate antimicrobial therapy and thus antibiotic therapy has been provided in previous studies [22]. differences in empirical antibiotic therapy could be avoided. Statistical analyses Materials and methods Categorical variables were compared with Pearson’s X test and non-categorical variables with Student’s t-test. Odds Study population ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Univariate factors with Multicenter and retrospective study with 90 days follow-up p < 0.1 were entered into Cox regression model (propor- was performed. All adult patients with at least one blood tional hazards regression). Furthermore, a propensity-score culture for MS-SAB from five universities and seven central adjusted Cox regression model analysis was performed to hospitals in Finland during January 1999–May 1999 and evaluate the explicit prognostic impact of formal ISC in aged January 2000–August 2002 were recruited. Furthermore, as patients. First, propensity-scores were estimated by logistic an extension, each adult patient with positive blood culture regression and variables with significant connection to ISC for S. aureus from Helsinki University Hospital in Finland identified. Second, a propensity-score adjusted Cox regres- in 2006–2007 was included. Two time-periods were manda- sion analysis was performed for prognostic parameters of tory to account for possible temporary differences in treat- 90-day outcome. Tests were two-tailed and p < 0.05 consid- ment management. Documentation included: gender, age, ered significant. Analyses were done with SPSS 12.0 (SPSS diseases, infection acquisition, illness severity, antibiotic Inc., Chicago, IL, USA). therapy, infection foci, ISC, outcome and autopsy results. The primary outcome was mortality at 90 days. Secondary outcome measures were identification and eradication of Results infection foci and time to defervescence. Exclusions were: age < 18 years, pregnancy, epilepsy, bacteremia 28 days Patient characteristics prior to the study and poly-microbial bacteremia. A total of 617 SAB patients were identified. Altogether 46% Definitions (286) were aged ≥ 60 years. Formal ISC was provided to 87% (250) of patients aged ≥ 60 years and 82% (270) of Healthcare-acquired SAB was defined as bacteremia patients aged < 60 years (Fig. 1). When comparing patients with the first positive blood culture for S. aureus received aged ≥ 60 years according to presence of formal ISC, no (1) ≥ 48 h after hospital admission or (2) within 48 h of hos- differences were seen regarding gender, SAB acquisition, pital admission with a preceding previous hospital discharge previous hospitalization or underlying diseases. However, within 1 week. Diseases were classified with McCabe’s cri- among patients receiving formal ISC, those aged ≥ 60 years, teria [20]. Severe sepsis was categorized as sepsis in com- compared to those < 60 years, had more healthcare-acquired bination with hypotension, hypo-perfusion or organ failure SAB (63 vs. 44%), more previous hospitalization (62 vs. 1 3 European Geriatric Medicine (2018) 9:355–363 357 Fig. 1 Study profile. Pres- 617 patients with entation of 617 methicillin- Staphylococcus aureus sensitive Staphylococcus aureus bacteremia (SAB) bacteremia patients stratified according to break-point age of 60 years and presence of formal Age ≥ 60 years Age < 60 years (bedside) infectious specialist consultation (ISC) into different n = 286 (46) n = 331 (54) groups (groups 1–4) Group 1 Group 2 Group 3 Group 4 ISC provided No ISC ISCprovided No ISC n = 250 (87) n = 36 (13) n = 270 (82) n = 61 (18) 42%) and less healthy or non-fatal underlying diseases (61 Antibiotic therapy vs. 85%) (p < 0.001). A total of 9% (56) had severe sepsis at blood culture collection. No differences in severe sepsis All patients were provided with an intravenous standard anti- were observed for patients aged over or under 60 years when microbial agent effective in vitro against S. aureus blood compared according to presence of formal ISC (Table 1). isolate from the first day of the positive blood culture: 53% (327) received standard antibiotic cloxacillin, 37% (228) Deep infection foci cefuroxime or ceftriaxone and 2% (12) vancomycin. The remaining received clindamycin or a carbapenem. Adjunc- Deep infection foci were identified in 75% (463) of patients. tive rifampicin and fluoroquinolone therapy was provided In patients aged ≥ 60 years, presence of formal ISC, com- to altogether 57 and 49% of patients aged  ≥  60  years, pared to lack of formal ISC, resulted in more deep infection respectively. The total intravenous antibiotic duration foci (80 vs. 53%, p < 0.001), osteomyelitis or septic arthri- for patients aged  ≥  60  years receiving formal ISC was tis (38 vs. 8%) and deep abscesses (34 vs. 6%) (p = 0.001) 24.6 ± 13 (days ± SD) and for patients managed without localized. However, when comparing formal ISC for patients formal ISC 19.8 ± 15 (days ± SD) (p = 0.038). Formal ISC aged ≥ 60 years with those aged < 60 years, no difference resulted in equal treatment with cloxacillin, cephalosporin was seen in the presence of deep infection foci (80 vs. 82%) and adjunctive antibiotics fluoroquinolone or rifampicin or peripheral or central venous catheters (18 vs. 12%), for patients aged over or under 60 years. None of patients whereas deep abscesses were encountered less (34 vs. 53%, aged  ≥  60  years that were managed without formal ISC p = 0.001) and foreign body infections more (24 vs. 10%, received cloxacillin as first-line antibiotics. Moreover, p = 0.001) (Table 1). administration of cephalosporins or other antibiotics as first-line choice was less common among patients aged ≥ 60 Clinical management receiving formal ISC compared to those managed without formal ISC (28 vs. 75% and 7 vs. 25%, p < 0.001) (Table 1). Trans-thoracic and trans-esophageal echocardiography (TTE and TEE) were provided to 64% (183) and 20% (57) Time to defervescence of patients aged  ≥  60  years. No difference in access to TTE was seen according to age over or under 60 years or Data for time to defervescence was retrieved for 578 presence or absence of formal ISC. However, in patients patients. Patients aged ≥ 60 years, compared to patients aged ≥ 60 years formal ISC, compared to lack of formal aged < 60 years, had shorter mean time to defervescence ISC, resulted in more TEE (22 vs. 6%, p  = 0.021). For- (days ± SD) (5.1 ± 7.7 vs. 7.2 ± 10.1) (p = 0.006) (Fig. 2). mal ISC resulted in active infection eradication in patients The impact of clinical management on defervescence in aged aged ≥ 60 years including infection removal (34%), heart patients was explored by categorizing time to defervescence valve replacement (< 1%) and joint lavage (3%). Formal according to cut-off value of 7 days. However, formal ISC ISC gave access to infection foci removal irrespective of age and localization or eradication of infection did not affect over or under 60 years. However, infection eradication was fever time in patients aged ≥ 60 years (Table 2). not provided to patients aged ≥ 60 years managed without formal ISC (Table 1). 1 3 358 European Geriatric Medicine (2018) 9:355–363 Table 1 Patient demographics, severity of illness, clinical management and outcome in 617 methicillin-sensitive Staphylococcus aureus bactere- mia patients stratified according to break-point age of 60 years and presence of formal (bedside) infectious specialist consultation (ISC) Patient characteristics Group 1 Group 2 Group 3 Group 1 vs. group 2 Group 1 vs. group 3 ≥ 60 years ≥ 60 years < 60 years OR (95% CI) p value OR (95% CI) p value Formal ISC present Formal ISC absent Formal ISC present n = 250 n = 36 n = 270 Demographics  Male sex 144 (58) 23 (64) 182 (67) 0.77 (0.37–1.59) 0.47 0.65 (0.46–0.94) 0.21  Age, years 72.6 ± 7.6 71.1 ± 7.9 43.0 ± 12.3 – 0.29 – < 0.001  Healthcare-acquired 157 (63) 19 (53) 118 (44) 1.51 (0.75–3.05) 0.25 2.18 (1.53–3.09) < 0.001  Previous 154 (62) 25 (69) 114 (42) 0.71 (0.33–1.50) 0.36 2.19 (1.55–3.12) < 0.001 hospitalization  Healthy-nonfatal 153 (61) 19 (53) 230 (85) 1.41 (0.69–2.85) 0.34 0.27 (0.18–0.42) < 0.001  Severe sepsis 21 (8) 5 (14) 18 (7) 0.57 (0.20–1.62) 0.28 1.28 (0.67–2.47) 0.45 Infection foci  Deep infections 200 (80) 19 (53) 222 (82) 3.58 (1.74–7.38) < 0.001 0.87 (0.56–1.34) 0.52  Pneumonia 99 (40) 12 (33) 103 (38) 1.31 (0.63–2.74) 0.47 1.06 (0.75–1.51) 0.73  Endocarditis 39 (16) 2 (6) 47 (17) 3.14 (0.73–13.6) 0.11 0.88 (0.55–1.39) 0.58  Osteomyelitis 94 (38) 3 (8) 110 (41) 6.63 (1.98–22.2) 0.001 0.87 (0.61–1.24) 0.44  Deep abscesses 85 (34) 2 (6) 143 (53) 8.76 (2.05–37.3) 0.001 0.46 (0.32–0.65) 0.001  Any foreign body 59 (24) 4 (11) 27 (10) 2.47 (0.84–7.27) 0.09 2.78 (1.69–4.55) 0.001 infection  Infected PVC or CVC 45 (18) 0 32 (12) – – 1.48 (0.89–2.44) 0.12 Clinical management  TTE 165 (66) 19 (53) 174 (64) 1.74 (0.86–3.51) 0.12 1.07 (0.75–1.54) 0.71 echocardiography  TEE 55 (22) 2 (6) 54 (21) 4.79 (1.12–20.6) 0.021 1.13 (0.74–1.72) 0.58 echocardiography  Any infection foci 84 (34) 0 94 (36) – – 0.95 (0.66–1.36) 0.77 removal  Heart valve replace- 2 (< 1) 0 4 (1) – – 0.54 (0.09–2.95) 0.47 ment  Infected joint lavage 7 (3) 0 6 (2) – – 1.27 (0.42–3.82) 0.67 Standard antibiotics  Cloxacillin 163 (65) 0 165 (61) – – 1.19 (0.83–1.70) 0.33  Cephalosporin 70 (28) 27 (75) 85 (31) 0.13 (0.06–0.29) < 0.001 0.85 (0.58–1.23) 0.39  Other antibiotics 17 (7) 9 (25) 20 (7) 4.57 (1.87–11.2) < 0.001 1.09 (0.56–2.14) 0.79  Treatment duration 24.6 ± 13 19.8 ± 15 26.1 ± 12 – 0.038 – 0.19 Adjunctive antibiotics  Fluoroquinolone 129 (52) 11 (31) 136 (50) 2.42 (1.14–5.14) 0.018 1.05 (0.75–1.48) 0.78  Rifampicin 152 (61) 11 (31) 175 (65) 3.53 (1.66–7.49) 0.001 0.84 (0.59–1.20) 0.34 Outcome  Hospital duration 38.7 ± 34 31.6 ± 26 32.7 ± 29 – 0.09 – 0.10  Mortality in 28 days 46 (18) 11 (31) 12 (4) 0.51 (0.24–1.12) 0.088 4.85 (2.50–9.39) < 0.001  Mortality in 90 days 61 (24) 17 (47) 21 (8) 0.36 (0.18–0.74) 0.004 3.83 (2.25–6.51) < 0.001 Altogether 61 (18%) patients were aged < 60 years and received no formal ISC and are omitted in the presentation. Values are expressed as num- ber of patients (%), odds ratios (ORs) with 95% confidence intervals (CI) and mean ± standard deviation (SD) Student’ s t test (mean ± SD) Within 2 months preceding SAB McCabe’s classification [20] At blood culture collection Including septic arthritis Peripheral or central venous catheter Thoracic or –esophageal Days (mean ± SD) 1 3 European Geriatric Medicine (2018) 9:355–363 359 prognosis were lack of underlying diseases (OR 0.27, p < 0.001), formal ISC (OR 0.36, p = 0.004) and adjunc- tive rifampicin therapy (OR 0.31, p < 0.001), whereas poor prognosis connected to severe sepsis (OR 2.52, p = 0.023), endocarditis (OR 2.41, p = 0.01) and pneumonia (OR 3.98, p < 0.001) (Table 3a). In Cox proportional regression analy- sis lack of underlying diseases (HR 0.38, p < 0.001), formal ISC (HR 0.45, p = 0.004) and adjunctive rifampicin therapy (HR 0.32, p < 0.001) were positive prognostic parameters, whereas severe sepsis (HR 1.98, p = 0.039), endocarditis (HR 2.09, p = 0.01) and pneumonia (HR 2.58, p < 0.001) were associated to poor prognosis (Table  3). When Cox proportional regression was repeated by including only patients aged ≥ 75 years or including only female patients aged ≥ 75 years, the positive prognostic impact of formal ISC remained (HR 0.18, p = 0.001 and HR 0.13, p = 0.005). In propensity-score-adjusted Cox proportional analysis, Fig. 2 Kaplan–Meier analysis for time to defervescence (days) in 578 methicillin-sensitive Staphylococcus aureus bacteremia patients cat- parameters for 90-days outcome were: formal ISC (HR 0.44, egorized according to the break-point age 60 years. Log rank = 0.006 p = 0.021), lack of underlying diseases (HR 0.37, p < 0.001), severe sepsis (HR 1.99, p = 0.039), endocarditis (HR 2.06, p = 0.014), pneumonia (HR 2.57, p < 0.001) and rifampicin Outcome adjunctive therapy (HR 0.31, p < 0.001) (Table 4). When propensity-score-adjusted Cox proportional regression The total hospital duration for patients aged  ≥  60  years receiving formal ISC was 38.7 ± 34 (days ± SD) and for was repeated by including only patients aged ≥ 75 years or including only female patients aged ≥ 75 years, the impact patients managed without formal ISC 31.6 ± 26 (days ± SD) (p value = 0.09). The overall case fatality in 617 patients was of formal ISC remained (HR 0.11, p = 0.003 and HR 0.13, p = 0.005). 13% at 28 days and 19% at 90 days. Patients aged ≥ 60 years receiving formal ISC, compared to those without, had To further evaluate differences between patients aged over or under 60 years, autopsy results were examined for lower mortality at 28 days (18 vs. 31%, p = 0.088) and at 90 days (24 vs. 47%, p = 0.004) (Table 1). Parameters for altogether 57 patients. The immediate causes of death were stratified according to age. For patients aged < 60 years 90-days mortality in patients aged ≥ 60 years were evaluated (Table 3a, b). In univariate analysis, factors with positive (n  =  15), the three most common immediate causes of Table 2 The impact of Clinical management Time to defervescence clinical management on time to defervescence stratified < 7 days ≥ 7 days OR (95% CI) p value according to cut-off value n = 227 (85) n = 41 (15) of 7 days in 268 methicillin- Formal ISC 209 (92) 35 (85) 1.99 (0.74–5.36) 0.17 sensitive Staphylococcus aureus bacteremia patients Deep infection 173 (76) 35 (85) 0.55 (0.22–1.38) 0.19 aged ≥ 60 years Endocarditis 34 (15) 7 (17) 0.86 (0.35–2.09) 0.73 Pneumonia 86 (38) 19 (46) 0.71 (0.36–1.38) 0.31 Osteomyelitis 81 (36) 14 (34) 1.07 (0.53–2.16) 0.85 Foreign body infection 52 (23) 8 (20) 1.23 (0.53–2.82) 0.63 Surgical-radiological infection 74 (33) 10 (24) 1.49 (0.69–3.22) 0.29 removal Heart valve replacement 2 (1) 0 – – Infected joint lavage 7 (3) 0 – – Values are expressed as number of patients (%) and odds ratios (ORs) with 95% confidence intervals (CI) or mean ± standard deviation according to Student’s t test Including septic arthritis 1 3 360 European Geriatric Medicine (2018) 9:355–363 Table 3 Cox proportional Patient characteristics Outcome Univariate analysis Cox regression regression for prognostic factors of 90-day mortality Died Survived OR (95% CI) p value HR (95% CI) p value in methicillin-sensitive n = 78 (27) n = 208 (73) Staphylococcus aureus Male sex 46 (59) 121 (58) 1.03 (0.61–1.75) NS – – bacteremia patients aged ≥ 60 years (n = 286) Healthcare-acquired 48 (62) 128 (62) 1.00 (0.59–1.71) NS – – Healthy—nonfatal 29 (37) 143 (69) 0.27 (0.16–0.46) < 0.001 0.38 (0.24–0.61) < 0.001 Severe sepsis 12 (15) 14 (7) 2.52 (1.11–5.72) 0.023 1.98 (1.04–3.79) 0.039 Formal ISC 61 (78) 189 (91) 0.36 (0.18–0.74) 0.004 0.45 (0.26–0.78) 0.004 Endocarditis 18 (23) 23 (11) 2.41 (1.22–4.77) 0.01 2.09 (1.19–3.64) 0.01 Pneumonia 49 (63) 62 (30) 3.98 (2.30–6.88) < 0.001 2.58 (1.59–4.18) < 0.001 d,e Rifampicin 20 (26) 110 (53) 0.31 (0.17–0.55) < 0.001 0.32 (0.19–0.54) < 0.001 35 (45) 105 (50) 0.79 (0.47–1.35) NS – – Fluoroquinolone Values are expressed as number of patients (%) and odds ratios (OR), hazards ratio (HR) and 95% confi- dence intervals (95% CI) are presented NS non-significant McCabe’s classification [20] At blood culture collection time-point Infectious specialist consultation Adjunctive therapy For at least 14 days Table 4 Propensity-score-adjusted Cox proportional regression Discussion analysis for 90-day mortality in methicillin-sensitive Staphylococcus aureus bacteremia patients aged  ≥  60  years (n  =  286) according to The main observations were that formal ISC ensures infectious specialist consultation proper clinical management irrespective of age and for- Patient characteristics Propensity-score-adjusted mul- p value mal ISC improves prognosis of aged patients with MS- tivariate analysis HR (95% CI) SAB. Accounting for all prognostic parameters, patients Absence of formal ISC 1.0 – aged  ≥  60  years, patients aged  ≥  75  years and female Presence of formal ISC 0.44 (0.22–0.88) 0.021 patients aged ≥ 75 years, had a more than twofold lower Healthy—nonfatal 0.37 (0.23–0.60) < 0.001 odds ratio for a fatal outcome due to formal ISC. Severe sepsis 1.99 (1.03–3.81) 0.039 Previous reports connect ISC to improved antibiotic Endocarditis 2.06 (1.16–3.67) 0.014 therapies, accelerated diagnostics and eradications of deep Pneumonia 2.57 (1.58–4.17) < 0.001 infection foci and better outcomes in SAB [6–10, 23]. Cor- d,e Rifampicin 0.31 (0.18–0.54) < 0.001 responding observations were seen in the present study. We provided formal ISC within 7 days of SAB diagnosis and, Infectious specialist consultation among patients aged ≥ 60 years, this resulted in echocardi- McCabe’s classification [20] ography in up to 66%, deep infection foci identification in At blood culture collection time-point 80% and infection eradication provided to 34% of patients. Adjunctive therapy Formal ISC resulted in radiological infection diagnostics, For at least 14 days localization and eradication irrespective of age over or under 60 years. However, patients aged ≥ 60 years managed with- out formal ISC had less infection foci diagnosed and were death were acute subarachnoid or gastrointestinal hemor- provided no infection foci eradications compared to those rhages (43%), severe sepsis (20%) or pneumonia (20%). receiving formal ISC. Similar trends were observed also for For patients aged ≥ 60 years (n = 42), the corresponding antibiotics. Patients aged ≥ 60 years managed by formal ISC causes were SAB with or without a background condition had anti-staphylococcal penicillin as first-line alternative in (43%), acute cardio-pulmonary disease (21%) or deep infec- 2/3 of cases, whereas cephalosporins or other antibiotics tion (19%). Altogether, the immediate causes of death were were used in under 1/3 and adjunctive antibiotics in over infection related in 67% of patients aged ≥ 60 years and 60% 50% of cases. Most important, formal ISC resulted in anti- in patients aged < 60 years. biotic therapies irrespective of age over or under 60 years. Contrary, no of patients aged ≥ 60 years managed without 1 3 European Geriatric Medicine (2018) 9:355–363 361 formal ISC had anti-staphylococcal penicillin as first-line fluoroquinolone therapy did not impact outcome and this is antibiotics, whereas 3/4 had cephalosporins as first-line in line with previous observations [22]. alternative and adjunctive antibiotics were provided in only Previous studies on aged SAB patients do not report 1/3 of cases. fever [14–16, 18, 24], whereas two studies reported that Deep infection foci have been identified in only 14–31% aged SAB patients were more likely to be afebrile prior of aged patients in earlier studies on SAB [14–16, 18, 24]. to SAB [17, 19]. In the present study, defervescence was Previous reports have stated that aged SAB patients are significantly shorter for aged patients compared to young. less likely to receive ISC, echocardiography or infection We have previously shown that ISC reduced fever duration foci identification or eradication, and extensive diagnostics in SAB [10]. However, in the present study clinical man- have not been pursued in aged patients due to presumed agement or formal ISC had no impact on defervescence poor outcome [17, 19, 24, 25]. To the best of our knowl- in patients aged ≥ 60 years. Hence, time to defervescence edge, only three studies report presence of ISC stating that among patients aged ≥ 60 years does not seem to correlate patients were managed in conjunction with an ISC [14, 18], with treatment strategies. whereas one report concluded that aged patients were less MRSA weakens prognosis [27] and MRSA in previous likely to receive ISC guidance [19]. However, the content or reports on aged SAB patients has been as much as 52–100% nature of ISC or the impact of ISC on disease progression [14–16, 18]. We included only MS-SAB. Thus, patients or prognosis was not evaluated [14, 18, 19]. The importance had proper antibiotic therapy from the first day of positive of infection identification and eradication in SAB has been blood culture excluding bias from differences in empiri- confirmed [4 , 26] and lack of echocardiography and undiag- cal antibiotic therapy. In the present study 1/2 of patients nosed infection foci have been suspected to connect to mor- aged ≥ 60 years received adjunctive rifampicin therapy. We tality in aged SAB patients [14, 17]. Autopsy examinations have shown that rifampicin adjunctive therapy may impact in the present study revealed that for deceased patients both prognosis positively [22, 28]. However, among patients bacteremia and deep infection foci account for a larger part aged  ≥  60  years, the risk of drug interactions may have of mortalities of aged patients compared to young ones. The resulted in a selection bias favoring rifampicin treatment present study demonstrate that formal ISC-guided clinical in less comorbid patients and hence, the potential positive management result in frequent localization and eradication prognostic impact of rifampicin in aged patients should be of deep infection with subsequent positive prognostic impact interpreted with caution. The authors recommend that pro- in aged patients with SAB. spective randomized clinical trials evaluate the potential Comparison of prognosis in aged and young SAB patients advantage of rifampicin therapy before it can be routinely is challenging due to differences in age categorizations and recommended as part of treatment of aged patients with reported follow-up time and in earlier studies. We applied SAB. break-point ages of 60 and 75 years with mortality rates There are weaknesses in the present study that have to for patients aged over 60 years at 28 and 90 days of 18 and be accounted for when interpreting results. First, the ret- 24% for patients managed by formal ISC and 31 and 47% rospective design includes risk for bias due to differences for patients not receiving formal ISC. Previous reports have in patient groups. However, propensity-score adjustment presented results according to mean ages of 63–85 years may reduce potential bias [29]. Second, aged infectious [14, 15] or break-point age of 60–65 years [16, 18, 19]. In patients may lack fever and present non-specific symptoms. older patients, the mortalities have varied considerably with Moreover, declined functional status has been connected to 15% at 7 days [15], 11–36% at 30 days [18, 24], 29% at mortality among aged infectious patients [30]. Correspond- 90 days [17] and 33–56% at 6 months [14]. The present ing data were not recorded. Third, the patient cohort of the study observed higher fatalities for aged patients com- present study was originally collected to investigate trends pared to young. This is in line with earlier reports [16, 17, of nosocomial SAB and prognostic impact of fluoroqui- 19, 24] but deviate from one study with no link between nolones, rifampicin and ISC [10, 12, 22, 28]. However, the age and clinical outcome [18]. Previous reports have pre- authors noticed that, although the incidence of SAB among sented age, comorbidity, MRSA and unknown bacteremia older persons is rising, the prognostic impact of ISC has not source as independent parameters for mortality among aged been extensively evaluated among aged patients with SAB. patients with SAB [14, 16, 17, 19, 24]. Parameters influ- Regarding the earlier time-period of the patient cohort, the encing outcome in patients aged ≥ 60 years in the present question of whether the patient data in the present study is study have been identified earlier in SAB patient cohorts valid to current clinical practice may be raised. Management without age specification, i.e. comorbidity [5 , 6], sever- of SAB is continuously developed, however, fundamental ity of illness [7], ISC [7–10], pneumonia or endocarditis elements of SAB management remain unchanged over the [7, 10] and rifampicin therapy [22]. Moreover, adjunctive years, e.g. the importance of proper non-delayed antibiotic therapy and diagnostics of infection foci. The authors view 1 3 362 European Geriatric Medicine (2018) 9:355–363 6. Pragman AA, Kuskowski MA, Abraham JM, Filice GA (2012) that the high presence of formal ISC has ensured record- Infectious disease consultation for Staphylococcus aureus bac- ing of relevant data and high-standard management of SAB. teremia improves patient management and outcomes. Infect Dis Hence, the authors conclude that the patient data are not Clin Pract 20:261–267 outdated for current clinical practice. 7. Rieg S, Peyerl-Hoffmann G, de With K (2009) Mortality of S. aureus bacteremia and infectious diseases specialist consulta- tion—a study of 521 patients in Germany. J Infect 59:232–239 8. Robinson JO, Pozzi-Langhi S, Phillips M, Pearson JC, Chris- Conclusion tiansen KJ, Coombs GW et al (2012) Formal infectious diseases consultation is associated with decreased mortality in Staphy- lococcus aureus bacteraemia. Eur J Clin Microbiol Infect Dis Formal ISC ensures proper and active clinical management 31:2421–2428 irrespective of age and improve prognosis in aged patients 9. Lahey T, Shah R, Gittzus J, Schwartzman J, Kirkland K (2009) with MS-SAB. The authors encourage clinicians to manage Infectious disease consultation lowers mortality from Staphylo- aged patients with MS-SAB through formal ISC guidance. coccus aureus bacteremia. Medicine 88:263–267 10. Forsblom E, Ruotsalainen E, Ollgren J, Järvinen A (2012) Tel- ephone consultation cannot replace bedside infectious disease Funding The study has been supported by Grants from Helsinki Uni- consultation in the management of Staphylococcus aureus bac- versity Central Hospital, the Medical Society of Finland and Svenska teraemia. Clin Infect Dis 56:527–535 Kulturfonden. The funders had no role in study design, data collection 11. National Center for Chronic Disease Prevention and Health and analysis, decision to publish, or preparation of the manuscript. Promotion DoPH, CDC (2013) The state of aging and health in The study was funded by Maud Kuistila Foundation and Perkléns America 2013 Foundation. 12. Lyytikäinen O, Ruotsalainen E, Järvinen A, Valtonen V, Ruutu P (2005) Trends and outcome of nosocomial and community- Compliance with ethical standards associated bloodstream infections due to Staphylococcus aureus in Finland, 1995–2001. Eur J Clin Microbiol Infect Dis 24:399–404 Conflict of interest The authors declare that they have no conflict of 13. Benfield T, Espersen F, Frimodt-Møller N, Jensen AG, Larsen interest. AR, Pallesen LV et al (2007) Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia Ethics statement The trial was approved by The Institutional Review between 1981 and 2000. Clin Microbiol Infect 13:257–263 Board of Helsinki University Central Hospital and The Ethical Com- 14. Big C, Malani PN (2010) Staphylococcus aureus bloodstream mittee of Helsinki University Central Hospital. infections in older adults: clinical outcomes and risk factors for in-hospital mortality. 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McClelland RS, Fowler VG Jr, Sanders LL, Gottlieb G, Kong LK, as you give appropriate credit to the original author(s) and the source, Sexton DJ et al (1999) Staphylococcus aureus bacteremia among provide a link to the Creative Commons license and indicate if changes elderly vs younger adult patients: comparison of clinical features were made. and mortality. Arch Intern Med 14:1244–1247 18. Kullar R, Rybak MJ, Kaye KS (2013) Comparative epidemiology of bacteremia due to methicillin-resistant Staphylococcus aureus between older and younger adults: a propensity score analysis. References Infect Control Hosp Epidemiol 34:400–406 19. Yahav D, Schlesinger A, Shaked H (2017) Clinical presentation, 1. Jensen AG, Wachmann CH, Espersen F, Scheibel J, Skinhoj P, management and outcomes of Staphylococcus aureus bacteremia Frimodt-Moller N (2002) Treatment and outcome of Staphylo- (SAB) in older adults. Aging Clin Exp Res 29:127–133 coccus aureus bacteremia: a prospective study of 278 cases. 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Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karch- dictors of mortality in patients with bacteremia: the importance mer AW, Carmeli Y (2003) Comparison of mortality associated of functional status. J Am Geriatr Soc 46:14–18 with methicillin-resistant and methicillin-susceptible Staphylococ- cus aureus bacteremia: a meta-analysis. Clin Infect Dis 36:53–59 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Geriatric Medicine Springer Journals

Methicillin-sensitive Staphylococcus aureus bacteremia in aged patients: the importance of formal infectious specialist consultation

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Medicine & Public Health; Geriatrics/Gerontology; Internal Medicine
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Abstract

Background Infectious specialist consultations (ISC) provide ever more evidence for improved outcome in Staphylococcus aureus bacteremia (SAB). Most ISC are formal (bedside). However, the impact of ISC on clinical management and prognosis lacks evaluation in aged patients with SAB. Methods Multicenter retrospective analysis of methicillin-sensitive (MS) SAB. Patients were stratified according to age ≥ 60 years (sub-analyses for ≥ 75 years and females) and formal (bedside) ISC given within 7 days of SAB diagnosis. The impact on management and outcome of formal ISC was explored. Statistics were performed with univariate analysis, Cox proportional hazards regression model analysis, including propensity-score adjustment, and graphic Kaplan–Meier interpretation. Results Altogether 617 patients were identified and 520 (84%) had formal ISC. Presence of formal ISC resulted in equiva - lent clinical management regardless of age over or under 60 years: localization and eradication of infection foci (80 vs. 82% and 34 vs. 36%) and use of anti-staphylococcal antibiotics (65 vs. 61%). Patients aged ≥ 60 years managed without formal ISC, compared to those with formal ISC, had less infection foci diagnosed (53 vs. 80%, p < 0.001). Lack of formal ISC in patients aged ≥ 60 years resulted in no infection eradication and absence of first-line anti-staphylococcal antibiotics. Formal ISC, compared to absence of formal ISC, lowered mortality at 90 days in patients aged ≥ 60 years (24 vs. 47%, p = 0.004). In Cox proportional regression, before and after propensity-score adjustment, formal ISC was a strong positive prognostic parameter in patients aged ≥ 60 years (HR 0.45; p = 0.004 and HR 0.44; p = 0.021), in patients aged ≥ 75 years (HR 0.18; p = 0.001 and HR 0.11; p = 0.003) and in female patients aged ≥ 75 years (HR 0.13; p = 0.005). Conclusion Formal ISC ensures proper active clinical management irrespective of age and improve prognosis in aged patients with MS-SAB. Keywords S. aureus bacteremia · High age · Infectious specialist consultation · Deep infection Introduction improved clinical management of SAB. ISC enhances choice and duration of antibiotic treatment [6] and accelerate radio- Staphylococcus aureus causes severe community- and logical diagnostics [7], localization [8] and eradication [9] healthcare-acquired bacteremia (SAB) [1, 2]. Despite anti- of infection foci. Most ISC are given formal (bedside) and staphylococcal agents, new potent antimicrobials, and identi- the superiority of formal ISC over other forms, e.g. informal fication and eradication of infection foci [ 3, 4], the mortality (telephone) ISC, has been demonstrated [10]. However, most in SAB remains high and ranges up to 30% [5]. Consul- important, ISC improve outcome of SAB [7–10]. tation by infectious specialist (ISC) provides evidence for There is a rapid expansion of the geriatric population in the Western countries [11] with rising incidences of SAB among older persons [12, 13]. Specific characteristics have * E. Forsblom been identified: aged SAB patients are comorbid, bactere - erik.forsblom@helsinki.fi mia often hospital-acquired and the mortality high [14, 15]. However, few studies have compared clinical management Division of Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Central and prognosis of aged versus young SAB patients and in Hospital, Aurora Hospital, Nordenskiöldinkatu 26, Building many reports parameters that may influence prognosis, e.g. 5, P.O. Box 348, 00029 HUS Helsinki, Finland Vol.:(0123456789) 1 3 356 European Geriatric Medicine (2018) 9:355–363 essential diagnostics, are unreported or performed rarely [21]. Formal ISC was defined as bedside consultation within and deep infection foci documented scarcely or not iden- 1 week of SAB diagnosis by infectious specialist including: tified [16– 19]. The presence of ISC has been recorded in review of patient records and physical investigation with only three studies on aged patients with SAB reporting that comprehensive written directives into patient records on patients were managed in conjunction with an ISC or that clinical management. an ISC assisted in evaluating the source of SAB [14, 18], whereas one report concluded that aged patients were less Antibiotic therapy likely to receive ISC guidance [19]. However, despite certi- fication that ISC improve prognosis, the nature of ISC and The standard antibiotic therapy was anti-staphylococcal the impact of ISC on clinical management and outcome have penicillin cloxacillin. Patients with penicillin contradictions been neglected in previous reports on aged patients with received cephalosporin, either cefuroxime of ceftriaxone, SAB [14–19]. as a first-line alternative therapy, or vancomycin, clindamy - The objective was to explore how formal ISC impacts cin or a carbapenem as second-line choice. Rifampicin and/ clinical management and prognosis of aged patients with or fluoroquinolone were provided as an adjunctive therapy. methicillin-sensitive (MS) SAB. Main analyses were per- Antibiotic therapy was regarded correct when given intra- formed with patients aged  ≥  60  years and sub-analyses venously for at least 28 days for a deep infection focus and with patients aged ≥ 75 years and aged female patients. The 14 days in the absence of deep infection. Detailed informa- inclusion of MS-SAB only enabled a setting where each tion on indications, dosages and administration routes for patient received appropriate antimicrobial therapy and thus antibiotic therapy has been provided in previous studies [22]. differences in empirical antibiotic therapy could be avoided. Statistical analyses Materials and methods Categorical variables were compared with Pearson’s X test and non-categorical variables with Student’s t-test. Odds Study population ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Univariate factors with Multicenter and retrospective study with 90 days follow-up p < 0.1 were entered into Cox regression model (propor- was performed. All adult patients with at least one blood tional hazards regression). Furthermore, a propensity-score culture for MS-SAB from five universities and seven central adjusted Cox regression model analysis was performed to hospitals in Finland during January 1999–May 1999 and evaluate the explicit prognostic impact of formal ISC in aged January 2000–August 2002 were recruited. Furthermore, as patients. First, propensity-scores were estimated by logistic an extension, each adult patient with positive blood culture regression and variables with significant connection to ISC for S. aureus from Helsinki University Hospital in Finland identified. Second, a propensity-score adjusted Cox regres- in 2006–2007 was included. Two time-periods were manda- sion analysis was performed for prognostic parameters of tory to account for possible temporary differences in treat- 90-day outcome. Tests were two-tailed and p < 0.05 consid- ment management. Documentation included: gender, age, ered significant. Analyses were done with SPSS 12.0 (SPSS diseases, infection acquisition, illness severity, antibiotic Inc., Chicago, IL, USA). therapy, infection foci, ISC, outcome and autopsy results. The primary outcome was mortality at 90 days. Secondary outcome measures were identification and eradication of Results infection foci and time to defervescence. Exclusions were: age < 18 years, pregnancy, epilepsy, bacteremia 28 days Patient characteristics prior to the study and poly-microbial bacteremia. A total of 617 SAB patients were identified. Altogether 46% Definitions (286) were aged ≥ 60 years. Formal ISC was provided to 87% (250) of patients aged ≥ 60 years and 82% (270) of Healthcare-acquired SAB was defined as bacteremia patients aged < 60 years (Fig. 1). When comparing patients with the first positive blood culture for S. aureus received aged ≥ 60 years according to presence of formal ISC, no (1) ≥ 48 h after hospital admission or (2) within 48 h of hos- differences were seen regarding gender, SAB acquisition, pital admission with a preceding previous hospital discharge previous hospitalization or underlying diseases. However, within 1 week. Diseases were classified with McCabe’s cri- among patients receiving formal ISC, those aged ≥ 60 years, teria [20]. Severe sepsis was categorized as sepsis in com- compared to those < 60 years, had more healthcare-acquired bination with hypotension, hypo-perfusion or organ failure SAB (63 vs. 44%), more previous hospitalization (62 vs. 1 3 European Geriatric Medicine (2018) 9:355–363 357 Fig. 1 Study profile. Pres- 617 patients with entation of 617 methicillin- Staphylococcus aureus sensitive Staphylococcus aureus bacteremia (SAB) bacteremia patients stratified according to break-point age of 60 years and presence of formal Age ≥ 60 years Age < 60 years (bedside) infectious specialist consultation (ISC) into different n = 286 (46) n = 331 (54) groups (groups 1–4) Group 1 Group 2 Group 3 Group 4 ISC provided No ISC ISCprovided No ISC n = 250 (87) n = 36 (13) n = 270 (82) n = 61 (18) 42%) and less healthy or non-fatal underlying diseases (61 Antibiotic therapy vs. 85%) (p < 0.001). A total of 9% (56) had severe sepsis at blood culture collection. No differences in severe sepsis All patients were provided with an intravenous standard anti- were observed for patients aged over or under 60 years when microbial agent effective in vitro against S. aureus blood compared according to presence of formal ISC (Table 1). isolate from the first day of the positive blood culture: 53% (327) received standard antibiotic cloxacillin, 37% (228) Deep infection foci cefuroxime or ceftriaxone and 2% (12) vancomycin. The remaining received clindamycin or a carbapenem. Adjunc- Deep infection foci were identified in 75% (463) of patients. tive rifampicin and fluoroquinolone therapy was provided In patients aged ≥ 60 years, presence of formal ISC, com- to altogether 57 and 49% of patients aged  ≥  60  years, pared to lack of formal ISC, resulted in more deep infection respectively. The total intravenous antibiotic duration foci (80 vs. 53%, p < 0.001), osteomyelitis or septic arthri- for patients aged  ≥  60  years receiving formal ISC was tis (38 vs. 8%) and deep abscesses (34 vs. 6%) (p = 0.001) 24.6 ± 13 (days ± SD) and for patients managed without localized. However, when comparing formal ISC for patients formal ISC 19.8 ± 15 (days ± SD) (p = 0.038). Formal ISC aged ≥ 60 years with those aged < 60 years, no difference resulted in equal treatment with cloxacillin, cephalosporin was seen in the presence of deep infection foci (80 vs. 82%) and adjunctive antibiotics fluoroquinolone or rifampicin or peripheral or central venous catheters (18 vs. 12%), for patients aged over or under 60 years. None of patients whereas deep abscesses were encountered less (34 vs. 53%, aged  ≥  60  years that were managed without formal ISC p = 0.001) and foreign body infections more (24 vs. 10%, received cloxacillin as first-line antibiotics. Moreover, p = 0.001) (Table 1). administration of cephalosporins or other antibiotics as first-line choice was less common among patients aged ≥ 60 Clinical management receiving formal ISC compared to those managed without formal ISC (28 vs. 75% and 7 vs. 25%, p < 0.001) (Table 1). Trans-thoracic and trans-esophageal echocardiography (TTE and TEE) were provided to 64% (183) and 20% (57) Time to defervescence of patients aged  ≥  60  years. No difference in access to TTE was seen according to age over or under 60 years or Data for time to defervescence was retrieved for 578 presence or absence of formal ISC. However, in patients patients. Patients aged ≥ 60 years, compared to patients aged ≥ 60 years formal ISC, compared to lack of formal aged < 60 years, had shorter mean time to defervescence ISC, resulted in more TEE (22 vs. 6%, p  = 0.021). For- (days ± SD) (5.1 ± 7.7 vs. 7.2 ± 10.1) (p = 0.006) (Fig. 2). mal ISC resulted in active infection eradication in patients The impact of clinical management on defervescence in aged aged ≥ 60 years including infection removal (34%), heart patients was explored by categorizing time to defervescence valve replacement (< 1%) and joint lavage (3%). Formal according to cut-off value of 7 days. However, formal ISC ISC gave access to infection foci removal irrespective of age and localization or eradication of infection did not affect over or under 60 years. However, infection eradication was fever time in patients aged ≥ 60 years (Table 2). not provided to patients aged ≥ 60 years managed without formal ISC (Table 1). 1 3 358 European Geriatric Medicine (2018) 9:355–363 Table 1 Patient demographics, severity of illness, clinical management and outcome in 617 methicillin-sensitive Staphylococcus aureus bactere- mia patients stratified according to break-point age of 60 years and presence of formal (bedside) infectious specialist consultation (ISC) Patient characteristics Group 1 Group 2 Group 3 Group 1 vs. group 2 Group 1 vs. group 3 ≥ 60 years ≥ 60 years < 60 years OR (95% CI) p value OR (95% CI) p value Formal ISC present Formal ISC absent Formal ISC present n = 250 n = 36 n = 270 Demographics  Male sex 144 (58) 23 (64) 182 (67) 0.77 (0.37–1.59) 0.47 0.65 (0.46–0.94) 0.21  Age, years 72.6 ± 7.6 71.1 ± 7.9 43.0 ± 12.3 – 0.29 – < 0.001  Healthcare-acquired 157 (63) 19 (53) 118 (44) 1.51 (0.75–3.05) 0.25 2.18 (1.53–3.09) < 0.001  Previous 154 (62) 25 (69) 114 (42) 0.71 (0.33–1.50) 0.36 2.19 (1.55–3.12) < 0.001 hospitalization  Healthy-nonfatal 153 (61) 19 (53) 230 (85) 1.41 (0.69–2.85) 0.34 0.27 (0.18–0.42) < 0.001  Severe sepsis 21 (8) 5 (14) 18 (7) 0.57 (0.20–1.62) 0.28 1.28 (0.67–2.47) 0.45 Infection foci  Deep infections 200 (80) 19 (53) 222 (82) 3.58 (1.74–7.38) < 0.001 0.87 (0.56–1.34) 0.52  Pneumonia 99 (40) 12 (33) 103 (38) 1.31 (0.63–2.74) 0.47 1.06 (0.75–1.51) 0.73  Endocarditis 39 (16) 2 (6) 47 (17) 3.14 (0.73–13.6) 0.11 0.88 (0.55–1.39) 0.58  Osteomyelitis 94 (38) 3 (8) 110 (41) 6.63 (1.98–22.2) 0.001 0.87 (0.61–1.24) 0.44  Deep abscesses 85 (34) 2 (6) 143 (53) 8.76 (2.05–37.3) 0.001 0.46 (0.32–0.65) 0.001  Any foreign body 59 (24) 4 (11) 27 (10) 2.47 (0.84–7.27) 0.09 2.78 (1.69–4.55) 0.001 infection  Infected PVC or CVC 45 (18) 0 32 (12) – – 1.48 (0.89–2.44) 0.12 Clinical management  TTE 165 (66) 19 (53) 174 (64) 1.74 (0.86–3.51) 0.12 1.07 (0.75–1.54) 0.71 echocardiography  TEE 55 (22) 2 (6) 54 (21) 4.79 (1.12–20.6) 0.021 1.13 (0.74–1.72) 0.58 echocardiography  Any infection foci 84 (34) 0 94 (36) – – 0.95 (0.66–1.36) 0.77 removal  Heart valve replace- 2 (< 1) 0 4 (1) – – 0.54 (0.09–2.95) 0.47 ment  Infected joint lavage 7 (3) 0 6 (2) – – 1.27 (0.42–3.82) 0.67 Standard antibiotics  Cloxacillin 163 (65) 0 165 (61) – – 1.19 (0.83–1.70) 0.33  Cephalosporin 70 (28) 27 (75) 85 (31) 0.13 (0.06–0.29) < 0.001 0.85 (0.58–1.23) 0.39  Other antibiotics 17 (7) 9 (25) 20 (7) 4.57 (1.87–11.2) < 0.001 1.09 (0.56–2.14) 0.79  Treatment duration 24.6 ± 13 19.8 ± 15 26.1 ± 12 – 0.038 – 0.19 Adjunctive antibiotics  Fluoroquinolone 129 (52) 11 (31) 136 (50) 2.42 (1.14–5.14) 0.018 1.05 (0.75–1.48) 0.78  Rifampicin 152 (61) 11 (31) 175 (65) 3.53 (1.66–7.49) 0.001 0.84 (0.59–1.20) 0.34 Outcome  Hospital duration 38.7 ± 34 31.6 ± 26 32.7 ± 29 – 0.09 – 0.10  Mortality in 28 days 46 (18) 11 (31) 12 (4) 0.51 (0.24–1.12) 0.088 4.85 (2.50–9.39) < 0.001  Mortality in 90 days 61 (24) 17 (47) 21 (8) 0.36 (0.18–0.74) 0.004 3.83 (2.25–6.51) < 0.001 Altogether 61 (18%) patients were aged < 60 years and received no formal ISC and are omitted in the presentation. Values are expressed as num- ber of patients (%), odds ratios (ORs) with 95% confidence intervals (CI) and mean ± standard deviation (SD) Student’ s t test (mean ± SD) Within 2 months preceding SAB McCabe’s classification [20] At blood culture collection Including septic arthritis Peripheral or central venous catheter Thoracic or –esophageal Days (mean ± SD) 1 3 European Geriatric Medicine (2018) 9:355–363 359 prognosis were lack of underlying diseases (OR 0.27, p < 0.001), formal ISC (OR 0.36, p = 0.004) and adjunc- tive rifampicin therapy (OR 0.31, p < 0.001), whereas poor prognosis connected to severe sepsis (OR 2.52, p = 0.023), endocarditis (OR 2.41, p = 0.01) and pneumonia (OR 3.98, p < 0.001) (Table 3a). In Cox proportional regression analy- sis lack of underlying diseases (HR 0.38, p < 0.001), formal ISC (HR 0.45, p = 0.004) and adjunctive rifampicin therapy (HR 0.32, p < 0.001) were positive prognostic parameters, whereas severe sepsis (HR 1.98, p = 0.039), endocarditis (HR 2.09, p = 0.01) and pneumonia (HR 2.58, p < 0.001) were associated to poor prognosis (Table  3). When Cox proportional regression was repeated by including only patients aged ≥ 75 years or including only female patients aged ≥ 75 years, the positive prognostic impact of formal ISC remained (HR 0.18, p = 0.001 and HR 0.13, p = 0.005). In propensity-score-adjusted Cox proportional analysis, Fig. 2 Kaplan–Meier analysis for time to defervescence (days) in 578 methicillin-sensitive Staphylococcus aureus bacteremia patients cat- parameters for 90-days outcome were: formal ISC (HR 0.44, egorized according to the break-point age 60 years. Log rank = 0.006 p = 0.021), lack of underlying diseases (HR 0.37, p < 0.001), severe sepsis (HR 1.99, p = 0.039), endocarditis (HR 2.06, p = 0.014), pneumonia (HR 2.57, p < 0.001) and rifampicin Outcome adjunctive therapy (HR 0.31, p < 0.001) (Table 4). When propensity-score-adjusted Cox proportional regression The total hospital duration for patients aged  ≥  60  years receiving formal ISC was 38.7 ± 34 (days ± SD) and for was repeated by including only patients aged ≥ 75 years or including only female patients aged ≥ 75 years, the impact patients managed without formal ISC 31.6 ± 26 (days ± SD) (p value = 0.09). The overall case fatality in 617 patients was of formal ISC remained (HR 0.11, p = 0.003 and HR 0.13, p = 0.005). 13% at 28 days and 19% at 90 days. Patients aged ≥ 60 years receiving formal ISC, compared to those without, had To further evaluate differences between patients aged over or under 60 years, autopsy results were examined for lower mortality at 28 days (18 vs. 31%, p = 0.088) and at 90 days (24 vs. 47%, p = 0.004) (Table 1). Parameters for altogether 57 patients. The immediate causes of death were stratified according to age. For patients aged < 60 years 90-days mortality in patients aged ≥ 60 years were evaluated (Table 3a, b). In univariate analysis, factors with positive (n  =  15), the three most common immediate causes of Table 2 The impact of Clinical management Time to defervescence clinical management on time to defervescence stratified < 7 days ≥ 7 days OR (95% CI) p value according to cut-off value n = 227 (85) n = 41 (15) of 7 days in 268 methicillin- Formal ISC 209 (92) 35 (85) 1.99 (0.74–5.36) 0.17 sensitive Staphylococcus aureus bacteremia patients Deep infection 173 (76) 35 (85) 0.55 (0.22–1.38) 0.19 aged ≥ 60 years Endocarditis 34 (15) 7 (17) 0.86 (0.35–2.09) 0.73 Pneumonia 86 (38) 19 (46) 0.71 (0.36–1.38) 0.31 Osteomyelitis 81 (36) 14 (34) 1.07 (0.53–2.16) 0.85 Foreign body infection 52 (23) 8 (20) 1.23 (0.53–2.82) 0.63 Surgical-radiological infection 74 (33) 10 (24) 1.49 (0.69–3.22) 0.29 removal Heart valve replacement 2 (1) 0 – – Infected joint lavage 7 (3) 0 – – Values are expressed as number of patients (%) and odds ratios (ORs) with 95% confidence intervals (CI) or mean ± standard deviation according to Student’s t test Including septic arthritis 1 3 360 European Geriatric Medicine (2018) 9:355–363 Table 3 Cox proportional Patient characteristics Outcome Univariate analysis Cox regression regression for prognostic factors of 90-day mortality Died Survived OR (95% CI) p value HR (95% CI) p value in methicillin-sensitive n = 78 (27) n = 208 (73) Staphylococcus aureus Male sex 46 (59) 121 (58) 1.03 (0.61–1.75) NS – – bacteremia patients aged ≥ 60 years (n = 286) Healthcare-acquired 48 (62) 128 (62) 1.00 (0.59–1.71) NS – – Healthy—nonfatal 29 (37) 143 (69) 0.27 (0.16–0.46) < 0.001 0.38 (0.24–0.61) < 0.001 Severe sepsis 12 (15) 14 (7) 2.52 (1.11–5.72) 0.023 1.98 (1.04–3.79) 0.039 Formal ISC 61 (78) 189 (91) 0.36 (0.18–0.74) 0.004 0.45 (0.26–0.78) 0.004 Endocarditis 18 (23) 23 (11) 2.41 (1.22–4.77) 0.01 2.09 (1.19–3.64) 0.01 Pneumonia 49 (63) 62 (30) 3.98 (2.30–6.88) < 0.001 2.58 (1.59–4.18) < 0.001 d,e Rifampicin 20 (26) 110 (53) 0.31 (0.17–0.55) < 0.001 0.32 (0.19–0.54) < 0.001 35 (45) 105 (50) 0.79 (0.47–1.35) NS – – Fluoroquinolone Values are expressed as number of patients (%) and odds ratios (OR), hazards ratio (HR) and 95% confi- dence intervals (95% CI) are presented NS non-significant McCabe’s classification [20] At blood culture collection time-point Infectious specialist consultation Adjunctive therapy For at least 14 days Table 4 Propensity-score-adjusted Cox proportional regression Discussion analysis for 90-day mortality in methicillin-sensitive Staphylococcus aureus bacteremia patients aged  ≥  60  years (n  =  286) according to The main observations were that formal ISC ensures infectious specialist consultation proper clinical management irrespective of age and for- Patient characteristics Propensity-score-adjusted mul- p value mal ISC improves prognosis of aged patients with MS- tivariate analysis HR (95% CI) SAB. Accounting for all prognostic parameters, patients Absence of formal ISC 1.0 – aged  ≥  60  years, patients aged  ≥  75  years and female Presence of formal ISC 0.44 (0.22–0.88) 0.021 patients aged ≥ 75 years, had a more than twofold lower Healthy—nonfatal 0.37 (0.23–0.60) < 0.001 odds ratio for a fatal outcome due to formal ISC. Severe sepsis 1.99 (1.03–3.81) 0.039 Previous reports connect ISC to improved antibiotic Endocarditis 2.06 (1.16–3.67) 0.014 therapies, accelerated diagnostics and eradications of deep Pneumonia 2.57 (1.58–4.17) < 0.001 infection foci and better outcomes in SAB [6–10, 23]. Cor- d,e Rifampicin 0.31 (0.18–0.54) < 0.001 responding observations were seen in the present study. We provided formal ISC within 7 days of SAB diagnosis and, Infectious specialist consultation among patients aged ≥ 60 years, this resulted in echocardi- McCabe’s classification [20] ography in up to 66%, deep infection foci identification in At blood culture collection time-point 80% and infection eradication provided to 34% of patients. Adjunctive therapy Formal ISC resulted in radiological infection diagnostics, For at least 14 days localization and eradication irrespective of age over or under 60 years. However, patients aged ≥ 60 years managed with- out formal ISC had less infection foci diagnosed and were death were acute subarachnoid or gastrointestinal hemor- provided no infection foci eradications compared to those rhages (43%), severe sepsis (20%) or pneumonia (20%). receiving formal ISC. Similar trends were observed also for For patients aged ≥ 60 years (n = 42), the corresponding antibiotics. Patients aged ≥ 60 years managed by formal ISC causes were SAB with or without a background condition had anti-staphylococcal penicillin as first-line alternative in (43%), acute cardio-pulmonary disease (21%) or deep infec- 2/3 of cases, whereas cephalosporins or other antibiotics tion (19%). Altogether, the immediate causes of death were were used in under 1/3 and adjunctive antibiotics in over infection related in 67% of patients aged ≥ 60 years and 60% 50% of cases. Most important, formal ISC resulted in anti- in patients aged < 60 years. biotic therapies irrespective of age over or under 60 years. Contrary, no of patients aged ≥ 60 years managed without 1 3 European Geriatric Medicine (2018) 9:355–363 361 formal ISC had anti-staphylococcal penicillin as first-line fluoroquinolone therapy did not impact outcome and this is antibiotics, whereas 3/4 had cephalosporins as first-line in line with previous observations [22]. alternative and adjunctive antibiotics were provided in only Previous studies on aged SAB patients do not report 1/3 of cases. fever [14–16, 18, 24], whereas two studies reported that Deep infection foci have been identified in only 14–31% aged SAB patients were more likely to be afebrile prior of aged patients in earlier studies on SAB [14–16, 18, 24]. to SAB [17, 19]. In the present study, defervescence was Previous reports have stated that aged SAB patients are significantly shorter for aged patients compared to young. less likely to receive ISC, echocardiography or infection We have previously shown that ISC reduced fever duration foci identification or eradication, and extensive diagnostics in SAB [10]. However, in the present study clinical man- have not been pursued in aged patients due to presumed agement or formal ISC had no impact on defervescence poor outcome [17, 19, 24, 25]. To the best of our knowl- in patients aged ≥ 60 years. Hence, time to defervescence edge, only three studies report presence of ISC stating that among patients aged ≥ 60 years does not seem to correlate patients were managed in conjunction with an ISC [14, 18], with treatment strategies. whereas one report concluded that aged patients were less MRSA weakens prognosis [27] and MRSA in previous likely to receive ISC guidance [19]. However, the content or reports on aged SAB patients has been as much as 52–100% nature of ISC or the impact of ISC on disease progression [14–16, 18]. We included only MS-SAB. Thus, patients or prognosis was not evaluated [14, 18, 19]. The importance had proper antibiotic therapy from the first day of positive of infection identification and eradication in SAB has been blood culture excluding bias from differences in empiri- confirmed [4 , 26] and lack of echocardiography and undiag- cal antibiotic therapy. In the present study 1/2 of patients nosed infection foci have been suspected to connect to mor- aged ≥ 60 years received adjunctive rifampicin therapy. We tality in aged SAB patients [14, 17]. Autopsy examinations have shown that rifampicin adjunctive therapy may impact in the present study revealed that for deceased patients both prognosis positively [22, 28]. However, among patients bacteremia and deep infection foci account for a larger part aged  ≥  60  years, the risk of drug interactions may have of mortalities of aged patients compared to young ones. The resulted in a selection bias favoring rifampicin treatment present study demonstrate that formal ISC-guided clinical in less comorbid patients and hence, the potential positive management result in frequent localization and eradication prognostic impact of rifampicin in aged patients should be of deep infection with subsequent positive prognostic impact interpreted with caution. The authors recommend that pro- in aged patients with SAB. spective randomized clinical trials evaluate the potential Comparison of prognosis in aged and young SAB patients advantage of rifampicin therapy before it can be routinely is challenging due to differences in age categorizations and recommended as part of treatment of aged patients with reported follow-up time and in earlier studies. We applied SAB. break-point ages of 60 and 75 years with mortality rates There are weaknesses in the present study that have to for patients aged over 60 years at 28 and 90 days of 18 and be accounted for when interpreting results. First, the ret- 24% for patients managed by formal ISC and 31 and 47% rospective design includes risk for bias due to differences for patients not receiving formal ISC. Previous reports have in patient groups. However, propensity-score adjustment presented results according to mean ages of 63–85 years may reduce potential bias [29]. Second, aged infectious [14, 15] or break-point age of 60–65 years [16, 18, 19]. In patients may lack fever and present non-specific symptoms. older patients, the mortalities have varied considerably with Moreover, declined functional status has been connected to 15% at 7 days [15], 11–36% at 30 days [18, 24], 29% at mortality among aged infectious patients [30]. Correspond- 90 days [17] and 33–56% at 6 months [14]. The present ing data were not recorded. Third, the patient cohort of the study observed higher fatalities for aged patients com- present study was originally collected to investigate trends pared to young. This is in line with earlier reports [16, 17, of nosocomial SAB and prognostic impact of fluoroqui- 19, 24] but deviate from one study with no link between nolones, rifampicin and ISC [10, 12, 22, 28]. However, the age and clinical outcome [18]. Previous reports have pre- authors noticed that, although the incidence of SAB among sented age, comorbidity, MRSA and unknown bacteremia older persons is rising, the prognostic impact of ISC has not source as independent parameters for mortality among aged been extensively evaluated among aged patients with SAB. patients with SAB [14, 16, 17, 19, 24]. Parameters influ- Regarding the earlier time-period of the patient cohort, the encing outcome in patients aged ≥ 60 years in the present question of whether the patient data in the present study is study have been identified earlier in SAB patient cohorts valid to current clinical practice may be raised. Management without age specification, i.e. comorbidity [5 , 6], sever- of SAB is continuously developed, however, fundamental ity of illness [7], ISC [7–10], pneumonia or endocarditis elements of SAB management remain unchanged over the [7, 10] and rifampicin therapy [22]. Moreover, adjunctive years, e.g. the importance of proper non-delayed antibiotic therapy and diagnostics of infection foci. The authors view 1 3 362 European Geriatric Medicine (2018) 9:355–363 6. Pragman AA, Kuskowski MA, Abraham JM, Filice GA (2012) that the high presence of formal ISC has ensured record- Infectious disease consultation for Staphylococcus aureus bac- ing of relevant data and high-standard management of SAB. teremia improves patient management and outcomes. Infect Dis Hence, the authors conclude that the patient data are not Clin Pract 20:261–267 outdated for current clinical practice. 7. Rieg S, Peyerl-Hoffmann G, de With K (2009) Mortality of S. aureus bacteremia and infectious diseases specialist consulta- tion—a study of 521 patients in Germany. J Infect 59:232–239 8. Robinson JO, Pozzi-Langhi S, Phillips M, Pearson JC, Chris- Conclusion tiansen KJ, Coombs GW et al (2012) Formal infectious diseases consultation is associated with decreased mortality in Staphy- lococcus aureus bacteraemia. Eur J Clin Microbiol Infect Dis Formal ISC ensures proper and active clinical management 31:2421–2428 irrespective of age and improve prognosis in aged patients 9. Lahey T, Shah R, Gittzus J, Schwartzman J, Kirkland K (2009) with MS-SAB. The authors encourage clinicians to manage Infectious disease consultation lowers mortality from Staphylo- aged patients with MS-SAB through formal ISC guidance. coccus aureus bacteremia. Medicine 88:263–267 10. Forsblom E, Ruotsalainen E, Ollgren J, Järvinen A (2012) Tel- ephone consultation cannot replace bedside infectious disease Funding The study has been supported by Grants from Helsinki Uni- consultation in the management of Staphylococcus aureus bac- versity Central Hospital, the Medical Society of Finland and Svenska teraemia. Clin Infect Dis 56:527–535 Kulturfonden. The funders had no role in study design, data collection 11. National Center for Chronic Disease Prevention and Health and analysis, decision to publish, or preparation of the manuscript. Promotion DoPH, CDC (2013) The state of aging and health in The study was funded by Maud Kuistila Foundation and Perkléns America 2013 Foundation. 12. Lyytikäinen O, Ruotsalainen E, Järvinen A, Valtonen V, Ruutu P (2005) Trends and outcome of nosocomial and community- Compliance with ethical standards associated bloodstream infections due to Staphylococcus aureus in Finland, 1995–2001. Eur J Clin Microbiol Infect Dis 24:399–404 Conflict of interest The authors declare that they have no conflict of 13. Benfield T, Espersen F, Frimodt-Møller N, Jensen AG, Larsen interest. AR, Pallesen LV et al (2007) Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia Ethics statement The trial was approved by The Institutional Review between 1981 and 2000. Clin Microbiol Infect 13:257–263 Board of Helsinki University Central Hospital and The Ethical Com- 14. Big C, Malani PN (2010) Staphylococcus aureus bloodstream mittee of Helsinki University Central Hospital. infections in older adults: clinical outcomes and risk factors for in-hospital mortality. 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European Geriatric MedicineSpringer Journals

Published: Mar 6, 2018

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