Inappropriate Initial Antimicrobial Therapy Research Articles

239. Outcomes Associated with Empiric Aztreonam Use Compared to Anti-Pseudomonal β-lactams in Patients with Sepsis: An Opportunity for Allergy Stewardship

BackgroundAztreonam is often given to patients with a documented β-lactam allergy in lieu of a first-line anti-pseudomonal β-lactam (APBL). However, aztreonam offers no gram positive coverage and data suggest that gram negative organisms have lower susceptibility rates to this antibiotic than to APBLs. Septic patients are especially vulnerable to poor outcomes since inappropriate initial antimicrobial therapy has been shown to be an independent predictor of increased mortality. The purpose of this study was to determine whether septic patients treated with aztreonam experience inferior outcomes compared to those treated with an APBL.MethodsThis was a retrospective, multicenter, cohort study of all adult patients in metro Charlotte Atrium Health facilities treated for sepsis or septic shock from January 2014 to October 2017. Patients receiving either aztreonam or an APBL were identified using the system-wide sepsis database and enrolled in a 1:2 ratio. Patients were excluded if there was no infection-related discharge ICD-9 or ICD-10 code, if they received both aztreonam and an APBL in the first 8 hours, or if they received fewer than 2 doses of the study antibiotic. The primary endpoint was in-hospital mortality.ResultsA total of 194 patients received aztreonam and 388 patients received an APBL. β-lactam allergies were more common in patients who received aztreonam compared to APBL (97% vs. 14.2%, p < 0.01). In-hospital mortality rates were greater in the patients who received aztreonam vs. APBL (22.7% vs. 12.9%, p = 0.0025). After adjusting for APACHE II score, initial aztreonam exposure remained independently associated with hospital mortality (OR = 1.74, 95% CI: 1.0 – 2.8, p = 0.02). Additionally, we identified an increase in combination therapy with the use of aminoglycosides (28.9% vs. 12.4%, p < 0.0001) and fluoroquinolones (50.5% vs. 25.8%, p < 0.0001) in patients receiving aztreonam. No difference was found in overall length of stay or ICU length of stay.ConclusionIn septic patients, the use of aztreonam as the backbone of antimicrobial therapy may result in increased mortality. This highlights the importance of stewardship interventions that obtain an accurate allergy history and encourage the use of APBL antibiotics whenever feasible.Disclosures Kelly E. Pillinger, PharmD, BCIDP, Pharmacy Times (Other Financial or Material Support, Speaker)

Inappropriate initial antimicrobial therapy for hematological malignancies patients with Gram-negative bloodstream infections.

Inappropriate initial antimicrobial therapy (IIAT) may increase the mortality rate of hematological malignancies (HMs) patients with Gram-negative bacteria bloodstream infections (GN-BSI). The aim of this study is to determine whether IIAT affects the prognosis in this patient population and recommend the appropriate antibiotic regimen to minimize IIAT. We reviewed a retrospective cohort study of 361 HM patients with neutropenic fever from GN-BSI. The patients' clinical characteristics and the results of the drug sensitivity test in vitro were analyzed. IIAT rate was 21.3% in HM patients with neutropenic fever caused by GN-BSI. There was a significant difference in 7-day mortality rate between patients treated with appropriate antibiotics and those with IIAT (7.7% vs 29.9%, p < 0.01). Multivariate analysis confirmed that IIAT was an independent risk factors for early mortality [4.860 (1.541-15.323)]. Drug sensitivity data of GN-bacteria suggested that carbapenems monotherapy or beta-lactamase inhibitors (BLBLI) combined with amikacin as the initial therapy can effectively reduce the IIAT rate. In the stratified antibiogram based on prior antimicrobial exposure, our results showed that BLBLI monotherapy could be initially used as an empirical treatment in patients without prior antimicrobial exposure. In those who had received prior antimicrobial exposure, BLBLI (especially piperacillin-tazobactam) combined with amikacin is recommended. IIAT was a critical factor contributing to the mortality of HM patients with neutropenic fever from GN-BSI.

181. Antimicrobial Susceptibility Trends and Risk Factors for Antibiotic Resistance in Pseudomonas aeruginosa Bacteremia: A 10-Year Experience at a Korean Tertiary Hospital

BackgroundBacteremia due to Pseudomonas aeruginosa is associated with high mortality and inappropriate initial antimicrobial therapy leads to worse outcomes. We aimed to analyze clinical characteristics of P. aeruginosa bacteremia and risk factors for antibiotic resistance and investigate their antimicrobial susceptibility trends.MethodsWe retrospectively reviewed the medical records of patients with P. aeruginosa bacteremia admitted to a tertiary hospital between January 2009 and March 2019.ResultsA total of 242 patients were identified and the median age was 70 years [interquartile range (IQR) 57.6–75.4]. Hepatobiliary tract (28.5%) was most common primary site of infection, followed by respiratory tract (20.2%) and urinary tract (15.7%). Out of 197 (81.4%) patients treated with susceptible antibiotics and the median duration of active antibiotic therapy was 10 days (IQR 4–15.5). The percentages of susceptible P. aeruginosa to amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, colistin, gentamicin, imipenem, meropenem, piperacillin–tazobactam, and ticarcillin-clavulanate were 90.1%, 57.9%, 77.3%, 74.8%, 74.4%, 99.2%, 91.3%, 76.0%, 76.0%, 69.4%, and 51.2%. There were 24.8% carbapenem-resistant P. aeruginosa (CRPA), 36.4% multidrug-resistant P. aeruginosa (MDRPA), and 15.3% extensively drug-resistant P. aeruginosa (XDRPA). Susceptible P. aeruginosa to gentamycin and ticarcillin-clavulanate were significantly decreased in 2014–2019 than that in 2009–2013 (both; P < 0.001). Resistance rates to carbapenems and fluoroquinolones tended to increase over time. CRPA, MDRPA, and XDRPA were significantly associated with delayed active therapy (>48 h) (all; P < 0.001). Independent risk factors for CRPA were urinary tract infection (adjusted odds ratio [aOR], 3.4; 95% confidence interval [CI], 1.5–7.8), underlying hematologic malignancy (aOR, 3.0; 95% CI, 1.1–8.3) and cerebrovascular accident (aOR, 2.6; 95% CI, 1.1–5.9), hospital-acquired infection (aOR, 2.5; 95% CI, 1.0–6.1), and co-colonization with multidrug-resistant organisms (aOR, 2.2; 95% CI, 1.1–4.4).ConclusionThe identification of risk factors for antibiotic resistance and analysis of antibiotics susceptibility are useful for early initiation of appropriate antibiotics in patients with P. aeruginosa bacteremia.Disclosures All authors: No reported disclosures.

Risk factors for Pseudomonas aeruginosa infections in Asia-Pacific and consequences of inappropriate initial antimicrobial therapy: A systematic literature review and meta-analysis.

Treating infections of Gram-negative pathogens, in particular Pseudomonas aeruginosa, is a challenge for clinicians in the Asia-Pacific region owing to inherent and acquired antimicrobial resistance. This systematic review and meta-analysis provides updated information on risk factors for P. aeruginosa infection in Asia-Pacific as well as the consequences (e.g. mortality, costs) of initial inappropriate antimicrobial therapy (IIAT). Embase and MEDLINE databases were searched for Asia-Pacific studies reporting the consequences of IIAT versus initial appropriate antimicrobial therapy (IAAT) in Gram-negative bacterial infections as well as risk factors for serious P. aeruginosa infection. A meta-analysis of unadjusted mortality was performed using a random-effects model. A total of 22 studies reporting mortality and 13 reporting risk factors were identified. The meta-analysis demonstrated that mortality was significantly lower in patients receiving IAAT versus IIAT, with a 67% reduction observed for 28- or 30-day all-cause mortality (odds ratio=0.33, 95% confidence interval 0.20-0.55; P<0.001). Risk factors for serious P. aeruginosa infection include previous exposure to antimicrobials, mechanical ventilation and previous hospitalisation. High rates of antimicrobial resistance in Asia-Pacific as well as the increased mortality associated with IIAT and the presence of risk factors for serious infection highlight the importance of access to newer and appropriate antimicrobials.

Pseudomonas aeruginosa Antimicrobial Susceptibility Results from Four Years (2012 to 2015) of the International Network for Optimal Resistance Monitoring Program in the United States.

Pseudomonas aeruginosa represents a major cause of health care-associated infections, and inappropriate initial antimicrobial therapy is associated with increased morbidity and mortality. The International Network for Optimal Resistance Monitoring (INFORM) program monitors the in vitro activity of ceftazidime-avibactam and many comparator agents. We evaluated the antimicrobial susceptibility of 7,452 P. aeruginosa isolates collected from 79 U.S. medical centers in 2012 to 2015. The isolates were collected and tested consecutively for susceptibility by broth microdilution method. Infection types included mainly pneumonia (50.5%), skin and skin structure (24.0%), urinary tract (7.8%), and bloodstream (7.7%) infections. The only compounds with >90% susceptibility rates were colistin (MIC50/90, 1/2 mg/liter, respectively; 99.4% susceptible), ceftazidime-avibactam (MIC50/90, 2/4 mg/liter, respectively; 97.0% susceptible), and amikacin (MIC50/90, 2/8 mg/liter, respectively; 97.0/93.0% susceptible [CLSI/EUCAST, respectively]). The addition of avibactam to ceftazidime increased the percentage of susceptible P. aeruginosa isolates from 84.3% to 97.0%. Multidrug resistance (MDR) and extensive drug resistance (XDR) phenotypes were observed among 1,151 (15.4%) and 698 (9.4%) isolates, respectively, and ceftazidime-avibactam inhibited 82.1 and 75.8% of these isolates at ≤8 mg/liter, respectively. High rates of cross-resistance were observed with ceftazidime, meropenem, and piperacillin-tazobactam, whereas ceftazidime-avibactam retained activity against isolates nonsusceptible to ceftazidime (81.0% susceptible), meropenem (86.2% susceptible), and piperacillin-tazobactam (85.4% susceptible), as well as isolates nonsusceptible to these three β-lactams (71.2% susceptible). The only antimicrobial combinations that provided a better overall anti-Pseudomonas coverage than ceftazidime-avibactam (97.0% susceptibility rate) were those including amikacin (97.0 to 98.4% coverage). Susceptibility rates remained stable during the study period. The results of this investigation highlight the challenge of optimizing empirical antimicrobial therapy for P. aeruginosa infections.

Acinetobacter baumannii bacteraemia in patients with haematological malignancy: a multicentre retrospective study from the Infection Working Party of Jiangsu Society of Hematology.

Acinetobacter baumannii (Ab) bacteraemia in patients with haematological malignancies is fatal but rarely reported. We explored the clinical characteristics, drug resistances and prognostic factors in these patients. This multicentre, retrospective study was conducted at the department of haematology wards of 18 tertiary hospitals in China from January 2014 to June 2015. The total clinical isolates from every source were collected from patients with haematological malignancy. Haematological malignancy patients diagnosed with Ab bacteraemia were analysed. During the study period, 40 patients with Ab bacteraemia were identified, accounting for 2.9% (40/1358) of bacteraemia cases, of which 25 (62.5%) had acute leukaemia (AL) and 27 (67.5%) had neutropaenia. Compared with non-neutropaenic patients, neutropaenic patients showed higher Acute Physiology and Chronic Health Evaluation (APACHE) scores and 30-day mortality rates (p < 0.05). The in vitro antibiotic susceptibility of Ab to colistin was highest, at 100%, followed by that of tigecycline (91.30%) and amikacin (75.86%). Compared with the patients who had carbapenem-susceptible Ab infections, patients infected with carbapenem-resistant Ab (CRAB) had significantly longer hospital stays and were more likely to have had exposure to carbapenem before bacteraemia (p < 0.05). The 30-day mortality rate was 32.5%. CRAB, neutropaenia, higher APACHE score, Pitt bacteraemia score and inappropriate initial antimicrobial therapy were significantly associated with 30-day mortality. Multivariable analysis showed that APACHE score and CRAB were independent predictors of 30-day mortality. Haematologic patients with AL and febrile neutropaenia were at high risk of Ab bacteraemia. More attention should be paid to CRAB, which is an independent risk factor for mortality in haematological malignancy patients with Ab bacteraemia.

Bloodstream Infection: The Influence of Risk Factors, Etiology and Antimicrobial Therapy on Mortality Rates

Introduction: Inappropriate initial antimicrobial therapy leads to higher mortality in patients with bloodstream infection. This study aimed to evaluate the relationship between risk factors, etiology and antimicrobial therapy on mortality rates of patients with bloodstream infection. Methods: Between January 2016 to December 2016, 167 patients with bloodstream infection were prospectively evaluated according to the presence or absence of inappropriate antimicrobial therapy of infection. Hospital mortality was the main outcome variable compared between the two study groups. Results: Infected patients who received inappropriate antimicrobial therapy had statistically more diabetes mellitus, chronic obstructive pulmonary disease, chronic renal disease and death than infected patients who initially received appropriate antimicrobial therapy. Loading dose error and error in starting antimicrobial administration were the most frequently detected error in our study and both were determinant factors related to increased mortality. Initial antimicrobial therapy was maintained, escalation and de-escalation 67.6%, 22.7% and 9.6% of cases, respectively. Coagulase negative staphylococci represented the majority reaching 40.7% and multi-drug resistant microorganisms were detected in 27.3% of infections. There was no observed difference in mortality rates among infections caused by resistant or susceptible microorganisms. Conclusion: Loading dose error and error in starting antimicrobial administration, were the most frequently detected error in our study and both were determinant factors related to increased mortality. Beside the multiple logistic regression analysis revealed that the delay in starting antimicrobial therapy was the only independent factor that increased mortality.

Appropriate antibiotic therapy in critically ill patients

Severe sepsis and septic shock are leading causes of morbidity and mortality in critically ill patients in and outside Intensive Care Units. Early hemodynamic and respiratory support, along with prompt appropriate antimicrobial therapy and source control of the infectious process are cornerstone management strategies to improve survival. Antimicrobial therapy should be as much appropriate as possible, since inappropriate initial antimicrobial therapy is associated with poorer outcome in different clinical settings. When prescribing antibiotic therapy, drug’s characteristics, along with dosing, pharmacokinetics, and pharmacodynamic properties related to the drug and to the clinical scenario should be well kept in mind in order to achieve maximal success.

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

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients.The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance.The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria.An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.

Appropriate and timely antimicrobial therapy in cirrhotic patients with spontaneous bacterial peritonitis-associated septic shock: a retrospective cohort study.

Spontaneous bacterial peritonitis (SBP)-associated septic shock carries significant mortality in cirrhosis. To determine whether practice-related aspects of antimicrobial therapy contribute to high mortality. Retrospective cohort study of all (n=126) cirrhotics with spontaneous bacterial peritonitis (neutrophil count >250 or positive ascitic culture)-associated septic shock (1996-2011) from an international, multicenter database. Appropriate antimicrobial therapy implied either in vitro activity against a subsequently isolated pathogen (culture positive) or empiric management consistent with broadly accepted norms (culture negative). Overall hospital mortality was 81.8%. Comparing survivors (n=23) with non-survivors (n=103), survivors had lower Acute Physiology and Chronic Health Evaluation (APACHEII) (mean±s.d.; 22±7 vs. 32±8) and model for end-stage liver disease (MELD) (24±9 vs. 34±11) scores and serum lactate on admission (4.9±3.1 vs. 8.9 ±5.3), P<0.001 for all. Survivors were less likely to receive inappropriate initial antimicrobial therapy (0% vs. 25%, P=0.013) and received appropriate antimicrobial therapy earlier [median 1.8 (1.1-5.2) vs. 9.5 (3.9-14.3)h, P<0.001]. After adjusting for covariates, APACHEII [OR, odds ratio 1.45 (1.04-2.02) per 1 unit increment, P=0.03], lactate [OR 2.34 (1.04-5.29) per unit increment, P=0.04] and time delay to appropriate antimicrobials [OR 1.86 (1.10-3.14) per hour increment, P=0.02] were significantly associated with increased mortality. Cirrhotic patients with septic shock secondary to spontaneous bacterial peritonitis have high mortality (>80%). Each hour of delay in appropriate antimicrobial therapy was associated with a 1.86 times increased hospital mortality. Admission APACHEII and serum lactate also significantly impacted hospital mortality. Earlier initiation of appropriate antimicrobial therapy could substantially improve outcome.

260 Inappropriate Initial Antimicrobial Therapy in the Emergency Department and Mortality in Severe Sepsis and Septic Shock

260 Inappropriate Initial Antimicrobial Therapy in the Emergency Department and Mortality in Severe Sepsis and Septic Shock

Risk Factors and Outcome Analysis of Acinetobacter baumannii Complex Bacteremia in Critical Patients*

Acinetobacter baumannii complex bacteremia has been identified increasingly in critical patients admitted in ICUs. Notably, A. baumannii complex bacteremia has a high mortality rate, yet the risk factors associated with mortality remain unclear and controversial. Retrospective study. All adult ICUs at a tertiary care medical center. All patients with A. baumannii complex bacteremia admitted in 2009-2010. None. Risk factors for mortality were analyzed. Bacterial isolates were identified by 16S-23S ribosomal RNA intergenic spacer region sequencing for genospecies and genotyped by pulsed-field gel electrophoresis. Carbapenemase genes were detected by polymerase chain reaction and sequencing. A total of 298 patients met the inclusion criteria, including 73 (24.5%) infected by imipenem-resistant A. baumannii complex. The overall 30-day mortality was 33.6% (100 of 298). Imipenem-resistant A. baumannii complex bacteremia specifically showed a high mortality (69.9%) and was associated with prior use of broad-spectrum antibiotics for more than 5 days for treating ventilator-associated pneumonia before the occurrence of bacteremia. Mortality was associated with inappropriate initial antimicrobial therapy, which was correlated with imipenem-resistant A. baumannii complex but not with any specific genospecies. ISAba1-blaOXA-23-ISAba1 (Tn2006) was found in most (66.7%, 40 of 68) imipenem-resistant A. baumannii (genospecies 2) and also spread beyond species border to all imipenem-resistant genospecies 3 (2), 13TU (2), and 10 (1). For critical patients with A. baumannii complex infection, ventilator-associated pneumonia in particular, the selective pressure from prior use of broad-spectrum antibiotics for 5 days or more increased risk of subsequent imipenem-resistant A. baumannii complex bacteremia. To reduce mortality, rapid identification of imipenem-resistant A. baumannii complex and early initiation of appropriate antimicrobial therapy in these high-risk patients are crucial.

Outcomes and risk factors for mortality in community-onset bacteremia caused by extended-spectrum beta-lactamase-producing Escherichia coli, with a special emphasis on antimicrobial therapy

Although extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli has emerged as a significant pathogen, there is little information regarding treatment outcomes in community-onset bacteremia due to ESBL E. coli. The purpose of this study was to evaluate treatment outcomes of community-onset bacteremia caused by ESBL-producing E. coli and the factors associated with mortality. A retrospective cohort study was performed, including 92 adult patients with community-onset bacteremia caused by ESBL-producing E. coli. The 30-day mortality rate was 10.9% (10/92). Independent risk factors for mortality were underlying liver disease and severity of illness (e.g., high Pitt bacteremia score, the presence of severe sepsis or septic shock; p < 0.05). Mortality in patients receiving inappropriate initial antimicrobial therapy was not significantly higher than mortality in those receiving appropriate empirical antimicrobial therapy (10.9 vs 10.7%; p = 0.975), if antimicrobial therapy was adjusted appropriately according to susceptibility results. Carbapenems, piperacillin/tazobactam, fluoroquinolones, and amikacin were the most effective antibiotics for community-onset bacteremia caused by ESBL-producing E. coli, although susceptibility profiles confirmed that alternatives to carbapenems are limited. Of 68 isolates in which the ESBLs and their molecular relationships were studied, all isolates produced ESBLs from the CTX-M family (CTX-M-14, 30 isolates; CTX-M-15, 22; and other CTX-M, 16). In patients with community-onset bacteremia caused by ESBL-producing E. coli, severe sepsis and underlying liver disease were significantly associated with mortality, and a delay in appropriate antimicrobial therapy was not associated with a higher mortality if therapy was adjusted appropriately according to the susceptibility results.

Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis

It is unclear whether practice-related aspects of antimicrobial therapy contribute to the high mortality from septic shock among patients with cirrhosis. We examined the relationship between aspects of initial empiric antimicrobial therapy and mortality in patients with cirrhosis and septic shock. This was a nested cohort study within a large retrospective database of septic shock from 28 medical centers in Canada, the United States, and Saudi Arabia by the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group between 1996 and 2008. We examined the impact of initial empiric antimicrobial therapeutic variables on the hospital mortality of patients with cirrhosis and septic shock. Among 635 patients with cirrhosis and septic shock, the hospital mortality was 75.6%. Inappropriate initial empiric antimicrobial therapy was administered in 155 (24.4%) patients. The median time to appropriate antimicrobial administration was 7.3 hours (interquartile range, 3.2-18.3 hours). The use of inappropriate initial antimicrobials was associated with increased mortality (adjusted odds ratio [aOR], 9.5; 95% confidence interval [CI], 4.3-20.7], as was the delay in appropriate antimicrobials (aOR for each 1 hour increase, 1.1; 95% CI, 1.1-1.2). Among patients with eligible bacterial septic shock, a single rather than two or more appropriate antimicrobials was used in 226 (72.9%) patients and was also associated with higher mortality (aOR, 1.8; 95% CI, 1.0-3.3). These findings were consistent across various clinically relevant subgroups. Conclusion: In patients with cirrhosis and septic shock, inappropriate and delayed appropriate initial empiric antimicrobial therapy is associated with increased mortality. Monotherapy of bacterial septic shock is also associated with increased mortality. The process of selection and implementation of empiric antimicrobial therapy in this high-risk group should be restructured. (Hepatology 2012;56:2305–2315)

Clinical impact of inappropriate initial antimicrobial therapy on outcome in bacteremic biliary tract infections

The marked increase in the incidence of biliary tract infections due to antimicrobial-resistant pathogens in recent years is of great concern, as patients infected by these isolates might initially receive antibiotics ineffective against the responsible pathogens. A retrospective cohort study including 556 episodes of bacteremic biliary tract infection was designed to evaluate the impact of inappropriate initial antimicrobial therapy on the clinical outcomes of patients with biliary tract infections. Of 556 episodes, 257 (46.2%) received inappropriate initial antimicrobial therapy. Although Escherichia coli and Klebsiella species are the most common pathogens, the pathogens that were most frequently associated with inappropriate therapy were Pseudomonas aeruginosa and Enterococcus spp. In multivariable analysis, inappropriate initial antimicrobial therapy was found to be independently associated with increased mortality (odds ratio (OR) 2.25, 95% confidence interval (CI) 1.13-4.48; p = 0.021), along with pancreaticobiliary tract cancer, liver cirrhosis, Enterobacter infection, and a high Pitt bacteremia score (All p < 0.05). Subgroup multivariate analyses showed that inappropriate initial therapy was not a significant factor associated with mortality in cases where therapeutic decompression or drainage procedures were employed (OR 1.24, 95% CI 0.43-3.54; p = 0.691) or in cases with appropriate definitive antimicrobial therapy (OR 1.61, 95% CI 0.69-3.72; p = 0.270) after adjustment for other variables. Our findings suggest that the administration of inappropriate initial antimicrobial therapy might be associated with an adverse outcome in patients experiencing bacteremic biliary tract infections, and that the impact of inappropriate therapy on the outcome may be dependent on therapeutic drainage and appropriate definitive antimicrobial therapy.

Dendritic Cells Are Central Coordinators of the Host Immune Response to Staphylococcus aureus Bloodstream Infection

Dendritic cells (DCs) play an important role in integration of the immune responses induced by pathogens. The purpose of this study was to determine the importance of DCs in host defense against Staphylococcus aureus bacteremia. Using a murine infection model, we demonstrated that DCs are rapidly recruited into infected tissue after intravenous inoculation with S. aureus. The recruited DCs were fully functional and in a more advanced stage of maturation than those isolated from uninfected mice. Depletion of DCs in CD11c-DTR transgenic mice resulted in substantial worsening of infection, as indicated by increased bacterial loads in kidneys and lungs, accelerated mortality, and more severe pathology. Furthermore, DC depletion completely abolished IL-12 production in response to infection. The beneficial effect afforded by DCs during S. aureus infection was not mediated by their contribution to direct bacterial killing, nor by increased neutrophil recruitment. Instead, neutrophil influx (along with expression of CXC chemokines) was significantly enhanced in infected tissue after depletion of DCs. We also found that the bactericidal capacity of the recruited neutrophils was significantly impaired in DC-depleted mice. More importantly, the detrimental effect of DC depletion was practically reversed by treatment with exogenous recombinant mouse IL-12. Our results demonstrated that DCs, probably through their production of IL-12, play an important role in coordinating the inflammatory response during S. aureus infection.

An institutional perspective on the impact of recent antibiotic exposure on length of stay and hospital costs for patients with gram-negative sepsis

BackgroundPrior antibiotic exposure has been associated with the emergence of antibiotic resistance in subsequent bacterial infections, whose outcomes are typically worse than similar infections with more antibiotic susceptible infections. The influence of prior antibiotic exposure on hospital length of stay (LOS) and costs in patients with severe sepsis or septic shock attributed to Gram-negative bacteremia has not been previously examined.MethodsA retrospective cohort study of hospitalized patients (January 2002-December 2007) was performed at Barnes-Jewish Hospital, a 1200-bed urban teaching hospital. Patients with Gram-negative bacteremia complicated by severe sepsis or septic shock had data abstraction from computerized medical records. We examined a consecutive cohort of 754 subjects (mean age 59.3 ± 16.3 yrs, mean APACHE II 23.7 ± 6.7).ResultsEscherichia coli (30.8%), Klebsiella pneumoniae (23.2%), and Pseudomonas aeruginosa (17.6%) were the most common organisms isolated from blood cultures. 310 patients (41.1%) had exposure to antimicrobial agents in the previous 90 days. Patients with recent antibiotic exposure had greater inappropriate initial antimicrobial therapy (45.4% v. 21.2%; p < 0.001) and hospital mortality (51.3% v. 34.0%; p < 0.001) compared to patients without recent antibiotic exposure. The unadjusted median LOS (25th percentile, 75th percentile) following sepsis onset in patients with prior antimicrobial exposure was 13.0 days (5.0 days, 24.0 days) compared to 8.0 days (5.0 days, 14.0 days) in those without prior antimicrobial exposure (p < 0.001). In a Cox model controlling for multiple confounders, prior antibiotic exposure independently correlated with remaining hospitalized (Adjusted hazard ratio: 1.473, 95% CI: 1.297-1.672, p < 0.001). Adjusting for potential confounders indicated that prior antibiotic exposure independently increased median attributable LOS by 5.0 days. Similarly, total hospital costs following sepsis onset was significantly greater among patients with prior antimicrobial exposure (median values: $94,737 v. $21,329; p < 0.001).ConclusionsRecent antibiotic exposure is associated with increased LOS and hospital costs in Gram-negative bacteremia complicated by severe sepsis or septic shock. Clinicians and hospital administrators should consider the potential impact of recent antibiotic exposure when formulating empiric treatment decisions for patients with serious infections attributed to Gram-negative bacteria.

Health Care-Associated Pneumonia (HCAP)

Inappropriate initial antimicrobial therapy (IIAT) has been associated with decreased survival in patients with health care-associated pneumonia (HCAP). We performed a study to determine whether empiric HCAP antibiotic regimens targeting methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are associated with greater appropriate therapy. A retrospective cohort study of culture-positive HCAP over 6 years (January 2003-December 2008) was performed at Barnes-Jewish Hospital, a 1200-bed urban teaching hospital. We identified 757 consecutive patients with HCAP. IIAT was administered to 213 (28%) patients. The pathogens most frequently associated with IIAT included P. aeruginosa (n=60, 28%), MRSA (n=58, 27%), and Acinetobacter species (n=32, 15%).Multivariate logistic regression analysis demonstrated that empiric anti-pseudomonal antibiotics (adjusted odds ratio [AOR], 1.75; 95% confidence interval [CI], 1.34-2.29; p=0.036), empiric anti-MRSA antibiotics (AOR, 1.71; 95% CI, 1.36-2.14; p=0.018), infection with Streptococcus pneumoniae (AOR, 2.82; 95% CI, 2.03-3.91; p=0.002), absence of Acinetobacter species infection (AOR, 10.57; 95% CI, 7.29-15.33; p<0.001), absence of P. aeruginosa infection (AOR, 1.69; 95% CI, 1.36-2.05; p=0.014), and absence of Stenotrophomonas maltophilia infection (AOR, 20.43; 95% CI, 9.35-44.66; p<0.001) are independent predictors of appropriate therapy for HCAP. Our study suggests that initial therapy for HCAP should include antibiotics targeting MRSA and P. aeruginosa in order to provide appropriate initial therapy. However, the selection of individual antibiotic agents should be based on local patterns of infection and adjusted when microbiology results become available.

Risk factors for mortality in patients with Burkholderia cepacia complex bacteraemia

Over the last 2 decades, Burkholderia cepacia complex has emerged as a serious human pathogen, especially in critically ill patients. B. cepacia complex has been associated with increased morbidity and mortality in intensive care unit patients. However, in our literature search, we could not find studies on risk factors for mortality in patients with B. cepacia complex bacteraemia. Therefore, we investigated risk factors for mortality in B. cepacia complex bacteraemia. Clinical characteristics and laboratory parameters of 27 patients with 1 or more blood cultures positive for B. cepacia complex from January 2006 to October 2010 in Severance Hospital, Yonsei University College of Medicine, Korea were retrospectively analyzed. The main outcome measure was overall 28-day mortality. Appropriate initial empirical antimicrobial use was defined as administration of agent(s) to which the organism was susceptible within 24 h of obtaining blood for culture. The overall 28-day mortality rate was 41% (11/27). In univariate analysis, underlying diabetes mellitus (p = 0.033), inappropriate initial empirical antimicrobial therapy (p = 0.033), and an elevated Sequential Organ Failure Assessment (SOFA) score (p = 0.002) were significantly associated with mortality. In multivariate analysis, inappropriate initial empirical antimicrobial therapy and an elevated SOFA score were independent risk factors for increased mortality (p = 0.032 and p = 0.028, respectively). An elevated SOFA score and inappropriate initial empirical antimicrobial therapy were significantly associated with adverse outcome in patients with B. cepacia complex bacteraemia.

Impact of previous antibiotic therapy on outcome of Gram-negative severe sepsis*

To determine whether exposure to antimicrobial agents in the previous 90 days resulted in decreased bacterial susceptibility and increased hospital mortality in patients with severe sepsis or septic shock attributed to Gram-negative bacteremia. A retrospective cohort study of hospitalized patients (January 2002 to December 2007). Barnes-Jewish Hospital, a 1200-bed urban teaching hospital. Seven hundred fifty-four consecutive patients with Gram-negative bacteremia complicated by severe sepsis or septic shock. Data abstraction from computerized medical records. Escherichia coli (30.8%), Klebsiella pneumoniae (23.2%), and Pseudomonas aeruginosa (17.6%) were the most common isolates from blood cultures. Three hundred ten patients (41.1%) had recent antibiotic exposure. Cefepime was the most common agent with previous exposure (50.0%) followed by ciprofloxacin (32.6%) and imipenem or meropenem (28.7%). Patients with prior antibiotic exposure had significantly higher rates of resistance to cefepime (29.0% vs. 7.0%), piperacillin/tazobactam (31.9% vs. 11.5%), carbapenems (20.0% vs. 2.5%), ciprofloxacin (39.7% vs. 17.6%), and gentamicin (26.1% vs. 7.9%) (p < .001 for all comparisons). Patients with recent antibiotic exposure had greater inappropriate initial antimicrobial therapy (45.4% vs. 21.2%; p < .001) and hospital mortality (51.3% vs. 34.0%; p < .001) compared with patients without recent antibiotic exposure. Multivariate logistic regression analysis demonstrated that recent antibiotic exposure was independently associated with hospital mortality (adjusted odds ratio, 1.70; 95% confidence interval, 1.41-2.06; p = .005). Other variables independently associated with hospital mortality included use of vasopressors, infection resulting from P. aeruginosa, inappropriate initial antimicrobial therapy, increasing Acute Physiology and Chronic Health Evaluation II scores, and the number of acquired organ failures. Recent antibiotic exposure is associated with increased hospital mortality in Gram-negative bacteremia complicated by severe sepsis or septic shock. Clinicians caring for patients with severe sepsis or septic shock should consider recent antibiotic exposure when formulating empiric antimicrobial regimens for suspected Gram-negative bacterial infection.