Transition from intravenous to oral antimicrobial therapy in patients with uncomplicated and complicated bloodstream infections.

BACKGROUND: The role of oral antimicrobial agents in the management of bloodstream infections (BSI) is currently evolving. OBJECTIVES: This narrative review summarizes and appraises clinical studies that examined transition from intravenous to oral antimicrobials or compared effectiveness of various oral agents for definitive therapy of uncomplicated and complicated BSI in adults. SOURCES: Relevant English-language studies from MEDLINE (since inception) and presented abstracts at international scientific meetings (since 2017). CONTENT: Emerging data suggest potential utility of oral switch strategy, particularly to oxazolidinones, as an alternative to standard intravenous therapy in low-risk patients with uncomplicated Staphylococcus aureus BSI. Moreover, results of recent randomized clinical trials are promising that combination oral regimens may play a role in antimicrobial management of complicated Gram-positive BSI, including infective endocarditis, septic arthritis and osteomyelitis. Whereas oral fluoroquinolones have been used successfully for decades in both uncomplicated and complicated Gram-negative BSI, recent studies suggest that trimethoprim-sulfamethoxazole and aminopenicillins represent alternative oral options in uncomplicated Enterobacteriaceae BSI. Oral azoles have been used for definitive therapy of Candida species BSI and are currently recommended by the international management guidelines. IMPLICATIONS: Recent studies demonstrate that early transition from intravenous to oral therapy is a feasible and effective strategy in most patients with BSI due to Gram-negative bacteria, obligate anaerobic bacteria and Candida species. Oral antimicrobial combinations may be considered in select patients with complicated Gram-positive BSI after 10-14 days of intravenous therapy. Future studies will determine the role of oral agents for switch therapy in uncomplicated Gram-positive BSI.

Evaluation of early clinical failure criteria for gram-negative bloodstream infections.

OBJECTIVES: The aim was the development of early clinical failure criteria (ECFC) to predict unfavourable outcomes in patients with Gram-negative bloodstream infections (GN-BSI). METHODS: Adults with community-onset GN-BSI who survived hospitalization for ≥72 hr at Prisma Health-Midlands hospitals in Columbia, SC, USA from January 1, 2010 to June 30, 2015 were identified. Multivariable logistic regression was used to examine the association between clinical variables between 72 and 96 hr after GN-BSI and unfavourable outcomes (28-day mortality or hospital length of stay >14 days from GN-BSI onset). RESULTS: Among 766 patients, 225 (29%) had unfavourable outcomes. After adjustments for Charlson Comorbidity Index and appropriateness of empirical antimicrobial therapy in multivariable model, predictors of unfavourable outcomes included systolic blood pressure <100 mmHg or vasopressor use (adjusted odds ratio (aOR) 1.8, 95% confidence interval (CI) 1.2-2.9), heart rate >100 beats/minute (aOR 1.7, 95% CI 1.1-2.5), respiratory rate ≥22 breaths/minute or mechanical ventilation (aOR 2.1, 95% CI 1.4-3.3), altered mental status (aOR 4.5, 95% CI 2.8-7.1), and white blood cell count >12 000/mm3 (aOR 2.7, 95% CI 1.8-4.1) between 72 and 96 hr after index GN-BSI. Area under receiver operating characteristic curve of ECFC model in predicting unfavourable outcomes was 0.77 (0.84 and 0.71 in predicting 28-day mortality and prolonged hospitalization, respectively). CONCLUSIONS: Risk of 28-day mortality or prolonged hospitalization can be estimated between 72 and 96 hr after GN-BSI using ECFC. These criteria may have clinical utility in management of GN-BSI and may improve methodology of future investigations assessing response to antimicrobial therapy based on a standard evidence-based definition of early clinical failure.

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

Cumulative Effect of an Antimicrobial Stewardship and Rapid Diagnostic Testing Bundle on Early Streamlining of Antimicrobial Therapy in Gram-Negative Bloodstream Infections.

The use of rapid diagnostic tests (RDTs) enhances antimicrobial stewardship program (ASP) interventions in optimization of antimicrobial therapy. This quasi-experimental cohort study evaluated the combined impact of an ASP/RDT bundle on the appropriateness of empirical antimicrobial therapy (EAT) and time to de-escalation of broad-spectrum antimicrobial agents (BSAA) in Gram-negative bloodstream infections (GNBSI). The ASP/RDT bundle consisted of system-wide GNBSI treatment guidelines, prospective stewardship monitoring, and sequential introduction of two RDTs, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and the FilmArray blood culture identification (BCID) panel. The preintervention period was January 2010 through December 2013, and the postintervention period followed from January 2014 through June 2015. The postintervention period was conducted in two phases; phase 1 followed the introduction of MALDI-TOF MS, and phase 2 followed the introduction of the FilmArray BCID panel. The interventions resulted in significantly improved appropriateness of EAT (95% versus 91%; P = 0.02). Significant reductions in median time to de-escalation from combination antimicrobial therapy (2.8 versus 1.5 days), antipseudomonal beta-lactams (4.0 versus 2.5 days), and carbapenems (4.0 versus 2.5 days) were observed in the postintervention compared to the preintervention period (P < 0.001 for all). The reduction in median time to de-escalation from combination therapy (1.0 versus 2.0 days; P = 0.03) and antipseudomonal beta-lactams (2.2 versus 2.7 days; P = 0.04) was further augmented during phase 2 compared to phase 1 of the postintervention period. Implementation of an antimicrobial stewardship program and RDT intervention bundle in a multihospital health care system is associated with improved appropriateness of EAT for GNBSI and decreased utilization of BSAA through early de-escalation.

Impact of fluoroquinolone resistance in Gram-negative bloodstream infections on healthcare utilization.

There has been a concerning increase in fluoroquinolone resistance among Gram-negative bloodstream isolates. This retrospective cohort study examines the implications of fluoroquinolone resistance on use of healthcare resources in patients with Gram-negative bloodstream infections (BSI). Hospitalized adults with first episodes of community-onset Gram-negative BSI from 2010 to 2012 at Palmetto Health Hospitals in Columbia, SC, USA were identified. Multivariate linear regression was used to examine risk factors for prolonged hospital length of stay (HLOS) in survivors of Gram-negative BSI. Among 474 unique patients, 384 (81%) and 90 (19%) had BSI due to fluoroquinolone-susceptible (FQ-S) and fluoroquinolone non-susceptible (FQ-NS) Gram-negative bacilli, respectively. The FQ-NS bloodstream isolates, particularly Escherichia coli, were more likely than FQ-S isolates to be multi-drug resistant (56% versus 6%, p < 0.001). Compared with patients with BSI due to FQ-S bloodstream isolates, those with FQ-NS isolates were more likely to receive inappropriate empirical antimicrobial therapy (26% versus 3%, p < 0.001), have longer mean HLOS (11.6 versus 9.3 days, p 0.03) and treatment duration with intravenous antibiotics during hospitalization (9.1 versus 7.1 days, p 0.001), and use outpatient intravenous antibiotics at hospital discharge (15% versus 8%, p 0.05). After adjustments in the multivariate model, inappropriate empirical antimicrobial therapy was an independent risk factor for prolonged HLOS in survivors of Gram-negative BSI (parameter estimate 3.65 days, 95% CI 0.43-6.86). Multi-drug resistance among FQ-NS bloodstream isolates limits both empirical and definitive antimicrobial treatment options and poses excessive burdens on the healthcare system.

Dose reduction of scattered photons from concrete walls lined with lead: Implications for improvement in design of megavoltage radiation therapy facility mazes.

PURPOSE: This study explores the possibility of using lead to cover part of the radiation therapy facility maze walls in order to absorb low energy photons and reduce the total dose at the maze entrance of radiation therapy rooms. METHODS: Experiments and Monte Carlo simulations were utilized to establish the possibility of using high-Z materials to cover the concrete walls of the maze in order to reduce the dose of the scatteredphotons at the maze entrance. The dose of the backscatteredphotons from a concrete wall was measured for various scattering angles. The dose was also calculated by the FLUKA and EGSnrc Monte Carlo codes. The FLUKA code was also used to simulate an existing radiotherapy room to study the effect of multiple scattering when adding lead to cover the concrete walls of the maze. Monoenergetic photons were used to represent the main components of the x ray spectrum up to 10 MV. RESULTS: It was observed that when the concrete wall was covered with just 2 mm of lead, the measured dose rate at all backscattering angles was reduced by 20% for photons of energy comparable to Co-60 emissions and 70% for Cs-137 emissions. The simulations with FLUKA and EGS showed that the reduction in the dose was potentially even higher when lead was added. One explanation for the reduction is the increased absorption of backscatteredphotons due to the photoelectric interaction in lead. The results also showed that adding 2 mm lead to the concrete walls and floor of the maze reduced the dose at the maze entrance by up to 90%. CONCLUSIONS: This novel proposal of covering part or the entire maze walls with a few millimeters of lead would have a direct implication for the design of radiation therapy facilities and would assist in upgrading the design of some mazes, especially those in facilities with limited space where the maze length cannot be extended to sufficiently reduce the dose.

Dose reduction of scattered photons from concrete walls lined with lead: Implications for improvement in design of megavoltage radiation therapy facility mazes.

PURPOSE: This study explores the possibility of using lead to cover part of the radiation therapy facility maze walls in order to absorb low energy photons and reduce the total dose at the maze entrance of radiation therapy rooms. METHODS: Experiments and Monte Carlo simulations were utilized to establish the possibility of using high-Z materials to cover the concrete walls of the maze in order to reduce the dose of the scattered photons at the maze entrance. The dose of the backscattered photons from a concrete wall was measured for various scattering angles. The dose was also calculated by the FLUKA and EGSnrc Monte Carlo codes. The FLUKA code was also used to simulate an existing radiotherapy room to study the effect of multiple scattering when adding lead to cover the concrete walls of the maze. Monoenergetic photons were used to represent the main components of the x ray spectrum up to 10 MV. RESULTS: It was observed that when the concrete wall was covered with just 2 mm of lead, the measured dose rate at all backscattering angles was reduced by 20% for photons of energy comparable to Co-60 emissions and 70% for Cs-137 emissions. The simulations with FLUKA and EGS showed that the reduction in the dose was potentially even higher when lead was added. One explanation for the reduction is the increased absorption of backscattered photons due to the photoelectric interaction in lead. The results also showed that adding 2 mm lead to the concrete walls and floor of the maze reduced the dose at the maze entrance by up to 90%. CONCLUSIONS: This novel proposal of covering part or the entire maze walls with a few millimeters of lead would have a direct implication for the design of radiation therapy facilities and would assist in upgrading the design of some mazes, especially those in facilities with limited space where the maze length cannot be extended to sufficiently reduce the dose.

External validation of bloodstream infection mortality risk score in a population-based cohort.

A risk score was recently derived to predict mortality in adult patients with Gram-negative bloodstream infection (BSI). The aim of this study was to provide external validation of the BSI mortality risk score (BSIMRS) in a population-based cohort. All residents of Olmsted County, Minnesota, with Escherichia coli and Pseudomonas aeruginosa BSI from 1 January 1998 to 31 December 2007 were identified. Logistic regression was used to examine the association between BSIMRS and mortality. Area under receiver operating characteristic curve (AUC) was calculated to quantify the discriminative ability of the BSIMRS to predict a variety of short-term and long-term outcomes. Overall, 424 unique Olmsted County residents with first episodes of E. coli and P. aeruginosa BSI were included in the study. Median age was 68 (range 0-99) years, 280 (66%) were women, 61 (14%) had cancer and 9 (2%) had liver cirrhosis. The BSIMRS was associated with 28-day mortality (p <0.001) with an AUC of 0.86. There was an almost 56% increase in 28-day mortality for each point increase in BSIMRS (OR 1.56, 95% CI 1.40-1.78). A BSIMRS ≥ 5 had a sensitivity of 74% and a specificity of 87% to predict 28-day mortality with a negative predictive value of 97%. The BSIMRS had AUC of 0.85, 0.85 and 0.81 for 7-, 14- and 365-day mortality, respectively. BSIMRS stratified mortality with high discrimination in a population-based cohort that included patients of all age groups who had a relatively low prevalence of cancer and liver cirrhosis.

Overall burden of bloodstream infection and nosocomial bloodstream infection in North America and Europe.

In this systematic review, we estimated the total number of episodes of bloodstream infection (BSI) and deaths from BSI per year in North America and Europe, using data from population-based settings. Then, we estimated the number of episodes and deaths from nosocomial BSI from population-based studies and nosocomial infection surveillance systems. We estimated 575 000-677 000 episodes of BSI per year in North America (536 000-628 000 in the USA and 40 000-49 000 in Canada) and 79 000-94 000 deaths (72 000-85 000 in the USA and 7000-9000 in Canada), using estimates from three population-based studies. We estimated over 1 200 000 episodes of BSI and 157 000 deaths per year in Europe, using estimates from one population-based study in each of the following countries: Denmark (9100 episodes and 1900 deaths), Finland (8700 episodes and 1100 deaths) and England (96 000 episodes and 12 000-19 000 deaths). There were substantial differences in estimates of nosocomial BSI between population-based and nosocomial infection surveillance data. BSI has a major impact on the morbidity and mortality of the general population, as it ranks among the top seven causes of death in all included countries in North America and Europe. However, it is difficult to obtain precise estimates of nosocomial BSI, owing to the limited number of studies. This review highlights the need for a greater focus on BSI research in order to reduce the overall burden of disease by improving the outcome of patients with BSI. It also emphasizes the role of infection control and prevention methods in reducing the burden of nosocomial BSI.

Predictive scoring model of mortality in Gram-negative bloodstream infection.

Mortality is a well-recognized complication of Gram-negative bloodstream infection (BSI). The aim of this study was to develop a model to predict mortality in patients with Gram-negative BSI by using the Pitt bacteraemia score (PBS) and other clinical and laboratory variables. A cohort of 683 unique adult patients who were followed for at least 28 days after admission to Mayo Clinic Hospitals with Gram-negative BSI from 1 January 2001 to 31 October 2006 and who received clinically predefined appropriate empirical antimicrobial therapy was retrospectively identified. Multivariable logistic regression was used to identify independent risk factors for 28-day all-cause mortality. Regression coefficients from a multivariable model were used to develop a risk score to predict mortality following Gram-negative BSI. Malignancy (OR 3.48, 95% CI 1.94-6.22), liver cirrhosis (OR 5.42, 95% CI 2.52-11.65), source of BSI other than urinary tract or central venous catheter infection (OR 5.54, 95% CI 2.42-12.69), and PBS (OR 1.98, 95% CI 0.92-4.25 for PBS of 2-3 and OR 6.42, 95% CI 3.11-13.24 for PBS ≥4) were identified as independent risk factors for 28-day mortality in patients with Gram-negative BSI. A risk-score model was created by adding points for each independent risk factor, and had a c-statistic of 0.84. Patients with risk scores of 0, 4, 8, 12 and 16 had estimated 28-day mortality rates of approximately 0%, 3%, 14%, 45%, and 81%, respectively. The Gram-negative BSI risk score described herein estimated mortality risk with high discrimination in patients with Gram-negative BSI who received clinically adequate empirical antimicrobial therapy.

Impact of healthcare-associated acquisition on community-onset Gram-negative bloodstream infection: a population-based study: healthcare-associated Gram-negative BSI.

We performed a population-based study to examine the influence of healthcare-associated acquisition on pathogen distribution, antimicrobial resistance, short- and long-term mortality of community-onset Gram-negative bloodstream infections (BSI). We identified 733 unique patients with community-onset Gram-negative BSI (306 healthcare-associated and 427 community-acquired) among Olmsted County, Minnesota, residents from 1 January 1998 to 31 December 2007. Multivariate logistic regression was used to examine the association between healthcare-associated acquisition and microbiological etiology and antimicrobial resistance. Multivariate Cox proportional hazards regression was used to evaluate the influence of the site of acquisition on mortality. Healthcare-associated acquisition was predictive of Pseudomonas aeruginosa (odds ratio [OR] 3.14, 95% confidence intervals [CI]: 1.59-6.57) and the group of Enterobacter, Citrobacter, and Serratia species (OR 2.23, 95% CI: 1.21-4.21) as causative pathogens of community-onset Gram-negative BSI. Healthcare-associated acquisition was also predictive of fluoroquinolone resistance among community-onset Gram-negative bloodstream isolates (OR 2.27, 95% CI: 1.18-4.53). Healthcare-associated acquisition of BSI was independently associated with higher 28-day (hazard ratio [HR] 3.73, 95% CI: 2.13-6.93) and 1-year mortality (HR 3.60, 95% CI: 2.57-5.15). Because of differences in pathogen distribution, antimicrobial resistance, and outcomes between healthcare-associated and community-acquired Gram-negative BSI, identification of patients with healthcare-associated acquisition of BSI is essential to optimize empiric antimicrobial therapy.

Influence of referral bias on the clinical characteristics of patients with Gram-negative bloodstream infection.

Referral bias can influence the results of studies performed at tertiary-care centres. In this study, we evaluated demographic and microbiological factors that influenced referral of patients with Gram-negative bloodstream infection (BSI). We identified 2919 and 846 unique patients with Gram-negative BSI in a referral cohort of patients treated at Mayo Clinic Hospitals and a population-based cohort of Olmsted County, Minnesota, residents between 1 January 1998 and 31 December 2007, respectively. Multivariable logistic regression analysis was used to determine factors associated with referral. Elderly patients aged ≥80 years with Gram-negative BSI were less likely to be referred than younger patients [odds ratio (OR) 0·43, 95% confidence intervals (CI) 0·30-0·62] as were females (OR 0·63, 95% CI 0·53-0·74). After adjusting for age and gender, bloodstream isolates of Escherichia coli (OR 0·50, 95% CI 0·43-0·58) and Proteus mirabilis (OR 0·49, 95% CI 0·30-0·82) were underrepresented in the referral cohort; and Pseudomonas aeruginosa (OR 2·26, 95% CI 1·70-3·06), Enterobacter cloacae (OR 2·31, 95% CI 1·53-3·66), Serratia marcescens (OR 2·34, 95% CI 1·33-4·52) and Stenotrophomonas maltophilia (OR 17·94, 95% CI 3·98-314·43) were overrepresented in the referral cohort. We demonstrated that demographic and microbiological characteristics of patients with Gram-negative BSI had an influence on referral patterns. These factors should be considered when interpreting results of investigations performed at tertiary-care centres.

Epidemiology and outcome of Gram-negative bloodstream infection in children: a population-based study.

Population-based studies of Gram-negative bloodstream infection (BSI) in children are lacking. Therefore, we performed this population-based investigation in Olmsted County, Minnesota, to determine the incidence rate, site of acquisition, and outcome of Gram-negative BSI in children aged ⩽18 years. We used Kaplan-Meier method and Cox proportional hazard regression for mortality analysis. We identified 56 unique children with Gram-negative BSI during the past decade. The gender-adjusted incidence rate of Gram-negative BSI per 100 000 person-years was 129·7 [95% confidence interval (CI) 77·8-181·6]) in infants, with a sharp decline to 14·6 (95% CI 6·0-23·2) and 7·6 (95% CI 4·3-10·9) in children aged 1-4 and 5-18 years, respectively. The urinary tract was the most commonly identified source of infection (34%) and Escherichia coli was the most common pathogen isolated (38%). Over two-thirds (68%) of children had underlying medical conditions that predisposed to Gram-negative BSI. The overall 28-day and 1-year all-cause mortality rates were 11% (95% CI 3-18) and 18% (95% CI 8-28), respectively. Younger age and number of underlying medical conditions were associated with 28-day and 1-year mortality, respectively. Nosocomial or healthcare-associated acquisition was associated with both 28-day and 1-year mortality.

Temporal trends in Enterobacter species bloodstream infection: a population-based study from 1998-2007.

Enterobacter species are the fourth most common cause of Gram-negative bloodstream infection (BSI). We examined temporal changes and seasonal variation in the incidence rate of Enterobacter spp. BSI, estimated 28-day and 1-year mortality, and determined in vitro antimicrobial resistance rates of Enterobacter spp. bloodstream isolates in Olmsted County, Minnesota, from 1 January 1998 to 31 December 2007. Multivariable Poisson regression was used to examine temporal changes and seasonal variation in incidence rate and Kaplan-Meier method was used to estimate 28-day and 1-year mortality. The median age of patients with Enterobacter spp. BSI was 58 years and 53% were female. The overall age- and gender-adjusted incidence rate of Enterobacter spp. BSI was 3.3 per 100,000 person-years (95% CI 2.3-4.4). There was a linear trend of increasing incidence rate from 0.8 (95% CI 0-1.9) to 6.2 (95% CI 3.0-9.3) per 100,000 person-years between 1998 and 2007 (p 0.002). There was no significant difference in the incidence rate of Enterobacter spp. BSI during the warmest 4 months compared to the remainder of the year (incidence rate ratio 1.06; 95% CI 0.47-2.01). The overall 28-day and 1-year mortality rates of Enterobacter spp. BSI were 21% (95% CI 8-34%) and 38% (95% CI 22-53%), respectively. Up to 13% of Enterobacter spp. bloodstream isolates were resistant to third-generation cephalosporins. To our knowledge, this is the first population-based study to describe the epidemiology and outcome of Enterobacter spp. BSI. The increase in incidence rate of Enterobacter spp. BSI over the past decade, coupled with its associated antimicrobial resistance, dictate the need for further investigation of this syndrome.

Seasonal variation in Escherichia coli bloodstream infection: a population-based study.

Seasonal variation in the rates of infection with certain Gram-negative organisms has been previously examined in tertiary-care centres. We performed a population-based investigation to evaluate the seasonal variation in Escherichia coli bloodstream infection (BSI). We identified 461 unique patients in Olmsted County, Minnesota, from 1 January 1998 to 31 December 2007, with E. coli BSI. Incidence rates (IR) and IR ratios were calculated using Rochester Epidemiology Project tools. Multivariable Poisson regression was used to examine the association between the IR of E. coli BSI and average temperature. The age- and gender-adjusted IR of E. coli BSI per 100 000 person-years was 50.2 (95% CI 42.9-57.5) during the warmest 4 months (June through September) compared with 37.1 (95% CI 32.7-41.5) during the remainder of the year, resulting in a 35% (95% CI 12-66%) increase in IR during the warmest 4 months. The average temperature was predictive of increasing IR of E. coli BSI (p 0.004); there was a 7% (95% CI 2-12%) increase in the IR for each 10-degree Fahrenheit (c. 5.5 degrees C) increase in average temperature. To our knowledge, this is the first study to demonstrate seasonal variation in E. coli BSI, with a higher IR during the warmest 4 months than during the remainder of the year.

Incidence rate and outcome of Gram-negative bloodstream infection in solid organ transplant recipients.

Bacterial infections are common complications of solid organ transplantation (SOT). In this study, we defined the incidence, mortality and in vitro antimicrobial resistance rates of Gram-negative bloodstream infection (BSI) in SOT recipients. We identified 223 patients who developed Gram-negative BSI among a cohort of 3367 SOT recipients who were prospectively followed at the Mayo Clinic (Rochester, MN) from January 1, 1996 to December 31, 2007. The highest incidence rate (IR) of Gram-negative BSI was observed within the first month following SOT (210.3/1000 person-years [95% confidence interval (CI): 159.3-268.3]), with a sharp decline to 25.7 (95% CI: 20.1-32.1) and 8.2 (95% CI: 6.7-10.0) per 1000 person-years between 2 and 12 months and more than 12 months following SOT, respectively. Kidney recipients were more likely to develop Gram-negative BSI after 12 months following transplantation than were liver recipients (10.3 [95% CI: 7.9-13.1] vs. 5.2 [95% CI: 3.1-7.8] per 1000 person-years). The overall unadjusted 28-day all-cause mortality of Gram-negative BSI was 4.9% and was lower in kidney than in liver recipients (1.6% vs. 13.2%, p < 0.001). We observed a linear trend of increasing resistance among Escherichia coli isolates to fluoroquinolone antibiotics from 0% to 44% (p = 0.002) throughout the study period. This increase in antimicrobial resistance may influence the choice of empiric therapy.