1 Bloomsbury Institute of Intensive Care Medicine, University College London, Jules Thorn Building, Middlesex Hospital, Mortimer Street, London W1N 3AA; 2 Department of Clinical Microbiology, University College London Hospitals, London, UK; 3 Dipartimento di Scienze Sanitarie Applicate, Università di Pavia, Pavia, Italy
Received 16 January 2004; returned 4 April 2004; revised 25 May 2004; accepted 22 July 2004
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Abstract |
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Design: Six-month prospective observational study from February to July 2000.
Setting: Mixed medical-surgical tertiary referral ICU.
Patients: All 713 patients admitted to the ICU over the study period.
Measurements and results: In total, 102 bacteraemic episodes occurred in 84 patients. Eight (57%) of 14 community-acquired bacteraemias, 22 (79%) of 28 hospital-acquired bacteraemias, and 48 (80%) of 60 ICU-acquired bacteraemias (in 49 patients) were treated with short-course monotherapy. Compared with previous reported studies, these patients had a low rate (23.8%) of death directly attributable to the bacteraemia and a satisfactory clinical response in 72%. Of six relapses (all Gram-negative), four had received combination therapy for severe deep-seated infections. ICU-acquired multidrug-resistant Gram-negative bacteraemias (6.5%) and fungaemias (3%) were also uncommon. No patient discharged from ICU subsequently developed a new bacteraemia relapse, or any long-term complication such as osteomyelitis.
Conclusions: Our general strategy of short-course antibiotic monotherapy for treating bacteraemia in the critically ill appears to provide a satisfactory clinical response, low relapse rate and no long-term complications in a well-defined group of patients. Multicentre studies are warranted to compare short versus long course therapy, and monotherapy versus combination therapy.
Keywords: fungaemia , intensive care unit , antibiotic therapy
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Introduction |
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Appropriate antibiotic therapy is the mainstay of treatment, in conjunction with removal of any source (viscus perforation, abscess, foreign body, etc.), organ support, and amelioration or cure of the underlying disease. Timely selection of appropriate therapy influences patient outcome.13 Treatment response is primarily based on signs of clinical improvement, yet patients often deteriorate as a result of the ensuing inflammatory response, the underlying illness or a non-infectious complication, despite successful eradication of the responsible microorganism. Direct or indirect attribution of death to the bacteraemia can be difficult in the ICU setting.1013 As a consequence, optimal antibiotic therapy remains unknown.
As no ICU-specific randomized trials exist, individual ICUs have evolved different strategies, using short (47 days) or long (1014 days plus) courses of either mono- or combination antibiotic therapy.14 The latter offers broad spectrum and often synergic cover, whereas short-course monotherapy reduces both antibiotic pressure in the environment and drug expenditure.15,16 Prolonged combination therapy could carry inherent dangers such as drug toxicity and, possibly, a higher incidence of fungaemia.15,16 However, short-course monotherapy may not eradicate the infecting microorganisms, with an increased likelihood of relapse. Ironically, both policies are considered to be major influences on selection for antimicrobial resistance.15,16 Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Gram-negative bacillieither multidrug-resistant or producing extended-spectrum ß-lactamases (ESBL), fluconazole-resistant Candida spp. and, most recently, MRSA strains with reduced susceptibility to vancomycin, are nosocomial pathogens of increasing concern.17 Different strategies (e.g. periodic rotation of first-line therapies, restricted use of antibiotic classes), in combination with an infection control programme, are mooted to decrease the prevalence of multidrug-resistant pathogens within the ICU.1821 However, these have yet to be evaluated by appropriately designed multicentre studies.
Ideally, prospective randomized trials should be conducted to determine optimal antibiotic strategies for bacteraemia-related illnesses. As no data currently exist for the critically ill patient, we decided to conduct a 6-month prospective observational investigation to inform the design of any future study. We assessed:
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Materials and methods |
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Patients
The following data were collected on all patients admitted to the ICU from February 1st 2000 for 6 months: (i) demographics; (ii) admission diagnosis and first 24 h APACHE II score; (iii) risk factors (e.g. MRSA carriage, immunosuppression, recent surgery); and (iv) duration of ICU stay and outcome.
Bacteraemic/fungaemic cases
Clinically significant bacteraemias or fungaemias were identified by daily prospective surveillance of all positive blood cultures.22,23 Affected patients had the source of infection identified where possible. Collections were drained and intravascular catheters removed as appropriate. ACCP/SCCM sepsis criteria were collected retrospectively: (i) at the time blood cultures were taken; (ii) when culture results were notified; and (iii) when antibiotics were commenced.24
Patients were prospectively followed with recording of: (i) antibiotic therapy (type, duration, changes) and ACCP/SCCM sepsis criteria at the time of stopping (and changing, if necessary) antibiotic therapy; (ii) ICU support techniques (e.g. mechanical ventilation, intra-vascular catheter changes, abscess drainage or surgery); and (iii) development of further bacteraemic or fungaemic infections or relapses.
Microbiology
When systemic infection was clinically suspected, blood was taken for culture with gloved hands, through a clean stab and/or arterial and central venous lines via a three-way tap, though not through any diaphragm and with prior cleaning with an alcohol impregnated wipe. Five millilitres of blood were injected aseptically into aerobic and anaerobic bottles and incubated for a mean time of 5 days (Bactec 9240; Becton Dickinson Microbiology Systems, Sparks, MD, USA). Isolation and identification of microorganisms were usually made using standard media, methods and techniques. The API 20E system (bioMérieux, Marcy l'Étoile, France) was used to identify Gram-negative organisms, and DNAse and latex agglutination/coagulase to identify staphylococci. The Stokes disc diffusion method was used for antimicrobial susceptibility testing.25 The Maki roll plate semi-quantitative technique was used for catheter tip culture.25 The microbiology laboratory has clinical pathology accreditation and is subject to designated quality controls.
For all positive results, Gram stain, identification and antibiotic susceptibility patterns were noted. To assess the significance of isolates, laboratory results were reviewed in relation to clinical findings. Culture from swabs, catheter tips or fluid taken from other sites (e.g. tracheo-bronchial secretions, surgical wounds, line sites) was carried out as clinically indicated.
Statistical analysis
SPSS software (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. For continuous variables, rank values were compared using non-parametric tests (MannWhitney U-test, Wilcoxon Rank Sum W, or KruskalWallis one-way analysis of variance). Differences in proportions were compared using either 2 or Fisher's exact tests for expected cell frequencies less than 5. Multinomial logistic regression was used to estimate the independent effect of each risk factor on ICU-BACT. Binary logistic regression was used to estimate the effect of each risk factor on a death (yes/no) outcome for ICU-BACT patients. P values less than 0.05 were considered significant.
Definitions
See the Appendix. CDC definitions were used for every type of infection.26
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Results |
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In total, 713 patients [455 male; 47% surgical; median age 62 years (inter-quartile range, IQR 4572)] were admitted in the 6 month period. Median ICU stay was 3 days (IQR 25) with 143 (20%) dying in the ICU, 51 within 3 days. Twenty-five were transferred to other hospitals, and 545 were discharged to a general ward, of whom 30 died. Overall APACHE II standardized mortality rate (SMR) was 0.96. Patients admitted from the ward had higher APACHE II scores and hospital mortality (P<0.001, KruskalWallis test).
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Fourteen (1.9%) patients were admitted with C-BACT and 28 (3.9%) with H-BACT, 11 of whom had haematological malignancy. Six H-BACT patients subsequently developed ICU-BACT, but with different microorganisms. Forty-nine patients suffered 60 episodes of ICU-BACT, one patient having three episodes over 63 days. Using multinomial logistic regression, predictive factors for development of ICU bacteraemia were duration of ICU stay, coexisting renal failure [OR = 146.5 (95% CI: 6.43349)], MRSA carriage [OR = 0.021 (95% CI: 0.0010.68)], recent surgery [OR = 218.7 (95% CI: 2.2421 289)], and duration of mechanical ventilation [OR = 0.8 (95% CI: 0.570.99)] (P<0.01, for all). The risk of developing ICU-BACT rose progressively with time, being 39% after a stay of 7 days in the ICU, doubling after 14 days, and reaching 100% after 5 weeks.
Culture results and onset (Figure 1)
Gram-positive organisms caused the majority of bacteraemias in each subgroup. There was a median gap of 20 days between the onset of the first and second ICU-acquired bacteraemia episodes. Escherichia coli was the only causative pathogen of Gram-negative C-BACT, whereas Klebsiella spp. constituted 19.3% of all cases of H-BACT and ICU-BACT. Only two patients had ICU-acquired fungaemia, the monomicrobial case occurring after femoral venous catheter insertion into an infected groin.
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Main sources for C-BACT were cardiovascular (endocarditis) and urinary tract, and gastrointestinal and respiratory for H-BACT. Intravascular devices were considered the source in 27 (45%) of ICU-BACT. The rate of central venous catheter infections was 7 per 1000 line days. Line-related bacteraemias (40% due to coagulase-negative staphylococci) occurred after a median time post-insertion of 10 days (IQR 613).
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In the C-BACT group, MRSA was isolated from one previously hospitalized patient. Escherichia coli strains were susceptible to all antibiotics except amoxicillin. In the H-BACT group, two Staphylococcus aureus and all coagulase-negative staphylococci were methicillin-resistant; one Enterococcus faecium isolate was both vancomycin- and teicoplanin-resistant. Only two (13%) multidrug-resistant Gram-negatives were identified, one being extended-spectrum ß-lactamase (ESBL)-producing. Of seven Candida spp., five were fluconazole-resistant.
In the ICU-BACT group, all 13 S. aureus isolates were methicillin-resistant. Five (38%) were MRSA carriers before ICU admission, the others being colonized after a median ICU stay of 14 days (IQR 721). The former developed MRSA bacteraemia 21 days (IQR 922) earlier (P<0.05, MannWhitney test). All vancomycin-resistant organisms were isolated in long-stay hospital patients (median 2 months, IQR 1583 days), but no differences in either illness severity or mortality were recorded. Only two (6.5%) Gram-negative isolates were multidrug-resistant and no ESBL-producing microorganisms were found.
Severity of illness (Table 3)
Septic shock and severe sepsis were more common in C- and H-BACT (P<0.05, 2 test). Gram-negative microorganisms were more often related to septic shock in C-BACT (75%) and ICU-BACT (48%), whereas Gram-positive pathogens resulted in septic shock in 84% of H-BACT. Fungaemia was associated with septic shock in all hospital-acquired episodes, but with a low-grade illness severity in community- and ICU-acquired cases.
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A 5 day median course of monotherapy was used in the majority of C-BACT (57%), H-BACT (79%) and ICU-BACT (80%) patients, despite many having septic shock or severe sepsis. Among 78 episodes (considering together C-BACT, H-BACT and ICU-BACT) treated with short-course monotherapy, 27 were central venous catheter (CVC)-related bacteraemia, 15 were respiratory tract infection related (11 pneumonia) and 15 had the gastrointestinal tract as a supposed source (two abdominal sepsis and one gall bladder empyema); only six episodes were considered primary bacteraemia. In terms of severity of illness: 34 (43.6%) episodes were complicated by a septic shock and 17 (21.8%) by a severe sepsis; no asymptomatic or low symptomatic bacteraemia were recorded. Combination therapy was reserved for severe deep-seated infections, i.e. endocarditis, necrotizing fasciitis, osteomyelitis, cerebral abscess (n=6), multidrug-resistant Gram-negative bacteraemia (n=2), and polymicrobial infections (n=7). Three ICU-BACT episodes had low-grade pyrexia and received no treatment other than vascular catheter change.
Despite opting for monotherapy, in most cases before culture results were known, antibiotic therapy was not subsequently altered in 12 (86%) episodes of C-BACT, 23 (88%) episodes of H-BACT and 48 (90%) episodes of ICU-BACT. Two patients with C-BACT, three with H-BACT and five with ICU-BACT received additional antibiotics due to lack of clinical response, even though therapy was appropriate in terms of laboratory susceptibility testing.
Eighteen patients died during therapy, and seven more within 3 days of stopping therapy. Excluding those 18 patients not completing their course of antibiotics, the median duration of treatment was not significantly prolonged for either C-BACT [monotherapy 6 days (IQR 56), combination 21 days (821)], H-BACT [monotherapy 6 days (58), combination 7 days (514)], or ICU-BACT [monotherapy 5 days (57), combination 8 days (513)]. Fourteen patients received 10 days of therapy and eight
14 days of therapy.
The decision to stop antibiotics was based upon clinical response, i.e. resolution of bacteraemia-related clinical findings±improvement in related organ dysfunction. Using these criteria, a clinical response was recorded in most patients for each episode treated with short-course monotherapy (Table 3). Thirteen patients responded to antibiotic therapy with resolution of the related systemic inflammatory response but subsequently died due to persisting organ failure. Twenty deaths were directly attributable to bacteraemia, where organ function continued to deteriorate despite susceptible antibiotic therapy.
Four H-BACT and three ICU-BACT patients who died while still receiving antibiotics developed breakthrough bacteraemia, three being due to S. aureus. An additional antibiotic was added in two cases, and a withdrawal decision taken in three cases. The deaths occurred after a median therapy duration of 4 (IQR 27) days for H-BACT and 5 (IQR 17) for ICU-BACT.
Relapses
Gram-negative microorganisms were responsible for all six relapse episodes, namely E. coli for one C-BACT, and Klebsiella spp. (3), Serratia marcescens (1) and a Pseudomonas spp. (1) for ICU-BACT. Four relapses likely resulted from non-changing of intravascular catheters colonized after the first episode. The other two ICU-BACT relapses occurred in patients with faecal peritonitis 7 days (IQR 59) after finishing antibiotic therapy. Four of five relapsing ICU-BACT had received an 8 day median course of combination therapy. Three relapsing episodes were treated with 7 days of monotherapy, and three with 7 days of combination therapy; no further relapses occurred.
Crude ICU and hospital mortality (unadjusted for illness severity) was higher in bacteraemic patients (P<0.001, 2 test). Thirty-eight of the 84 bacteraemic patients died, providing a crude mortality rate of 45%, however the directly attributable mortality rate was 23.8% (20 patients). ICU-BACT was not a predictive factor for death [OR = 0.7 (95% CI: 0.41.7), P=0.394] using binary logistic regression with death (yes/no) as the response variable and ICU-BACT, APACHE II probability and score, age, sex, diabetes, renal failure, liver failure, neoplasia, immunosuppression, ARDS, neutropenia and the presence of other infection as explanatory variables. As a result of low patient numbers, C-BACT and H-BACT were not examined. Out of all MRSA bacteraemia (considering together C-BACT, H-BACT and ICU-BACT), 56.5% of patients survived, whereas 34.3% died directly related and 8.7% indirectly.
Six of the seven patients with more than one bacteraemia (i.e. H-BACT + ICU-BACT, or C-BACT + H-BACT) died, with five being directly related. Six of the 10 patients developing more than one ICU-BACT episode died, four being directly related. Of the six patients relapsing with the same microorganism, four died though only one was directly related to the bacteraemia. Three of the 46 (55%) bacteraemic patients who survived were transferred to other hospitals and the remaining 43 were discharged to hospital wards. During a 3 week (IQR 775) median follow-up, none developed either relapses or further bacteraemic episodes. No long-term complications such as osteomyelitis or endocarditis have since come to our attention. Six (two C-BACT, two H-BACT and two ICU-BACT) patients subsequently died in hospital.
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Discussion |
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In our practice, antibiotic therapy is usually stopped promptly on resolution of bacteraemia-related clinical findings±improvement in related organ dysfunction. However, due to the severity of underlying disease and concurrent multiple organ failure, it is often difficult to establish when clinical response actually occurs, or whether death can be directly or indirectly attributed to the bacteraemia. Clinical response could be corroborated by microbiological response, i.e. negative blood cultures taken after cessation of appropriate therapy. However, our standard practice dictates that blood cultures are not taken unless the patient clinically deteriorates and infection is suspected. Furthermore, concurrent renal and/or hepatic dysfunction may result in an antibiotic presence persisting for days (or even weeks). Thus, for the purpose of this observational study, a positive microbiological response included either non-appearance of the infecting microorganism or the lack of clinical need for subsequent blood cultures, extended into the duration of hospital stay post-ICU discharge to exclude late reoccurrence.
In keeping with accepted practice, longer duration combination therapy was prescribed for deep-seated infections such as endocarditis, necrotizing fasciitis, osteomyelitis, and faecal peritonitis. Relapses were more frequent in these patients, with failure to eradicate microorganisms being more likely with intra-vascular device colonization and persistence of intra-abdominal abscesses. The worse clinical response and higher mortality in these patients reflect their underlying illness severity. Similarly, the poorer outcome in H-BACT patients reflects their higher APACHE II score, their underlying disease severity and the high proportion (46%) of immunosuppression.27 The higher mortality in ward patients has been attributed to delays in antibiotic treatment and inadequate resuscitation.27
Patients that developed ICU-BACT were sicker on ICU admission compared with other long-stay (3 days) patients not developing ICU-BACT. This increased susceptibility with related to their underlying disease processes and the greater requirement for invasive procedures (e.g. vascular access, mechanical ventilation).39 If admission illness severity was taken into account, logistic regression showed that ICU-BACT was not an independent variable predictive of death, notwithstanding its effect on prolonging stay.10
The low incidence of ICU-acquired multidrug-resistant microorganisms and the zero incidence of ESBL-producing Gram-negative pathogens are uncommon when compared with recent North American and European studies that routinely express concern about the high frequency of such infections.28,29 All ICU-acquired S. aureus bacteraemias were methicillin-resistant. All patients affected were MRSA carriers, a known risk factor for MRSA bacteraemia. An earlier onset was recorded in those carrying MRSA before ICU admission than those colonized during their ICU stay.30 Our short-course treatment approach to MRSA and pseudomonas bacteraemia differs from the orthodoxy that is based on expert consensus rather than prospective randomized trials.31,32 Our 38.5% mortality rate recorded in the 13 ICU-acquired MRSA bacteraemic patients compares favourably with the 63.8% mortality recently reported by Blot et al.33 The apparent success of this strategy over many years, with an absence of long-term complications, does suggest the need for prospective controlled studies to resolve this conflict of opinion.
Our incidence of 1.4 ICU acquired fungaemias per 500 patients (0.5% of long-stay patients) is similar to two multicentre studies from Germany and Spain, but much lower than reported by the EPIC or SENTRY surveillance studies.34 Any link between short-course monotherapy and a low incidence of fungaemia and multidrug-resistant Gram-negative bacteraemia must remain as supposition at present, but offers an important hypothesis that warrants further investigation. In support of this theory, multidrug-resistant Gram-negative bacteraemia and fungaemia occurred more often in those H-BACT patients suffering from malignancy, with prolonged hospital stay and/or receiving prolonged courses of antibiotic therapy.30 Moreover, as reported by others, we recorded a higher prevalence of non-albicans Candida species; this is likely due to over-utilization of fluconazole which has shifted the spectrum of Candida to more resistant species such as Candida glabrata and Candida krusei.3537
The limitations of this study are its observational nature and the relatively small numbers of patients considered. However, this study is the first, to our knowledge, that suggests short-course monotherapy does result in a satisfactory clinical response and a low relapse rate. The concurrent low rate of ICU-acquired fungaemia and multidrug-resistant and ESBL-producing Gram-negative pathogens suggests the intriguing possibility that these findings are related. Presentation of this work has stimulated the development of a large, prospective, international audit that is under way. Verification of the above findings will hopefully lead to randomized controlled studies and important guidance as to optimal antibiotic treatment strategies in the critically ill.
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Appendix: definitions |
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Coagulase-negative staphylococci and all common skin contaminants (Bacillus spp., Corynebacterium spp.) isolated, from at least two blood cultures, that met the above definition, were considered as infection-associated; they were otherwise designated as contaminant. If associated with a device-culture positive result for the same microorganism, only one positive blood culture from a distant site was necessary to consider this as a related bacteraemia.39
An episode of bacteraemia was defined when one or more microorganisms were isolated from one or more blood cultures, and clinical evidence suggested they had arisen from a common source and were part of the same episode. If the source was unknown, all positive blood cultures occurring within 48 h of each other are considered as a single bacteraemic episode.1,26,38
Polymicrobial bacteraemia: either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode (<48 h) and with clinical or microbiological evidence of the same source.40
Break-through bacteraemia: bacteraemia due to the same microorganism and occurring in patients treated with appropriate therapy for more than 24 h.41
Relapse: a recurrent bacteraemia due to the same microorganism occurring within 1 week of cessation of appropriate antibiotic therapy.1,26,38
Bacteraemia was defined as community-acquired if occurring within 72 h of hospital admission; as hospital-acquired if occurring within 72 h of patient admission from the ward to the ICU; and ICU-acquired either when occurring after 72 h following ICU admission, or sooner if the bacteraemia could be directly sourced to an ICU procedure, e.g. catheter insertion.1
Sepsis was defined by having at least two of the four (Bone) criteria for the systemic inflammatory response syndrome (SIRS), i.e. body temperature 38°C or <36°C, heart rate
90 beats/min, respiratory rate >20 breaths/min, WBC >12 000 or
4000 cells/mm3 or
10% immature bands, which were associated with positive blood cultures. Severe sepsis: sepsis with organ dysfunction (we used a SOFA score
3 for one or more organ systems). Septic shock: sepsis or severe sepsis with a persisting fall in blood pressure despite adequate fluid resuscitation, plus perfusion abnormalities and the need for inotrope or vasopressor support.25
Appropriate antibiotic therapy: refers to an antimicrobial agent shown to be effective in vitro against the microorganism(s) responsible for the infection and considered to be an acceptable option by standard guidelines, at sufficient dosage, and by an acceptable route of administration.1,1012
Clinical response to treatment: this was deemed positive if the bacteraemia-related systemic inflammatory response had resolved at the time of antibiotic cessation, though organ dysfunction may have still persisted.
Microbiological response: strictly speaking, this requires negative blood cultures taken after cessation of appropriate therapy. However, as routine clinical practice on the UCLH ICU is to take blood cultures only when clinically indicated, many responders would not have had repeat cultures taken unless there was clinical deterioration for which infection was suspected. Furthermore, concurrent renal and/or hepatic dysfunction may result in an antibiotic presence persisting for days (or even weeks) following cessation. Thus, for the purpose of this observational study, a positive microbiological response included either non-appearance of the infecting microorganism or the lack of clinical need for subsequent blood culture testing. This was extended into the duration of hospital stay post-ICU discharge to exclude late re-occurrence.
Multiple-drug resistance: resistance to at least three antibiotic classes in addition to any intrinsic resistance of the particular species.1,1012
Primary bacteraemia: a bacteraemia occurring without any recognized source; secondary bacteraemia when the blood culture was positive for the same microorganism isolated from another site, recognized as its source.1
A gastrointestinal source of bacteraemia was designated when significant intra-abdominal disease (biliary tract disease, bowel ischaemia, infarction or perforation) was present in conjunction with an appropriate organism isolated from blood. The source was defined as recognized if the bacteraemia was related to an infection caused by the same microorganism; suspected if the bacteraemia was related to an infection only clinically defined, or due to the same microorganism colonizing the patient at any site; or unrecognized in the absence of a primary focus.19 In the case of likely multiple sources, we considered the primary source of bacteraemia as the first both clinically and microbiologically defined.
Intravascular device related infection was defined when the semi-quantitative culture (yielding 15 colonies) of the catheter tip was positive for the same microorganism isolated from blood taken from a distant site.1,26
Onset day of bacteraemia was considered the day when the positive blood culture was taken.
Death was considered attributable to the bacteraemia if it could be readily explained by infection without any other recognized causes of death; indirectly related if the bacteraemia caused organ dysfunction or failure resulting in death after the infection was clinically and microbiologically eradicated; or unrelated if death was related to a cause independent of the bacteraemia.1,1012
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Acknowledgements |
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Footnotes |
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References |
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2 . Valles, J., Ochagavia, A., Rue, M. et al. & the Spanish Study Group of Infection Disease in ICU. (2000). Critically ill patients with community acquired bacteremia: characteristics and prognosis. Intensive Care Medicine 26, Suppl. 3, 21 (abstract).
3 . Brun-Buisson, C., Doyon, F., Carlet, J. et al. (1985). Incidence, risk factors and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. Journal of the American Medical Association 274, 96874.
4 . Vincent, J. L., Bihari, D. J., Suter, P. M. et al. (1995). Prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. Journal of the American Medical Association 274, 63944.[Abstract]
5 . Brun-Buisson, C., Doyon, F. & Carlet, J. (1996). Bacteremia and severe sepsis in adults: a multicenter prospective survey in ICUs and wards of 24 hospitals. French bacteremia sepsis study group. American Journal of Respiratory and Critical Care Medicine 154, 61724.[Abstract]
6 . Rello, J., Ricart, M., Mirelis, B. et al. (1994). Nosocomial bacteremia in a medical-surgical intensive care unit: epidemiologic characteristics and factors influencing mortality in 111 episodes. Intensive Care Medicine 20, 948.[ISI][Medline]
7 . Edgeworth, J. D., Treacher, D. F. & Eykyn, S. J. (1999). A 25-year study of nosocomial bacteremia in an adult intensive care unit. Critical Care Medicine 27, 14218.[ISI][Medline]
8 . Valles, J., Cristobal, L. & Alvarez-Lerma, F. (1997). Nosocomial bacteraemia in critically ill patients: a multicentre study evaluating epidemiology and prognosis. The Spanish Collaborative Group for Infections in Intensive Care Units of Sociedad Espanola de Medicina Intensiva y Unidades Coronarias (SEMIUC). Clinical Infectious Diseases 24, 38795.[ISI][Medline]
9 . Antonelli, M., Moro, M. L., D'Errico, R. R. et al. (1996). Early and late onset bacteremia have different risk factors in trauma patients. Intensive Care Medicine 22, 73541.[CrossRef][ISI][Medline]
10 . Pittet, D., Tarara, D. & Wenzel, R. P. (1994). Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs and attributable mortality. Journal of the American Medical Association 271, 1598601.[Abstract]
11 . Pittet, D., Thievent, B., Wenzel, R. P. et al. (1996). Bedside prediction of mortality from bacteremic sepsis. American Journal of Respiratory and Critical Care Medicine 153, 68493.[Abstract]
12 . Friedman, G., Silva, E. & Vincent, J. L. (1998). Has the mortality of septic shock changed with time? Critical Care Medicine 26, 207886.[ISI][Medline]
13
.
Ibrahim, E. H., Sherman, G., Ward, S. et al. (2000). The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 118, 14655.
14
.
Corona, A., Bertolini, G., Ricotta, A. M. et al. (2003). Variability of treatment duration for bacteraemia in the critically ill: a multinational survey. Journal of Antimicrobial Chemotherapy 52, 84952.
15
.
Weber, D. J., Raasch, R. & Rutala, W. A. (1999). Nosocomial infections in the ICU: the growing importance of antibiotic-resistant pathogens. Chest 115, Suppl. 3, 34S41S.
16 . Yates, R. R. (2000). New intervention strategies for reducing antibiotic resistance. Chest 115, Suppl. 3, 24S27S.[ISI]
17 . CDC Update. (1997). Staphylococcus aureus with reduced susceptibility to vancomycin in United States. Morbidity and Mortality Weekly Report 46, 8135.[Medline]
18 . McGowan, J. E. (2000). Strategies for study of the role of cycling on antimicrobial use and resistance. Infection Control and Hospital Epidemiology 21, Suppl. 1, S3643.[ISI][Medline]
19
.
Burgess, D. S. (1999). Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance. Chest 115, Suppl. 3, 19S23S.
20 . Mouton, J. W. (1999). Combination therapy as a tool to prevent emergence of bacterial resistance. Infection 27, Suppl. 2, S248.
21 . Elliott, T. S. J. & Lambert, H. A. (1999). Antibacterial resistance in the intensive care unit: mechanism and management. British Medical Bulletin 55, 25976.[Abstract]
22 . Freeman, J. & McGowan, J. E., Jr (1981). Methodologic issues in hospital epidemiology. I. Rates, case-finding and interpretation. Review of Infectious Diseases 3, 65867.[ISI][Medline]
23 . Pottinger, J. M., Herwaldt, L. A. & Perl, T. M. (1997). Basics of surveillancean overview. Infection Control and Hospital Epidemiology 18, 51327.[ISI][Medline]
24 . Bone, R. C., Balk, R. A., Cerra, F. B. et al. (1992). Definition for sepsis and organ failure and guidelines for use of innovative therapy in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest 101, 164455.[Abstract]
25 . Stokes, E. J., Ridgeway, G. L. & Wren, M. W. D. (1993). Clinical Microbiology, 7th edn. E. Arnold, London, UK.
26 . Garner, J. S., Jarvis, W. R., Emori, T. G. et al. (1988). CDC definitions for nosocomial infections. American Journal of Infection Control 16, 12840.[ISI][Medline]
27 . Lundberg, J. S., Perl, T. M. & Wiblin, T. (1998). Septic shock: an analysis of outcomes for patients with onset on hospital wards versus intensive care units. Critical Care Medicine 26, 10204.[ISI][Medline]
28 . Yuan, M., Aucken, H., Hall, L. et al. (1998). Epidemiological typing of klebsiellae with extended spectrum ß-lactamases from European intensive care units. Journal of Antimicrobial Chemotherapy 41, 52739.[Abstract]
29 . Livermore, D. M. & Yuan, M. (1996). Antibiotic resistance and production of extended-spectrum ß-lactamases amongst Klebsiella spp. from intensive care units in Europe. Journal of Antimicrobial Chemotherapy 38, 40924.[Abstract]
30 . Pujol, M., Pena, C., Pallares, R. et al. (1996). Nosocomial Staphylococcus aureus bacteremia among nasal carriers of methicillin-resistant and methicillin-susceptible strains. American Journal of Medicine 100, 50916.[CrossRef][ISI][Medline]
31 . Perez-Gorricho, B. & Ripoll, M. (2003). Does short-course antibiotic therapy better meet patient expectations? International Journal of Antimicrobial Agents 21, 2228.[CrossRef][ISI][Medline]
32
.
Ribera, E., Gomez-Jimenez, J., Cortes, E. et al. (1996). Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial. Annals of Internal Medicine 125, 96974.
33
.
Blot, S. I., Vandewoude, K. H., Hoste, E. A. et al. (2002). Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Archives of Internal Medicine 162, 222935.
34 . Pfaller, M. A., Jones, R. N. & Doern, G. V. (1999). International surveillance of bloodstream infections due to Candida spp. in the European SENTRY program: species, distribution and antifungal susceptibility including the investigational triazole and echinocandin agents. Diagnostic Microbiology and Infectious Disease 35, 1925.[CrossRef][ISI][Medline]
35 . Nolla-Salas, J., Sitges-Serra, A. & Leon-Gil, C. (1997). Candidaemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy. Study Group of Fungal Infections in the ICU. Intensive Care Medicine 23, 2330.[CrossRef][ISI][Medline]
36 . Vincent, J. L., Anaissie, E. & Bruining, H. (1998). Epidemiology, diagnosis and treatment of systemic Candida infection in surgical patients under intensive care. Intensive Care Medicine 24, 20616.[CrossRef][ISI][Medline]
37 . Flanagan, P. G. & Barnes, R. A. (1998). Fungal infections in the intensive care unit. Journal of Hospital Infection 38, 16377.[ISI][Medline]
38 . Weinstein, M. P., Towns, M. L. & Quartey, S. M. (1997). The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology and outcome of bacteremia and fungemia in adults. Clinical Infectious Diseases 24, 584602.[ISI][Medline]
39 . Herwaldt, L. A., Geiss, M., Kao, C. et al. (1996). The positive predictive value of isolating coagulase-negative staphylococci from blood cultures. Clinical Infectious Diseases 22, 1420.[ISI][Medline]
40 . Roberts, F. J. (1989). Definition of polymicrobial bacteremia. Review of Infectious Diseases 11, 102930.[ISI][Medline]
41 . Weinstein, M. P. & Reller, L. B. (1984). Clinical importance of breakthrough bacteremia. American Journal of Medicine 76, 17580.
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