Initiation Of Effective Antimicrobial Therapy Research Articles

Antimicrobial Resistance in Ventilator-Associated Pneumonia: Predictive Microbiology and Evidence-Based Therapy.

Ventilator-associated pneumonia (VAP) is a serious intensive care unit (ICU)-related infection in mechanically ventilated patients that is frequent, as more than half of antibiotics prescriptions in ICU are due to VAP. Various risk factors and diagnostic criteria for VAP have been referred to in different settings. The estimated attributable mortality of VAP can go up to 50%, which is higher in cases of antimicrobial-resistant VAP. When the diagnosis of pneumonia in a mechanically ventilated patient is made, initiation of effective antimicrobial therapy must be prompt. Microbiological diagnosis of VAP is required to optimize timely therapy since effective early treatment is fundamental for better outcomes, with controversy continuing regarding optimal sampling and testing. Understanding the role of antimicrobial resistance in the context of VAP is crucial in the era of continuously evolving antimicrobial-resistant clones that represent an urgent threat to global health. This review is focused on the risk factors for antimicrobial resistance in adult VAP and its novel microbiological tools. It aims to summarize the current evidence-based knowledge about the mechanisms of resistance in VAP caused by multidrug-resistant bacteria in clinical settings with focus on Gram-negative pathogens. It highlights the evidence-based antimicrobial management and prevention of drug-resistant VAP. It also addresses emerging concepts related to predictive microbiology in VAP and sheds lights on VAP in the context of coronavirus disease 2019 (COVID-19).

Clinical manifestations, treatment and outcomes of patients infected with Mycobacterium haemophilum with a focus on immune reconstitution inflammatory syndrome: a retrospective multi-site study

Background Mycobacterium haemophilum is a nontuberculous mycobacterium with fastidious in vitro growth requirements and an increasingly reported cause of extrapulmonary disease. Timely diagnosis and management of M. haemophilum infections and the immune reconstitution inflammatory syndromes (IRIS) observed in a subset of patients during treatment remain challenging. Methods We conducted a retrospective chart review between January 1, 2010, and January 1, 2022 and identified 26 patients diagnosed with M. haemophilum infection at our institution. We describe their clinical presentation, diagnostic results, management, and outcomes. Results The majority of patients in our cohort had upper and/or lower extremity skin involvement, were immunosuppressed, and had generally favourable treatment outcomes. All tested M. haemophilum isolates were susceptible in vitro to clarithromycin and trimethoprim-sulfamethoxazole. Moreover, high rates of susceptibility were noted for ciprofloxacin (95%), linezolid (90%), and rifampin (85%). IRIS was identified in 31% of cases and should be considered in patients who develop worsening skin lesions or systemic symptoms following the initiation of effective antimicrobial therapy. Visualisation of acid-fast bacilli on initial tissue stains, a positive mycobacterial blood culture, and rapid de-escalation of tumour necrosis factor-α inhibitors and/or corticosteroids were more frequently encountered among patients in our cohort who developed IRIS. Conclusion M. haemophilum infection should be considered among patients receiving immunomodulatory therapy who develop discoloured or nodular skin lesions involving the extremities, worsening focal arthritis, tenosynovitis, or isolated adenopathy. A heightened awareness of this pathogen’s clinical and laboratory characteristics can lead to a timely diagnosis and favourable outcome.

Laboratory and clinical impacts of an overnight laboratory service.

Delayed initiation of effective antimicrobial therapy for sepsis is associated with increased mortality. Whilst automated blood culture machines operate continuously, this does not align with conventional staff working hours and so turn-around-times (TAT) for reporting gram stains to clinicians are 3-7 times longer for blood cultures that flag positive overnight. We retrospectively compared laboratory TATs and clinical outcomes for blood cultures from 183 patients that flagged positive overnight during a 4-month period before and after the implementation of an overnight laboratory service. Enterobacterales and urinary tract infections were the most frequent pathogens and clinical syndrome respectively, and the prevalence of multi-resistant organisms was 15%. Compared with the pre-implementation period, the post-implementation period was associated with shorter median time from blood culture positivity to gram stain (7.4 vs 1.2 h), first genus level identification (7.2 vs 5.8 h) and first antimicrobial susceptibility result (24.1 vs 7.9 h). Similarly, the median time from blood culture positivity to clinicians first being informed was significantly shorter (9.2 vs 1.3 h). After removal of likely contaminants, 78% of patients were on effective empiric antimicrobials and for patients on ineffective empiric antimicrobials, effective therapy was initiated a median of 3.2 h sooner during the post-implementation period, without impact on mortality. Implementation of an overnight laboratory service was associated with significantly faster TAT for reporting blood culture results and more prompt initiation of effective antimicrobials for patients receiving ineffective empiric therapy, improving attainment of sepsis management goals.

Implementation of an adult code sepsis protocol and its impact on SEP-1 core measure perfect score attainment in the ED

IntroductionTimely management of sepsis has become an urgent concern among most hospitals. Institutions have been searching for unique ways to increase the quality of care and timely adherence to proven therapies. The objective of this study was to determine the impact of an Adult Code Sepsis Protocol on the rate of SEP-1 perfect score attainment (PSA) among patients who presented to the emergency department (ED) with severe sepsis or septic shock, as defined by the Centers for Medicare and Medicaid Services (CMS). MethodsThis was a retrospective, observational cohort study in a 35-bed tertiary care hospital ED from December 2016 to February 2018. Adults (≥18 years of age) who met the CMS-case definition of severe sepsis or septic shock presenting to the ED either prior to or after implementation of an Adult Code Sepsis Protocol were included. ResultsThe primary outcome of SEP-1 PSA, which was abstracted in an all-or-none fashion, increased from 30.7% to 71.3% (p < 0.001). Inpatient mortality was reduced from 4% to 0% (p = 0.011) after protocol implementation. Protocol initiation also resulted in a significant reduction in both time to initiation of appropriate, empiric and effective antimicrobial therapy, based on culture results by 48 and 111 min, respectively (p < 0.001). There were no significant differences in other secondary outcomes including ICU length-of-stay, readmission, or economic outcome measures. ConclusionsThe addition of an Adult Code Sepsis Protocol in the ED significantly increased the rate of SEP-1 PSA, reduced inpatient mortality, and improved the time to initiation of effective antimicrobial therapy.

919. Clinical and Microbiologic Characteristics Associated With Long-Term Orthopedic Complications Following Staphylococcus aureus Acute Hematogenous Osteoarticular Infections in Children

Background Staphylococcus aureus is the most common cause of acute hematogenous osteoarticular infections (AHOAIs) in children. While the vast majority of patients do well, a small proportion experience significant morbidity, including chronic infection and pathologic fractures. We sought to describe clinical and microbiologic variables present on the index admission that may predict long-term orthopedic complications (OC).MethodsCases of S. aureus AHOAI were identified from 2011 to 2016 at Texas Children’s Hospital (TCH). All cases were reviewed for the development of OC until April 1, 2018. OC included chronic osteomyelitis (CO), growth arrest/limb length discrepancy, avascular necrosis, chronic dislocation, and pathologic fracture (PF) with or without angular deformity. All S. aureus isolates were characterized by PCR for Panton–Valentine Leukocidin (PVL) genes and agr group. Statistical Analyses were performed with STATA.ResultsA total of 252 cases were identified meeting inclusion criteria (figure). Twenty-four (9.5%) developed OC; of which, 50% were CO and 25% PF. Patients who developed CO more often had positive blood cultures during the index admission (P < 0.001), surgical drainage after hospital day 2 (33.3% vs. 8.8%, P = 0.02) as well as a longer time to 50% reduction in C-reactive protein (CRP, 9 vs. 7 days, P = 0.01). Patients who developed PF more often had infection due to PVL-positive organisms (83.3% vs. 38.6%, P = 0.03) and had a longer duration of fever after admission (9.5 vs. 2.5 days, P = 0.03). Overall, OC were associated with ICU admission (P = 0.04), a slower decline in CRP (P = 0.02) and a greater proportion of patients with surgery after hospital day 2 (P = 0.04) as well as infection secondary to agr III isolates (P = 0.03). There was no statistically significant relationship between OC and patient age, affected bone, time to initiation of effective antimicrobial therapy, duration of intravenous therapy, or final antibiotic choice.ConclusionPatients with S. aureus AHOAI with a delay in source control, slow decline in CRP, prolonged fever or ICU admission are at higher risk of OC. While nonspecific, these findings suggest that such patients may warrant especially cautious clinical follow-up to identify sequelae early. Large multicenter studies are needed to better predict OC in this setting. Disclosures All authors: No reported disclosures.

Communicating antimicrobial resistance and stewardship in the national press: Lessons from sepsis awareness campaigns

1The Review on AMR was an expert panel commissioned by the UK Government in 2014 tasked with analysing the economic and social impacts of AMR and proposing solutions to these. 2NICE is a UK non-departmental public body that sponsored by but separate from the Department of Health that produces evidence-based guidance for health practitioners. 3NHS England is a non-departmental public body sponsored by the Department of Health that oversees planning and delivery of health services in England. 4Note that circulation of the News of the World ceased in July 2011; the Sun on Sunday was launched by the same newsgroup in 2012, but is unavailable on the Nexis database.

Impact of real-time notification of Clostridium difficile test results and early initiation of effective antimicrobial therapy

Clostridium difficile is a prominent nosocomial pathogen and is the most common causative organism of health care-associated diarrhea. To our knowledge, no studies have investigated the impact of real-time notification of culture results with rapid antimicrobial stewardship program (ASP) intervention in the setting of C difficile infection (CDI). The purpose of this study was to assess the impact of real-time notification of detection of toxigenic C difficile by DNA amplification results in patients with confirmed CDI. This is a single-center, retrospective cohort study at a 433-bed tertiary medical center in central Kentucky. The study consisted of 2 arms: patients treated for CDI prior to implementation of real-time provider notification and patients postimplementation. The primary outcome was time to initiation of effective antimicrobial therapy. The median time to initiation of effective antimicrobial therapy decreased from 5.75 hours in the preimplementation cohort to 2.05 hours in the postimplementation cohort (P = .001). ASP intervention also resulted in a shorter time from detection of CDI to order entry of effective antimicrobial therapy in the patient's electronic medical record (3.0 vs 0.6 hours; P = .001). The implementation of a real-time notification system to alert a pharmacist-led ASP of toxigenic CDI resulted in statistically significant shorter times to order entry and subsequent initiation of effective antimicrobial therapy and contact precautions.

The challenges in creating an institution‐specific antibiogram based on blood culture isolates

AbstractEarly initiation of effective antimicrobial therapy reduces morbidity and mortality. Annual institution‐specific antimicrobial susceptibility tables or antibiograms can be used to guide empiric antimicrobial therapy and monitor resistance. This paper describes the development of an antibiogram for a metropolitan hospital based on the international standard CLSI M39 document. An antibiogram was created each year using positive blood cultures for the years 2009 to 2011, excluding coagulase‐negative staphylococcus isolates which were assumed to be contaminants. Duplicate isolates within a 30‐day interval were also excluded. Challenges included, for example, attaining all the relevant information from the laboratory information system in a usable format, and the need for significant manual manipulation of the data. The development of the antibiogram for our institution was driven by the pharmacy department as an initiative to improve appropriate and effective use of antimicrobials.

Rapid Identification and Multiple Susceptibility Testing of Pathogens from Positive-Culture Sterile Body Fluids by a Combined MALDI-TOF Mass Spectrometry and Vitek Susceptibility System.

Infections of the bloodstream, central nervous system, peritoneum, joints, and other sterile areas are associated with high morbidity and sequelae risk. Timely initiation of effective antimicrobial therapy is crucial to improving patient prognosis. However, standard final identification and antimicrobial susceptibility tests (ASTs) are reported 16–48 h after a positive alert. For a rapid, effective and low-cost diagnosis, we combined matrix-assisted laser desorption/ionization time of flight mass spectrometry with a Vitek AST system, and performed rapid microbial identification (RMI) and rapid multiple AST (RMAST) on non-duplicated positive body fluid cultures collected from a hospital in Shanghai, China. Sterile body fluid positive culture and blood positive culture caused by Gram negative (GN) or polymicrobial were applied to the MALDI–TOF measurement directly. When positive blood culture caused by Gram positive (GP) bacteria or yeasts, they were resuspended in 1 ml brain heart infusion for 2 or 4 h enrichment, respectively. Regardless of enrichment, the RMI (completed in 40 min per sample) accurately identified GN and GP bacteria (98.9 and 87.2%, respectively), fungi (75.7%), and anaerobes (94.7%). Dominant species in multiple cultures and bacteria that failed to grow on the routing plates were correctly identified in 81.2 and 100% of cases, respectively. The category agreements of RMAST results, determined in the presence of various antibiotics, were similarly to previous studies. The RMI and RMAST results not only reduce the turnaround time of the patient report by 18–36 h, but also indicate whether a patient's antibiotic treatment should be accelerated, ceased or de-escalated, and adjusted the essential drugs modification for an optimized therapy.

Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients.

Limitations in methods for the rapid diagnosis of hospital-acquired infections often delay initiation of effective antimicrobial therapy. New diagnostic approaches offer potential clinical and cost-related improvements in the management of these infections. We developed a decision modeling framework to assess the potential cost-effectiveness of a rapid biomarker assay to identify hospital-acquired infection in high-risk patients earlier than standard diagnostic testing. The framework includes parameters representing rates of infection, rates of delayed appropriate therapy, and impact of delayed therapy on mortality, along with assumptions about diagnostic test characteristics and their impact on delayed therapy and length of stay. Parameter estimates were based on contemporary, published studies and supplemented with data from a four-site, observational, clinical study. Extensive sensitivity analyses were performed. The base-case analysis assumed 17.6% of ventilated patients and 11.2% of nonventilated patients develop hospital-acquired infection and that 28.7% of patients with hospital-acquired infection experience delays in appropriate antibiotic therapy with standard care. We assumed this percentage decreased by 50% (to 14.4%) among patients with true-positive results and increased by 50% (to 43.1%) among patients with false-negative results using a hypothetical biomarker assay. Cost of testing was set at $110/d. In the base-case analysis, among ventilated patients, daily diagnostic testing starting on admission reduced inpatient mortality from 12.3 to 11.9% and increased mean costs by $1,640 per patient, resulting in an incremental cost-effectiveness ratio of $21,389 per life-year saved. Among nonventilated patients, inpatient mortality decreased from 7.3 to 7.1% and costs increased by $1,381 with diagnostic testing. The resulting incremental cost-effectiveness ratio was $42,325 per life-year saved. Threshold analyses revealed the probabilities of developing hospital-acquired infection in ventilated and nonventilated patients could be as low as 8.4 and 9.8%, respectively, to maintain incremental cost-effectiveness ratios less than $50,000 per life-year saved. Development and use of serial diagnostic testing that reduces the proportion of patients with delays in appropriate antibiotic therapy for hospital-acquired infections could reduce inpatient mortality. The model presented here offers a cost-effectiveness framework for future test development.

Aggressive versus conservative initiation of antibiotics

www.thelancet.com/infection Vol 13 May 2013 389 2 Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34: 1589–96. 3 Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38: 1045–53. 4 Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296–327. 5 Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366: 2055–64. than 2 h. It is unclear why an ICU should be different, especially when the starting point is the drawing of blood cultures. By treating their aggressive group very late, the potential benefit of early antibiotics might have waned, while the hypothesised detrimental effects of empirical antibiotics remained. If true, a high case-fatality rate would be expected in the aggressive group. A high rate was indeed reported: overall 40% died in the aggressive group, with 66% mortality in the subset with septic shock. By contrast, the case fatality rate in the recent PROWESS-SHOCK study, in which all patients had septic shock, was only 24·2–26·4%. Waiting for positive cultures before starting antibiotics might only be effective when compared with very delayed empirical therapy. The aggressive protocol required antibiotics to be discontinued at day 3 if no positive cultures had been obtained. All the patients in Hranjec and colleagues’ study were in a surgical ICU, so presumably most received intraoperative prophylactic antibiotics, which might have increased the chance of a negative culture result. Mortality in the aggressive group might have been artificially high because of this policy. These substantial concerns warrant the investigators’ interpretation that practice should only change (if at all) in a context in which outcomes are rigorously and frequently analysed.

Is There a Starling Curve for Intensive Care?

Large differences exist in the provision of ICU beds worldwide, with a complicated mix of risks and benefits to the population of having either too few or too many beds. Having too few beds can result in delayed admission of patients to the ICU or no admission at all, with either scenario potentially increasing mortality. Potential societal benefits of having few beds include lower costs for health care and less futile intensive care at the end of life. With added ICU beds for a population, mortality benefit should accrue, but there is still the question of whether the addition of beds always means that more lives will be saved or whether there is a point at which no additional mortality benefit is gained. With an abundance of ICU beds may come the possibility of increasing harm in the forms of unnecessary costs, poor quality of deaths (ie, excessively intensive), and iatrogenic complications. The possibility of harm may be likened to the concept of falling off a Starling curve, which is traditionally used to describe worsening heart function when overfilling occurs. This commentary examines the possible implications of having too few or too many ICU beds and proposes the concept of a family of Starling curves as a way to conceptualize the balance of societal benefits and harms associated with different availability of ICU beds for a population.

Retrospective evaluation of colistin versus tigecycline for the treatment of Acinetobacter baumannii and/or carbapenem-resistant Enterobacteriaceae infections

Therapeutic options are limited for infections because of Acinetobacter baumannii and carbapenem-resistant Enterobacteriaceae (CRE). Study aim was to compare the efficacy of colistin to tigecycline for the treatment of these types of infections. A retrospective study was conducted at the Detroit Medical Center. Adult patients with infections because of A baumannii or CRE in 2009 who received ≥2 doses of colistin or tigecycline were studied. Risk factors, outcomes, and costs were analyzed. There were 82 patients with infections because of A baumannii, 12 with CRE, and 12 with A baumannii and CRE coinfection. Seventy-one patients received colistin, 16 received tigecycline, and 19 received both colistin and tigecycline. Seven isolates were nonsusceptible to colistin and 79 to tigecycline. Patients receiving colistin alone or in combination were more likely to die during their hospitalization than patients receiving only tigecycline (P = .002). However, patients receiving colistin had higher severity of acute illness and had notable delays in initiation of effective antimicrobial therapy (P < .001). Compared with patients who received tigecycline alone, patients who received colistin alone or in combination had a higher severity of acute illness indices and delays in initiation of effective therapy. This increased severity of illness contributed to the increased rate of mortality among patients treated with colistin for A baumannii or CRE infections.

Impact of stroke on therapeutic decision making in infective endocarditis

The diagnosis of infective endocarditis (IE) must be made as soon as possible to initiate antimicrobial therapy and identify patients at high risk for complications who may be best managed by early surgery. Cerebral complications make the timing of cardiac surgery difficult. The safety of cardiopulmonary bypass (CPB) surgery in stroke patients remains controversial. Stroke complicates the outcome of left-sided IE in 20-40% of cases and is associated with poor outcome. The risk of stroke in IE falls rapidly after the initiation of effective antimicrobial therapy. The risk of embolization is highest during the first week of therapy, and in patients with mobile vegetations or vegetations >10 mm in diameter occurring on the anterior mitral leaflet. Indications for valvular surgery are significant congestive heart failure or valvular regurgitation, myocardial abscess, persistent bacteremia and large-size vegetations with high risk of embolism. Decisions regarding surgical intervention in patients with IE should be individualized. In the absence of large prospective studies, optimal timing of surgery is still discussed when stroke complicates IE. A multidisciplinary assessment of the situation, involving cardiologists, cardiac surgeons, infectiologists and neurologists, is recommended. Estimating the risk of recurrence after a first embolic event and careful evaluation of the indication for valve replacement are essential steps in making the therapeutic decision. Surgery should be delayed if possible in the event of large cerebral infarction or ICH in order to prevent neurological deterioration. It has been suggested that valve replacement should be considered within the first 72 h if the patients with brain infarction have severe heart failure, otherwise after 4 weeks. Early surgery appears safe in patients presenting transient ischemic attacks or "silent" cerebral embolism.

Treatment of critically ill patients with candidemia

Early initiation of effective antimicrobial therapy is crucial for the prognosis of any infection, especially in the critically ill patient. This is particularly true in the case of candidemia. However, the earlier an empirical antimicrobial regimen is started, the greater the probability of diagnostic error and the possibility of side-effects. Recent experience of the clinical efficacy and good tolerance of echinocandins in the treatment of candidemia obliges us to review the indications for empirical antifungal treatment and the choice of antifungal agent in the critically ill patient.

Broad‐Spectrum Antimicrobials and the Treatment of Serious Bacterial Infections: Getting It Right Up Front

The treatment of serious bacterial infections is complicated by the fact that time to initiation of effective antimicrobial therapy is a strong predictor of mortality. Therefore, therapy must be initiated before the causative pathogen is identified. However, inappropriate or inadequate initial empirical therapy is associated with increased mortality, morbidity, and length of hospital stay. Initial empirical therapy with broad-spectrum antimicrobials attempts to address this dilemma by "getting it right up front." The goal is to provide treatment active against the most likely pathogens until culture/susceptibility test results are obtained. After the causative pathogen is identified, streamlining to more-precise therapy of the shortest acceptable duration is implemented. In this way, the risks of death, morbid complications, increased duration of hospital stay (as a result of ineffective initial treatment), and emergence of resistance (due to extended treatment with broad-spectrum agents) are lowered. Improved clinical and economic outcomes after such an approach have been demonstrated.

The relationship between the initiation of antimicrobial therapy and the incidence of stroke in infective endocarditis: An analysis from the ICE Prospective Cohort Study (ICE-PCS)

Embolic events to the central nervous system are a major cause of morbidity and mortality in patients with infective endocarditis (IE). The appropriate role of valvular surgery in reducing such embolic events is unclear. The purpose of this study was to determine the relationship between the initiation of antimicrobial therapy and the temporal incidence of stroke in patients with IE and to determine if this time course differs from that shown for embolic events in previous studies. Prospective incidence cohort study involving 61 tertiary referral centers in 28 countries. Case report forms were analyzed from 1437 consecutive patients with left-sided endocarditis admitted directly to participating centers. The crude incidence of stroke in patients receiving appropriate antimicrobial therapy was 4.82/1000 patient days in the first week of therapy and fell to 1.71/1000 patient days in the second week. This rate continued to decline with further therapy. Stroke rates fell similarly regardless of the valve or organism involved. After 1 week of antimicrobial therapy, only 3.1% of the cohort experienced a stroke. The risk of stroke in IE falls dramatically after the initiation of effective antimicrobial therapy. The falling risk of stroke in patients with IE as a whole precludes stroke prevention as the sole indication for valvular surgery after 1 week of therapy.

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*

To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock. A retrospective cohort study performed between July 1989 and June 2004. Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States. Medical records of 2,731 adult patients with septic shock. None. The main outcome measure was survival to hospital discharge. Among the 2,154 septic shock patients (78.9% total) who received effective antimicrobial therapy only after the onset of recurrent or persistent hypotension, a strong relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted (adjusted odds ratio 1.119 [per hour delay], 95% confidence interval 1.103-1.136, p<.0001). Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital mortality rate was significantly increased relative to receiving therapy within the first hour (odds ratio 1.67; 95% confidence interval, 1.12-2.48). In multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest predictor of outcome. Median time to effective antimicrobial therapy was 6 hrs (25-75th percentile, 2.0-15.0 hrs). Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.