Management of possible serious bacterial infection in young infants where referral is not possible in the context of existing health system structure in Ibadan, South-west Nigeria.

INTRODUCTION: Neonatal infections contribute substantially to infant mortality in Nigeria and globally. Management requires hospitalization, which is not accessible to many in low resource settings. World Health Organization developed a guideline to manage possible serious bacterial infection (PSBI) in young infants up to two months of age when a referral is not feasible. We evaluated the feasibility of implementing this guideline to achieve high coverage of treatment. METHODS: This implementation research was conducted in out-patient settings of eight primary health care centres (PHC) in Lagelu Local Government Area (LGA) of Ibadan, Oyo State, Nigeria. We conducted policy dialogue with the Federal and State officials to adopt the WHO guideline within the existing programme setting and held orientation and sensitization meetings with communities. We established a Technical Support Unit (TSU), built the capacity of health care providers, supervised and mentored them, monitored the quality of services and collected data for management and outcomes of sick young infants with PSBI signs. The Primary Health Care Directorate of the state ministry and the local government led the implementation and provided technical support. The enablers and barriers to implementation were documented. RESULTS: From 1 April 2016 to 31 July 2017 we identified 5278 live births and of these, 1214 had a sign of PSBI. Assuming 30% of births were missed due to temporary migration to maternal homes for delivery care and approximately 45% cases came from outside the catchment area due to free availability of medicines, the treatment coverage was 97.3% (668 cases/6861 expected births) with an expected 10% PSBI prevalence within the first 2 months of life. Of 1214 infants with PSBI, 392 (32%) infants 7-59 days had only fast breathing (pneumonia), 338 (27.8%) infants 0-6 days had only fast breathing (severe pneumonia), 462 (38%) presented with signs of clinical severe infection (CSI) and 22 (1.8%) with signs of critical illness. All but two, 7-59 days old infants with pneumonia were treated with oral amoxicillin without a referral; 80% (312/390) adhered to full treatment; 97.7% (381/390) were cured, and no deaths were reported. Referral to the hospital was not accepted by 87.7% (721/822) families of infants presenting with signs of PSBI needing hospitalization (critical illness 5/22; clinical severe infection; 399/462 and severe pneumonia 317/338). They were treated on an outpatient basis with two days of injectable gentamicin and seven days of oral amoxicillin. Among these 81% (584/721) completed treatment; 97% (700/721) were cured, and three deaths were reported (two with critical illness and one with clinical severe infection). We identified health system gaps including lack of staff motivation and work strikes, medicines stockouts, sub-optimal home visits that affected implementation. CONCLUSIONS: When a referral is not feasible, outpatient treatment for young infants with signs of PSBI is possible within existing programme structures in Nigeria with high coverage and low case fatality. To scale up this intervention successfully, government commitment is needed to strengthen the health system, motivate and train health workers, provide necessary commodities, establish technical support for implementation and strengthen linkages with communities. REGISTRATION: Trial is registered on Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617001373369.

Comprehensive analysis of prognostic factors in hospitalized patients with pneumonia occurring outside hospital: Serum albumin is not less important than pneumonia severity assessment scale.

PURPOSE: This study aimed to elucidate factors related to 30-day mortality of pneumonia occurring outside hospital by comprehensively analyzing data considered relevant to prognosis. METHODS: Data considered relevant to prognosis were retrospectively examined from clinical charts and chest X-ray images of all patients with pneumonia occurring outside hospital admitted to our hospital from 2010 to 2016. The primary outcome was 30-day mortality. RESULTS: Data were collected from 534 patients (317 community-acquired pneumonia and 217 nursing- and healthcare associated pneumonia patients; 338 men (63.3%); mean age, 76.2 years-old). Eighty-three patients (9.9%) died from pneumonia within 30 days from the date of admission. The numbers of patients with pneumonia severity index (PSI) classes of I/II/III/IV/V and age, dehydration, respiratory failure, orientation disturbance, pressure (A-DROP) scores of 0/1/2/3/4/5 were 29/66/127/229/83, and 71/107/187/132/30/7, respectively. Mean (standard deviation) body mass index (BMI), serum albumin, blood procalcitonin, white blood cell and C-reactive protein were 20.00 (4.12) kg/m2, 3.16 (0.60) g/dL, 3.69 (13.15) ng/mL, 11559.4 (5656.9)/mm3, and 10.92 (8.75) mg/dL, respectively. Chest X-ray images from 152 patients exhibited a pneumonia shadow over a quarter of total lung field. Logistic regression analysis revealed that PSI class or A-DROP score, BMI, serum albumin, and extent of pneumonia shadow were related to 30-day mortality. Receiver operating characteristics curve analysis revealed that serum albumin was superior to PSI class or A-DROP score for predicting 30-day mortality. CONCLUSION: Serum albumin is not less important than PSI class or A-DROP score for predicting 30-day mortality in hospitalized patients with pneumonia occurring outside hospital.

Epidemiology of community-acquired pneumonia and implications for vaccination of children living in developing and newly industrialized countries: A systematic literature review.

This systematic review evaluated the epidemiology of community-acquired pneumonia in children <6 y of age within 90 developing and newly industrialized countries. Literature searches (1990-2011), based on MEDLINE, EMBASE, Cochrane, CAB Global Health, WHO, UNICEF, country-specific websites, conferences, health-technology-assessment agencies, and the reference lists of included studies, yielded 8,734 records; 62 of 340 studies were included in this review. The highest incidence rate among included studies was 0.51 episodes/child-year, for children <5 y of age in Bangladesh. The highest prevalence was in Chinese children <6 months of age (37.88%). The main bacterial pathogens were Streptococcus pneumoniae, Haemophilus influenzae and Mycoplasma pneumoniae and the main viral pathogens were respiratory syncytial virus, adenovirus and rhinovirus. Community-acquired pneumonia remains associated with high rates of morbidity and mortality. Improved and efficient surveillance and documentation of the epidemiology and burden of community-acquired pneumonia across various geographical regions is warranted.

Prospective open-label randomized comparative, non-inferiority study of two initial antibiotic strategies for patients with nursing- and healthcare-associated pneumonia: Guideline-concordant therapy versus empiric therapy.

BACKGROUND AND OBJECTIVE: The nursing- and healthcare-associated pneumonia guideline, proposed by the Japan Respiratory Society, recommends that patients at risk of exposure to drug-resistant pathogens, classified as treatment category C, be treated with antipseudomonal antibiotics. This study aimed to prove the non-inferiority of empirical therapy in our hospital compared with guideline-concordant therapy. METHODS: This was a randomized controlled trial conducted from December 2011 to December 2012. Patients were randomized to the Guideline group receiving guideline-concordant therapy, and the Empiric group treated with sulbactam/ampicillin or ceftriaxone. The primary endpoint was in-hospital relapse of pneumonia and mortality within 30 days, with a predefined non-inferiority margin of 10%. The secondary endpoints included duration, adverse effects, and cost of antibiotic therapy. RESULTS: One hundred and eleven patients were assigned to the Guideline group (n = 55) and the Empiric group (n = 56; 3 of which were excluded). The incidence of relapse and death within 30 days was similar in the Guideline and the Empiric groups (31% vs. 26%, risk difference -4.5%, 95% CI -21.5% to 12.5%). While the duration of antibiotic therapy was slightly shorter in the Guideline group than in the Empiric group (7 vs. 8 days), there were no significant differences in adverse effects or cost. CONCLUSIONS: The efficacy of empiric therapy was comparable to guideline-concordant therapy, although non-inferiority was not proven. The administration of broad-spectrum antibiotics to patients at risk of exposure to drug-resistant pathogens may not necessarily improve the prognosis. TRIAL REGISTRATION: UMIN000006792.

A national point prevalence study on healthcare-associated infections and antimicrobial use in Austria.

BACKGROUND: The first point prevalence survey performed in Austria had the aim to assess the magnitude of healthcare-associated infections and antimicrobials use in the country. METHODS: A multicentre study was carried out from May until June 2012 in nine acute care hospitals with a mean bed number of 620. Data from 4321 patients' clinical charts were reviewed. RESULTS: The overall healthcare-associated infections prevalence was 6.2% (268/4321) with the highest rate in intensive care departments (20.9%; 49/234). In medical and surgical departments the healthcare-associated infections prevalence was 5.4% (95/1745) and 6.6% (105/1586), respectively. The most frequent healthcare-associated infections were: urinary tract infections (21.3%; 61/287), pneumonia (20.6%; 59/287) and surgical site infections (17.4%; 50/287). The most common isolated microorganisms were: Escherichia coli (14.8%; 26/176), Enterococcus species (13.1%; 23/176) and Pseudomonas aeruginosa (11.4%; 20/176). Thirty-three per cent (1425/4321) of the patients received antimicrobials because of community-acquired infections treatment (14.2%; 615/4321), healthcare-associated infections treatment (6.4%; 278/4321), and surgical (8.2%; 354/4321) and medical prophylaxis (3.2%; 138/4321). Surgical prophylaxis was the indication for 22.0% (394/1792) of the overall prescriptions and was prolonged for more than 1 day in 77.2% (304/394) of the cases. CONCLUSION: The national Austrian survey proved the feasibility of a nation-wide network of surveillance of both healthcare-associated infections and antimicrobial use that will be repeated in the future. Healthcare-associated infections and antimicrobial use have been confirmed to be a grave health problem. The excessive prolongation of perioperative prophylaxis in Austria needs to be limited.

Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review.

Pneumonia is a major cause of morbidity and mortality in infants and children worldwide, with most cases occurring in tuberculosis-endemic settings. Studies have emphasised the potential importance of Mycobacterium tuberculosis in acute severe pneumonia in children as a primary cause or underlying comorbidity, further emphasised by the changing aetiological range with rollout of bacterial conjugate vaccines in high mortality settings. We systematically reviewed clinical and autopsy studies done in tuberculosis-endemic settings that enrolled at least 100 children aged younger than 5 years with severe pneumonia, and that prospectively included a diagnostic approach to tuberculosis in all study participants. We noted substantial heterogeneity between studies in terms of study population and diagnostic methods. Of the 3644 patients who had culture of respiratory specimens for M tuberculosis undertaken, 275 (7·5%) were culture positive, and an acute presentation was common. Inpatient case-fatality rate for pneumonia associated with tuberculosis ranged from 4% to 21% in the four clinical studies that reported pathogen-related outcomes. Prospective studies are needed in high tuberculosis-burden settings to address whether tuberculosis is a cause or comorbidity of childhood acute severe pneumonia.

Association of guideline-based antimicrobial therapy and outcomes in healthcare-associated pneumonia.

OBJECTIVES: Guidelines for treatment of healthcare-associated pneumonia (HCAP) recommend empirical therapy with broad-spectrum antimicrobials. Our objective was to examine the association between guideline-based therapy (GBT) and outcomes for patients with HCAP. PATIENTS AND METHODS: We conducted a pharmacoepidemiological cohort study at 346 US hospitals. We included adults hospitalized between July 2007 and June 2010 for HCAP, defined as patients admitted from a nursing home, with end-stage renal disease or immunosuppression, or discharged from a hospital in the previous 90 days. Outcome measures included in-hospital mortality, length of stay and costs. RESULTS: Of 85 097 patients at 346 hospitals, 31 949 (37.5%) received GBT (one agent against MRSA and at least one against Pseudomonas). Compared with patients who received non-GBT, those who received GBT had a heavier burden of chronic disease and more severe pneumonia. GBT was associated with higher mortality (17.1% versus 7.7%, P < 0.001). Adjustment for demographics, comorbidities, propensity for treatment with GBT and initial severity of disease decreased, but did not eliminate, the association (OR 1.39, 95% CI 1.32-1.47). Using an adaptation of an instrumental variable analysis, GBT was not associated with higher mortality (OR 0.93, 95% CI 0.75-1.16). Adjusted length of stay and costs were also higher with GBT. CONCLUSIONS: Among patients who met HCAP criteria, GBT was not associated with lower adjusted mortality, length of stay or costs in any analyses. Better criteria are needed to identify patients at risk for MDR infections who might benefit from broad-spectrum antimicrobial coverage.

Evaluation of community-acquired sepsis by PIRO system in the emergency department.

The predisposition, infection/insult, response, and organ dysfunction (PIRO) staging system for septic patients allows grouping of heterogeneous patients into homogeneous subgroups. The purposes of this single-center, prospective, observational cohort study were to create a PIRO system for patients with community-acquired sepsis (CAS) presenting to the emergency department (ED) and assess its prognostic and stratification capabilities. Septic patients were enrolled and allocated to derivation (n = 831) or validation (n = 860) cohorts according to their enrollment dates. The derivation cohort was used to identify independent predictors of mortality and create a PIRO system by binary logistic regression analysis, and the prognostic performance of PIRO was investigated in the validation cohort by receiver operator characteristic (ROC) curve. Ten independent predictors of 28-day mortality were identified. The PIRO system combined the components of predisposition (age, chronic obstructive pulmonary disease, hypoalbuminemia), infection (central nervous system infection), response (temperature, procalcitonin), and organ dysfunction (brain natriuretic peptide, troponin I, mean arterial pressure, Glasgow coma scale score). The area under the ROC of PIRO was 0.833 for the derivation cohort and 0.813 for the validation cohort. There was a stepwise increase in 28-day mortality with increasing PIRO score and the differences between the low- (PIRO 0-10), intermediate- (11-20), and high- (>20) risk groups were very significant in both cohorts (p < 0.01). The present study demonstrates that this PIRO system is valuable for prognosis and risk stratification in patients with CAS in the ED.

Initial treatment failure in non-ICU community-acquired pneumonia: risk factors and association with length of stay, total hospital charges, and mortality.

OBJECTIVES: To identify risk factors for initial treatment failure in patients with community-acquired pneumonia (CAP) in non-intensive care unit (non-ICU) settings, and to characterize the association between initial treatment failure and length of stay, total hospital charges, and mortality. METHODS: Retrospective cohort study. Using data from >100 US hospitals, this study identified all adults (age ≥18 years) hospitalized for pneumonia between January 1, 2000 and June 30, 2009 who began antibiotic therapy within 24 h of admission and were treated for at least 48 h if alive; patients admitted to intensive care within the first 24 h in hospital were excluded. Initial therapy was defined as all parenteral antibiotics administered within the first 24 h in hospital. Treatment failure was assessed based on subsequent receipt of new antibiotic(s), excluding agents of similar/narrower spectrum and those begun at discharge. Multivariate logistic regression was used to identify risk factors for treatment failure, and multivariate linear and logistic regression to compare length of stay, total hospital charges, and in-hospital mortality between patients experiencing initial treatment failure and those who did not. RESULTS: Among 32,324 patients with non-ICU CAP, 4695 (14.6%) experienced initial treatment failure, most often within 72 h of hospital admission. Significant predictors of initial treatment failure included malnourishment (OR = 1.87; 95% CI = 1.60-2.18), receipt of vasoactive medications within 24 h of admission (1.51 [1.17-1.94]), and renal failure (1.45 [1.32-1.59]). Treatment failure was associated with higher case fatality (8.5% vs 3.3%), longer hospital stays (mean [SD] = 10.1 [8.1] days vs 4.9 [3.3] days), and higher total hospital charges ($37,602 [$71,876] vs $14,371 [$21,633]) (all comparisons, p < 0.01). Study limitations include possible inclusion of patients with healthcare-associated pneumonia (HCAP) in the study sample, our focus on the 40 most commonly used antibiotic regimens, and indirect measurement of treatment failure. CONCLUSIONS: Approximately one in seven non-ICU CAP patients experience failure of initial antibiotic therapy. Risk of failure is higher for patients with significant comorbidities and/or severe infections. Non-ICU patients who experience initial treatment failure have significantly longer hospital stays, higher total hospital charges, and higher rates of mortality.

Investigations on non-inferiority--the Food and Drug Administration draft guidance on treatments for nosocomial pneumonia as a case for exact tests for binomial proportions.

This paper addresses statistical issues in non-inferiority trials where the primary outcome is a fatal event. The investigations are inspired by a recent Food and Drug Administration (FDA) draft guideline on treatments for nosocomial pneumonia. The non-inferiority margin suggested in this guideline for the endpoint all-cause mortality is defined on different distance measures (rate difference and odds ratio) and is discontinuous. Furthermore, the margin enables considerable power for the statistical proof of non-inferiority at alternatives that might be regarded as clinically unacceptable, that is, even if the experimental treatment is harmful as compared with the control. We investigated the appropriateness of the proposed non-inferiority margin as well as the performance of possible test statistics to be used for the analysis. A continuous variant of the margin proposed in the FDA guideline together with the unconditional exact test according to Barnard showed favorable characteristics with respect to type I error rate control and power. To prevent harmful new treatments from being declared as non-inferior, we propose to add a 'second hurdle'. We discuss examples and explore power characteristics when requiring both statistical significance and overcoming the second hurdle.

Macrolides vs. quinolones for community-acquired pneumonia: meta-analysis of randomized controlled trials.

The relative efficacy, safety and ecological implications of macrolides vs. quinolones in the treatment of community-acquired pneumonia (CAP) are debatable. We performed a systematic review and meta-analysis of randomized controlled trials comparing any macrolide vs. any quinolone for the treatment of CAP among adult inpatients or outpatients, as monotherapy or both in combination with a beta-lactam. We did not limit inclusion by pneumonia severity, publication status, language or date of publication. The primary outcomes assessed were 30-day all-cause mortality and treatment failure. Two authors independently extracted the data. Fixed effect meta-analysis of risk ratios (RRs) with 95% confidence intervals was performed. Sixteen trials (4989 patients) fulfilling inclusion criteria were identified, mostly assessing outpatients with mild to moderate CAP. All-cause mortality was not significantly different for macrolides vs. quinolones, RR 1.03 (0.63-1.68, seven trials), with a low event rate (2%). Treatment failure was significantly lower with quinolones, RR 0.78 (0.67-0.91, 16 trials). The definition of failure used in the primary studies was not clearly representative of patients' benefit. Microbiological failure was lower with quinolones, RR 0.63 (0.49-0.81, 13 trials). All adverse events, adverse events requiring discontinuation and any premature antibiotic discontinuation were significantly more frequent with macrolides, mainly on account of gastrointestinal adverse events. Resistance development was not assessed in the trials. Randomized controlled trials show an advantage of quinolones in the treatment of CAP with regard to clinical cure without need for antibiotic modification at end of treatment and gastrointestinal adverse events. The clinical significance of this advantage is unclear.

Overview of community-acquired pneumonia and the role of inflammatory mechanisms in the immunopathogenesis of severe pneumococcal disease.

Community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality among the infectious diseases. Despite the implementation of national pneumococcal polyvalent vaccine-based immunisation strategies targeted at high-risk groups, Streptococcus pneumoniae (the pneumococcus) remains the most common cause of CAP. Notwithstanding the HIV pandemic, major challenges confronting the control of CAP include the range of bacterial and viral pathogens causing this condition, the ever-increasing problem of antibiotic resistance worldwide, and increased vulnerability associated with steadily aging populations in developed countries. These and other risk factors, as well as diagnostic strategies, are covered in the first section of this review. Thereafter, the review is focused on the pneumococcus, specifically the major virulence factors of this microbial pathogen and their role in triggering overexuberant inflammatory responses which contribute to the immunopathogenesis of invasive disease. The final section of the review is devoted to a consideration of pharmacological, anti-inflammatory strategies with adjunctive potential in the antimicrobial chemotherapy of CAP. This is focused on macrolides, corticosteroids, and statins with respect to their modes of anti-inflammatory action, current status, and limitations.

Can we use severity assessment tools to increase outpatient management of community-acquired pneumonia?

Outpatient management of community-acquired pneumonia (CAP) has several potential advantages, including significant cost-savings, a reduction in hospital-acquired infections and increased patient satisfaction. Despite the benefits, it is often difficult to identify which patients may be managed in the community without compromising patient safety. CAP severity scores, such as the pneumonia severity index (PSI) and the British Thoracic Society CURB65/CRB65 scores are designed to identify groups of patients at low risk of mortality who may be suitable for outpatient care. This review discusses the strengths and weaknesses of severity scores for use in determining site of care for patients with pneumonia. Use of the PSI in emergency departments has been shown to increase the proportion of patients treated in the community without increasing patient mortality or hospital readmissions. The CURB65 and CRB65 scores are less complex alternatives to the PSI that have been shown to perform similarly for prediction of 30-day mortality. All 3 scores identify populations at low risk of mortality who may be eligible for outpatient care. Nevertheless, a number of factors not included in severity scores may prevent discharge of these patients, including social factors, co-morbidities and severity markers not captured by severity scores. The limitations of severity scores are discussed along with recent attempts to improve predictive tools, with the development of new biomarkers and alternative scoring systems.

Costs of healthcare- and community-associated infections with antimicrobial-resistant versus antimicrobial-susceptible organisms.

OBJECTIVE: We compared differences in the hospital charges, length of hospital stay, and mortality between patients with healthcare- and community-associated bloodstream infections, urinary tract infections, and pneumonia due to antimicrobial-resistant versus -susceptible bacterial strains. METHODS: A retrospective analysis of an electronic database compiled from laboratory, pharmacy, surgery, financial, and patient location and device utilization sources was undertaken on 5699 inpatients who developed healthcare- or community-associated infections between 2006 and 2008 from 4 hospitals (1 community, 1 pediatric, 2 tertiary/quaternary care) in Manhattan. The main outcome measures were hospital charges, length of stay, and mortality among patients with antimicrobial-resistant and -susceptible infections caused by Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. RESULTS: Controlling for multiple confounders using linear regression and nearest neighbor matching based on propensity score estimates, resistant healthcare- and community-associated infections, when compared with susceptible strains of the same organism, were associated with significantly higher charges ($15,626; confidence interval [CI], $4339-$26,913 and $25,573; CI, $9331-$41,816, respectively) and longer hospital stays for community-associated infections (3.3; CI, 1.5-5.4). Patients with resistant healthcare-associated infections also had a significantly higher death rate (0.04; CI, 0.01-0.08). CONCLUSIONS: With careful matching of patients infected with the same organism, antimicrobial resistance was associated with higher charges, length of stay, and death rates. The difference in estimates after accounting for censoring for death highlight divergent social and hospital incentives in reducing patient risk for antimicrobial resistant infections.

Nationwide survey on the 2005 Guidelines for the Management of Community-Acquired Adult Pneumonia: validation of severity assessment.

INTRODUCTION: The Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia (CAP) in Adults (JRS 2005) were published to revise the Basic Concept for the Management of CAP in Adults (JRS 2000). Revisions in JRS 2005 mainly focused on the criteria for the assessment of pneumonia severity and the differentiation between bacterial pneumonia and atypical pneumonia. To evaluate the JRS 2005 criteria for the assessment of pneumonia severity, we conducted a prospective survey. SUBJECTS AND METHODS: The survey was conducted from July 2006 to March 2007 as a nationwide joint study by 200 institutions. The study subjects included patients aged ≥16 years of age who had CAP. The severity at initial consultation was determined using the criteria established by JRS 2005, JRS 2000, and Infectious Diseases Society of America Guidelines (IDSA-GLs). The survival outcome 30 days after the start of the initial antimicrobial agent treatment was confirmed. RESULTS: A total of 1875 patients were analyzed. The numbers of cases of pneumonia assessed as being moderate and severe were significantly lower when the JRS 2005 criteria were used than when the JRS 2000 criteria were used. Thus, the severity of pneumonia could be determined more appropriately using the JRS 2005 criteria. Furthermore, the severity-dependent prediction of fatal outcomes or mortality according to these criteria was similar to that determined using the IDSA-GLs. CONCLUSIONS: Determining severity on the basis of JRS 2005 can resolve nearly all the problems encountered with JRS 2000; these criteria were found to be useful and rapidly and easily applicable in clinical practice.

Quantitative assessment of combination antimicrobial therapy against multidrug-resistant bacteria in a murine pneumonia model.

BACKGROUND: Combination antimicrobial therapy is clinically used as a last-resort strategy to control multidrug-resistant bacterial infections. However, selection of antibiotics is often empirical, and conventional assessment of combined drug effect has not been correlated to clinical outcomes. Here, we report a quantitative method to assess combined killing of antimicrobial agents against 2 multidrug-resistant bacteria. METHODS: Combined time-kill studies were performed using clinically achievable concentrations for each 2-agent combination against clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. Bacterial burden observed at 24 h was mathematically modeled using a 3-dimensional response surface. Subsequently, a neutropenic murine pneumonia model with simulated clinical dosing exposures was used to validate our quantitative assessment of combined killing. RESULTS: Different antimicrobial combinations were found to have varying efficacy against the multidrug-resistant bacteria. As predicted by our quantitative method, cefepime plus amikacin was found to be the most superior combination, which was evidenced by a reduction in tissue bacterial burden and prolonged survival of infected animals. CONCLUSIONS: The consistency between the predictions of the mathematical model and in vivo observations substantiated the robustness of our quantitative method. These data highlighted a novel and promising method to guide rational selection of antimicrobial combination in the clinical setting.

Do hospitals provide lower quality of care to black patients for pneumonia?

OBJECTIVES: Recent studies reported lower quality of care for black vs. white patients with community-acquired pneumonia and suggested that disparities persist at the individual hospital level. We examined racial differences in emergency department and intensive care unit care processes to determine whether differences persist after adjusting for case-mix and variation in care across hospitals. DESIGN: Prospective, observational cohort study. SETTING: Twenty-eight U.S. hospitals. PATIENTS: Patients with community-acquired pneumonia: 1738 white and 352 black patients. INTERVENTIONS: None. MEASUREMENTS: We compared care quality based on antibiotic receipt within 4 hrs and adherence to American Thoracic Society antibiotic guidelines, and intensity based on intensive care unit admission and mechanical ventilation use. Using random effects and generalized estimating equations models, we adjusted for case-mix and clustering of racial groups within hospitals and estimated odds ratios for differences in care within and across hospitals. MAIN RESULTS: Black patients were less likely to receive antibiotics within 4 hrs (odds ratio, 0.55; 95% confidence interval, 0.43-0.70; p < .001) and less likely to receive guideline-adherent antibiotics (odds ratio, 0.72; 95% confidence interval, 0.57-0.91; p = .006). These differences were attenuated after adjusting for casemix (odds ratio, 0.59; 95% confidence interval; 0.46-0.76 and 0.84; 95% confidence interval, 0.66 -1.09). Within hospitals, black and white patients received similar care quality (odds ratio, 1; 95% confidence interval, 0.97-1.04 and 1; 95% confidence interval, 0.97-1.03). However, hospitals that served a greater proportion of black patients were less likely to provide timely antibiotics (odds ratio, 0.84; 95% confidence interval, 0.78-0.90). Black patients were more likely to receive mechanical ventilation (odds ratio, 1.57; 95% confidence interval, 1.02-2.42; p = .042). Again, within hospitals, black and white subjects were equally likely to receive mechanical ventilation (odds ratio, 1; 95% confidence interval, .94-1.06) and hospitals that served a greater proportion of black patients were more likely to institute mechanical ventilation (odds ratio, 1.13; 95% confidence interval, 1.02-1.25). CONCLUSIONS: Black patients appear to receive lower quality and higher intensity of care in crude analyses. However, these differences were explained by different case-mix and variation in care across hospitals. Within the same hospital, no racial differences in care were observed.