Vincent Quagliarello

Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing.

Despite advances in antibiotic therapy, bacterial meningitis continues to cause significant morbidity and mortality [1]. Rapid diagnosis and therapy are the cornerstones of management, but patient presentation and clinical outcomes vary. Whether clinical outcomes are influenced more by disease severity or delay in initiation of antibiotic therapy remains a problematic and litigious issue [2-4]. Accurate prognostic stratification at presentation facilitates interpretation of individual treatment results and of benefits of therapeutic interventions in clinical trials. Unfortunately, methodologic limitations of existing studies prevented the development of a clinically useful prognostic model for persons with bacterial meningitis [1, 5-26]. To create a prognostic model and risk stratification system, we conducted a retrospective, observational cohort study of persons with community-acquired, microbiologically proven bacterial meningitis. Methods Patients were identified through review of medical records and microbiology laboratories at four Connecticut hospitals. To develop and test the prognostic model, we divided patients in the total cohort into derivation and validation cohorts. The derivation cohort (n = 176) was assembled from persons at least 16 years of age in whom community-acquired bacterial meningitis was diagnosed at the two hospitals serving New Haven, Connecticut (Yale-New Haven Hospital and Hospital of Saint Raphael), from January 1970 through December 1995. The validation cohort (n = 93) was assembled similarly during the same period for patients given a diagnosis at the two hospitals serving a separate geographic location in Waterbury, Connecticut (Waterbury Hospital Health Center and St. Marys Hospital). Patients with community-acquired meningitis (initial lumbar puncture done within 24 hours of presentation in the emergency department) and a microbiologically identified bacterial cause were included. Bacterial meningitis was diagnosed on the basis of a compatible clinical picture and a positive cerebrospinal fluid culture [n = 226] or a negative cerebrospinal fluid culture with one or more of the following: 1) a positive result on a cerebrospinal fluid bacterial antigen or Quellung test [n = 10], 2) a positive blood culture in the presence of cerebrospinal fluid pleocytosis (defined as a leukocyte count 10 cells/mL of cerebrospinal fluid) [n = 39], or 3) identification of gram-negative diplococci after Gram staining of cerebrospinal fluid (n = 7). Patients with meningitis caused by Mycobacterium species, Treponema pallidum, or Borrelia burgdorferi and patients with intracranial devices were excluded. For patients who had multiple episodes of meningitis during the study period, only the first episode was analyzed. From medical records, we extracted information on sociodemographic data, comorbid conditions, immunocompetence, exposures, presenting symptoms, physical signs, laboratory and cranial imaging results, and clinical outcome. Precise times were recorded for arrival in the emergency department, administration of the first dose of effective antibiotics (defined as antibiotic therapy to which the identified bacteria were susceptible in vitro), and performance of lumbar puncture. Baseline characteristics were assessed at a specified zero time, defined as the time at which the first dose of effective antibiotics was administered. Comorbidity was assessed by using the Charlson comorbidity scale [27]. For the derivation cohort, bivariate analyses were done with the presence or absence of an adverse clinical outcome (defined as neurologic deficit at discharge or death during hospitalization) as the target end point. All patient episodes were followed from admission date to discharge or death. Baseline characteristics associated with adverse clinical outcome in the bivariate analyses were analyzed in a multivariable context by using multiple logistic regression modeling. Using these independently prognostic baseline variables, we developed a prognostic model that stratified patients into three levels of risk (low, intermediate, and high) for adverse clinical outcome. The prediction accuracy of the prognostic model was assessed in both the derivation and validation cohorts. The effect of antibiotic timing was evaluated for the total cohort and was analyzed for episodes in which the patient remained in the same prognostic stage as well as those in which the patients prognostic stage advanced from the time of arrival in the emergency department to the time of initiation of antibiotic therapy. Differences in proportions were tested by using the chi-square test or the Fisher exact test. For contrasts of dimensional variables, the Student t-test and the Wilcoxon rank-sum test were used. We used multiple logistic regression given the binary target outcome. To avoid overfitting, we entered no more than one variable per 10 outcome events in our logistic regression models [28-30]. The goodness of fit of the final model was examined by using the Hosmer-Lemeshow test. Prediction accuracy was calculated by using the concordance index (c-index) [31]. Results Cohort Assembly A total of 269 persons with community-acquired, microbiologically proven bacterial meningitis were identified at the four hospitals [176 patients in the derivation cohort and 93 patients in the validation cohort]. After initial screening of 1024 medical records, 755 episodes were excluded for the following reasons: 1) lumbar puncture was never done [n = 155], 2) lumbar puncture was done more than 24 hours after presentation [n = 185], 3) an incorrect International Classification of Diseases, Ninth Revision, diagnosis code was applied [n = 10], 4) the case definition was not fulfilled [n = 317], 5) the medical record was incomplete [n = 80], or 6) the patients meningitis episode was not the first episode in the study period (n = 8). Baseline Features and Microbial Causes Baseline patient characteristics, laboratory results, and microbial causes are shown in Table 1. The derivation and validation cohorts were similar with respect to age, sex, ethnicity, and baseline laboratory features. Baseline clinical features were also similar, but significantly more patients in the derivation cohort than in the validation cohort were immunocompromised (P = 0.03) and had focal neurologic examinations (P = 0.03). For the total cohort, fever and abnormal mental status were the most common presenting clinical features. Streptococcus pneumoniae caused nearly 50% of all cases, and Neisseria meningitidis, other streptococci, Staphylococcus aureus, and Listeria monocytogenes caused most of the remaining cases. The derivation cohort had a greater proportion of patients whose meningitis was caused by Staphylococcus aureus than did the validation cohort (P = 0.02). Table 1. Patient Characteristics, Laboratory Results, and Clinical Outcome Clinical Outcome The clinical outcome for all patients is shown in Table 1. The hospital mortality rate for the total cohort was 27%, and the median number of hospital days before death was 6 (range, 0 to 65). Of the 269 patients, 56 (28% of survivors; 21% of the total cohort) had a neurologic deficit and 25 (13% of survivors; 9% of the total cohort) had a neurologic deficit that persisted at discharge. The most common persisting neurologic deficit in the total cohort was hearing loss. Clinical outcome for the total cohort did not differ significantly when analyzed by time period (P > 0.2 when adverse outcome were compared between 5-year intervals). However, episodes of Streptococcus pneumoniae meningitis in the total cohort were associated with a greater proportion of adverse clinical outcomes than were episodes that were not caused by Streptococcus pneumoniae (P = 0.005). Bivariate analyses relating baseline characteristics to adverse clinical outcome in the derivation cohort are shown in Table 2 and Table 3. Hypotension (defined as systolic blood pressure 90 mm Hg or a 40 mm Hg decrease in systolic blood pressure), altered mental status (defined as lethargy, disorientation, or coma), seizures, and age all showed a bivariate association with adverse clinical outcome. To determine independent relations with adverse clinical outcome, these variables were entered into a logistic regression model with three other variables that had a biologically plausible relation to clinical outcome (immunocompetence, comorbidity, and leukocyte count in cerebrospinal fluid). In this model, only hypotension (adjusted odds ratio, 2.75 [95% CI, 1.22 to 6.18]; P < 0.001), altered mental status (adjusted odds ratio, 6.56 [CI, 1.71 to 25.2]; P = 0.006), and seizures (adjusted odds ratio, 4.42 [CI, 1.56 to 12.48]; P = 0.005) remained independently associated with adverse clinical outcome after adjustment for age, comorbidity, immunocompetence, and leukocyte count in cerebrospinal fluid. Table 2. Bivariate Association of Baseline Dichotomous Variables and Adverse Clinical Outcome for the Derivation Cohort (n = 176) Table 3. Bivariate Association of Baseline Dimensional Variables and Adverse Clinical Outcome for the Derivation Cohort (n = 176)* Development and Validation of the Prognostic Model Using the three independently predictive baseline variables from the logistic regression model (hypotension, altered mental status, and seizures), we created prognostic stages by stratifying patients who had 0, 1, and at least 2 of the variables into low-, intermediate-, and high-risk subgroups, respectively (Table 4). For the derivation cohort, the observed proportions of patients with adverse clinical outcome were 5% in stage I (low risk), 37% in stage II (intermediate risk), and 63% in stage III (high risk) (P = 0.001). For the validation cohort, the observed proportions of patients with adverse clinical outcome were 14% in stage I, 28% in stage II, and 43% in stage III (P = 0.06). The predicted probabilities of the model for each stage closely match the observ

Clinical practice guideline for the evaluation of fever and infection in older adult residents of long-term care facilities: 2008 update by the Infectious Diseases Society of America.

Residents of long-term care facilities (LTCFs) are at great risk for infection. Most residents are older and have multiple comorbidities that complicate recognition of infection; for example, typically defined fever is absent in more than one-half of LTCF residents with serious infection. Furthermore, LTCFs often do not have the on-site equipment or personnel to evaluate suspected infection in the fashion typically performed in acute care hospitals. In recognition of the differences between LTCFs and hospitals with regard to hosts and resources present, the Infectious Diseases Society of America first provided guidelines for evaluation of fever and infection in LTCF residents in 2000. The guideline presented here represents the second edition, updated by data generated over the intervening 8 years. It focuses on the typical elderly person institutionalized with multiple chronic comorbidities and functional disabilities (e.g., a nursing home resident). Specific topic reviews and recommendations are provided with regard to what resources are typically available to evaluate suspected infection, what symptoms and signs suggest infection in a resident of an LTCF, who should initially evaluate the resident with suspected infection, what clinical evaluation should be performed, how LTCF staff can effectively communicate about possible infection with clinicians, and what laboratory tests should be ordered. Finally, a general outline of how a suspected outbreak of a specific infectious disease should be investigated in an LTCF is provided.

The Diagnostic Accuracy of Kernig's Sign, Brudzinski's Sign, and Nuchal Rigidity in Adults with Suspected Meningitis

To determine the diagnostic accuracy of Kernigs sign, Brudzinskis sign, and nuchal rigidity for meningitis, 297 adults with suspected meningitis were prospectively evaluated for the presence of these meningeal signs before lumbar puncture was done. Kernigs sign (sensitivity, 5%; likelihood ratio for a positive test result [LR(+)], 0.97), Brudzinskis sign (sensitivity, 5%; LR(+), 0.97), and nuchal rigidity (sensitivity, 30%; LR(+), 0.94) did not accurately discriminate between patients with meningitis (>/=6 white blood cells [WBCs]/mL of cerebrospinal fluid [CSF]) and patients without meningitis. The diagnostic accuracy of these signs was not significantly better in the subsets of patients with moderate meningeal inflammation (>/=100 WBCs/mL of CSF) or microbiological evidence of CSF infection. Only for 4 patients with severe meningeal inflammation (>/=1000 WBCs/mL of CSF) did nuchal rigidity show diagnostic value (sensitivity, 100%; negative predictive value, 100%). In the broad spectrum of adults with suspected meningitis, 3 classic meningeal signs did not have diagnostic value; better bedside diagnostic signs are needed.

Modifiable Risk Factors for Nursing Home-Acquired Pneumonia

BACKGROUND This study sought to identify modifiable risk factors for pneumonia in elderly nursing home residents. METHODS A cohort of 613 elderly residents (age, >65 years) of 5 nursing homes in the New Haven, Connecticut, area was followed-up prospectively from February 2001 through March 2003. The primary outcome was radiographically documented pneumonia within a 12-month surveillance period. Baseline modifiable risk factors were evaluated for their independent association with pneumonia. RESULTS Of 613 elderly nursing home residents, 131 (21%) died, and an additional 112 (18%) developed a radiographically documented case of pneumonia during the 12-month surveillance period. Among the 9 candidate modifiable risk factors that were evaluated individually in Cox proportional hazards models adjusting for covariates (i.e., nursing home facility, age, race, coexisting conditions, and immobility), inadequate oral care (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.06-2.35; P=.024) and swallowing difficulty (HR, 1.65; 95% CI, 1.04-2.62; P=.033) were associated with pneumonia. When modifiable risk factors were evaluated simultaneously in the same Cox proportional hazards model, inadequate oral care (HR, 1.55; 95% CI, 1.04-2.30; P=.030) and swallowing difficulty (HR, 1.61; 95% CI, 1.02-2.55; P=.043) remained independently associated with pneumonia, adjusting for the same covariates. Calculation of population-based attributable fractions showed that 21% of all cases of pneumonia in our cohort could have been avoided if inadequate oral care and swallowing difficulty were not present. CONCLUSIONS Two biologically plausible and modifiable risk factors increased the risk of pneumonia in elderly nursing home residents. These results provide a framework for the development and testing of a targeted pneumonia prevention strategy.

A prognostic rule for elderly patients admitted with community-acquired pneumonia

PURPOSE We sought to identify admission characteristics predicting mortality in elderly patients hospitalized with community-acquired pneumonia and to develop a prognostic staging system and discriminant rule. PATIENTS AND METHODS We retrospectively analyzed data from 2,356 patients aged > or = 65 years admitted with community-acquired pneumonia. Multivariable analyses of a derivation cohort (n = 1,000) identified characteristics associated with hospital mortality. A staging system and discriminant rule based on these characteristics were tested in a validation cohort (n = 1,356). Our discriminant rule was compared with a rule formulated from a heterogeneous adult population with community-acquired pneumonia. RESULTS Hospital mortality rates were 9% (derivation cohort) and 12% (validation cohort). We identified five independent predictors of mortality: age > or = 85 years [odds ratio 1.8 (95% confidence interval 1.1-3.1)], comorbid disease [odds ratio 4.1 (2.1-8.1)], impaired motor response [odds ratio 2.3 (1.4-3.7)], vital sign abnormality [odds ratio 3.4 (2.1-5.4)], and creatinine level > or = 1.5 mg/dL [odds ratio 2.5 (1.5-4.2)]. These variables stratified patients into four distinct stages with increasing mortality in the derivation cohort (Stage 1, 2%; Stage 2, 7%; Stage 3, 22%; Stage 4, 45%; P = 0.001) as well as in the validation cohort (Stage 1, 4%; Stage 2, 11%; Stage 3, 23%; Stage 4, 41%; P = 0.001). The discriminant rule developed from the derivation cohort had greater overall accuracy (77.1%) in the validation cohort than a rule formulated from a heterogeneous adult population (68.0%, P = 0.001). CONCLUSION Elderly patients with community-acquired pneumonia have characteristics at admission that can predict mortality. Our staging system and discriminant rule improve prognostic stratification of these patients.

A New Paradigm for Clinical Investigation of Infectious Syndromes in Older Adults: Assessment of Functional Status as a Risk Factor and Outcome Measure

Adults aged >or=65 years comprise the fastest-growing segment of the United States population, and older adults experience greater morbidity and mortality due to infection than do young adults. Although age is well established as a risk factor for infection, most clinical investigations of infectious diseases in older adults focus on microbiology and on crude end points of clinical success, such as cure rates or death; however, they often fail to assess functional status, which is a critical variable in geriatric care. Functional status can be evaluated either as a risk factor for infectious disease or as an outcome of interest after specific interventions using well-validated instruments. This article outlines the currently available data that suggest an association between infection, immunity, and impaired functional status in elderly individuals, summarizes the instruments commonly used to determine specific aspects of functional status, and provides recommendations for a new paradigm in which clinical trials that involve older adults include assessment of functional status.

Clinical Features to Identify Urinary Tract Infection in Nursing Home Residents: A Cohort Study

OBJECTIVES: To identify clinical features associated with bacteriuria plus pyuria in noncatheterized nursing home residents with clinically suspected urinary tract infection (UTI).

Community-Acquired Bacterial Meningitis in Adults: Categorization of Causes and Timing of Death

The relationship between cause and timing of death in 294 adults who had been hospitalized with community-acquired bacterial meningitis was investigated. For 74 patients with community-acquired bacterial meningitis who died during hospitalization, the underlying and immediate causes of death were identified according to the criteria of the World Health Organization and National Center for Health Statistics. Patients were classified into 3 groups: category I, in which meningitis was the underlying and immediate cause of death (59% of patients; median duration of survival, 5 days); category II, in which meningitis was the underlying but not immediate cause of death (18%; median duration of survival, 10 days); and category III, in which meningitis was neither the underlying nor immediate cause of death (23%; median duration of survival, 32 days). In a substantial proportion of adults hospitalized with community-acquired bacterial meningitis, meningitis was neither the immediate nor the underlying cause of death. A 14-day survival end point discriminated between deaths attributable to meningitis and those with another cause.

The Microbiota and Microbiome in Aging: Potential Implications in Health and Age‐Related Diseases

Advances in bacterial deoxyribonucleic acid sequencing allow for characterization of the human commensal bacterial community (microbiota) and its corresponding genome (microbiome). Surveys of healthy adults reveal that a signature composite of bacteria characterizes each unique body habitat (e.g., gut, skin, oral cavity, vagina). A myriad of clinical changes, including a basal proinflammatory state (inflamm‐aging), that directly interface with the microbiota of older adults and enhance susceptibility to disease accompany aging. Studies in older adults demonstrate that the gut microbiota correlates with diet, location of residence (e.g., community dwelling, long‐term care settings), and basal level of inflammation. Links exist between the microbiota and a variety of clinical problems plaguing older adults, including physical frailty, Clostridium difficile colitis, vulvovaginal atrophy, colorectal carcinoma, and atherosclerotic disease. Manipulation of the microbiota and microbiome of older adults holds promise as an innovative strategy to influence the development of comorbidities associated with aging.

Acute Meningitis With a Negative Gram's Stain: Clinical and Management Outcomes in 171 Episodes

PURPOSE To characterize the diagnostic spectrum and physician management decisions of patients presenting to an emergency department with an acute, community-acquired illness, cerebrospinal fluid (CSF) white blood cell count > 5/mm3, and a negative Grams stain for bacteria. PATIENTS AND METHODS In this retrospective cohort study over a 2-year period, symptoms, examination findings, paraclinical data, physician management, and clinical outcomes were assessed for each patient. RESULTS One hundred sixty-eight patients (171 patient episodes) were evaluated. Almost half of the cohort presented in nonsummer months (48%); 20% of concurrent comorbid disease, and 15% had identified immunocompromising conditions. The reported examination findings were diverse, with diverse, with fever [49%] and neck stiffness [39%] being the most frequent findings. The majority were hospitalized (70%), with a median stay of 4 days. Approximately one half underwent computed tomography or magnetic resonance imaging (49%), and received empiric treatment with antibiotics (52%). A diagnostic cause was established in 23%, with the majority being inherently treatable diseases (including syphilis, bacteremia, Lyme disease). Variables significantly associated with a subsequent proven diagnostic cause included: age > 60 years; presence of comorbid disease (especially immunodeficiency); and presentation in winter months. CONCLUSIONS A large proportion of patients presenting with acute meningitis and a negative CSF Grams stain undergo hospitalization, noninvasive cranial imaging, and receive empiric antibiotic therapy. Better clinical guidelines are needed to identify the diagnostic and management decisions that benefit patient outcome.