Richard G. Wunderink

Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults

Lionel A. Mandell, Richard G. Wunderink, Antonio Anzueto, John G. Bartlett, G. Douglas Campbell, Nathan C. Dean, Scott F. Dowell, Thomas M. File, Jr. Daniel M. Musher, Michael S. Niederman, Antonio Torres, and Cynthia G. Whitney McMaster University Medical School, Hamilton, Ontario, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, and Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas; Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Mississippi School of Medicine, Jackson; Division of Pulmonary and Critical Care Medicine, LDS Hospital, and University of Utah, Salt Lake City, Utah; Centers for Disease Control and Prevention, Atlanta, Georgia; Northeastern Ohio Universities College of Medicine, Rootstown, and Summa Health System, Akron, Ohio; State University of New York at Stony Brook, Stony Brook, and Department of Medicine, Winthrop University Hospital, Mineola, New York; and Cap de Servei de Pneumologia i Allergia Respiratoria, Institut Clinic del Torax, Hospital Clinic de Barcelona, Facultat de Medicina, Universitat de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer, CIBER CB06/06/0028, Barcelona, Spain.

Linezolid vs Vancomycin*: Analysis of Two Double-Blind Studies of Patients With Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia

OBJECTIVE To assess the effect of baseline variables, including treatment, on outcome in patients with nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). DESIGN Retrospective analysis of data from two prospective, randomized, double-blind studies. SETTING Multinational study with 134 sites. PATIENTS A total of 1,019 patients with suspected Gram-positive nosocomial pneumonia, including 339 patients with documented S aureus pneumonia (S aureus subset) and 160 patients with documented MRSA pneumonia (MRSA subset). INTERVENTIONS Linezolid, 600 mg, or vancomycin, 1 g, q12h for 7 to 21 days, each with aztreonam. MEASUREMENTS AND RESULTS Outcome was measured by survival and clinical cure rates (assessed 12 to 28 days after the end of therapy). Logistic regression analysis was used to determine the effect of treatment and other baseline variables on outcome. Kaplan-Meier survival rates for linezolid vs vancomycin were 80.0% (60 of 75 patients) vs 63.5% (54 of 85 patients) for the MRSA subset (p = 0.03). Logistic regression analysis confirmed that the survival difference favoring linezolid remained significant after adjusting for baseline variables (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.0 to 4.8; p = 0.05). Other baseline variables associated with significantly higher survival rates in MRSA pneumonia were serum creatinine levels less than or equal to two times the upper limit of normal and absence of cardiac comorbidities. Clinical cure rates for linezolid vs vancomycin (excluding indeterminate or missing outcomes) were 59.0% (36 of 61 patients) vs 35.5% (22 of 62 patients) for the MRSA subset (p < 0.01). Logistic regression analysis confirmed that the difference favoring linezolid remained significant after adjusting for baseline variables (OR, 3.3; 95% CI, 1.3 to 8.3; p = 0.01). Other baseline variables associated with significantly higher clinical cure rates in MRSA pneumonia were single-lobe pneumonia, absence of ventilator-associated pneumonia, and absence of oncologic and renal comorbidities. CONCLUSIONS In this retrospective analysis, initial therapy with linezolid was associated with significantly better survival and clinical cure rates than was vancomycin in patients with nosocomial pneumonia due to MRSA.

Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults

BACKGROUND Community-acquired pneumonia is a leading infectious cause of hospitalization and death among U.S. adults. Incidence estimates of pneumonia confirmed radiographically and with the use of current laboratory diagnostic tests are needed. METHODS We conducted active population-based surveillance for community-acquired pneumonia requiring hospitalization among adults 18 years of age or older in five hospitals in Chicago and Nashville. Patients with recent hospitalization or severe immunosuppression were excluded. Blood, urine, and respiratory specimens were systematically collected for culture, serologic testing, antigen detection, and molecular diagnostic testing. Study radiologists independently reviewed chest radiographs. We calculated population-based incidence rates of community-acquired pneumonia requiring hospitalization according to age and pathogen. RESULTS From January 2010 through June 2012, we enrolled 2488 of 3634 eligible adults (68%). Among 2320 adults with radiographic evidence of pneumonia (93%), the median age of the patients was 57 years (interquartile range, 46 to 71); 498 patients (21%) required intensive care, and 52 (2%) died. Among 2259 patients who had radiographic evidence of pneumonia and specimens available for both bacterial and viral testing, a pathogen was detected in 853 (38%): one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and Streptococcus pneumoniae (in 5%). The annual incidence of pneumonia was 24.8 cases (95% confidence interval, 23.5 to 26.1) per 10,000 adults, with the highest rates among adults 65 to 79 years of age (63.0 cases per 10,000 adults) and those 80 years of age or older (164.3 cases per 10,000 adults). For each pathogen, the incidence increased with age. CONCLUSIONS The incidence of community-acquired pneumonia requiring hospitalization was highest among the oldest adults. Despite current diagnostic tests, no pathogen was detected in the majority of patients. Respiratory viruses were detected more frequently than bacteria. (Funded by the Influenza Division of the National Center for Immunizations and Respiratory Diseases.).

Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock

Summary Background Despite the availability of potent antibiotics and intensive care, mortality rates from septic shock are 40–70%. We assessed the safety and efficacy of murine monoclonal antibody to human tumour necrosis factor α (TNF α MAb) in the treatment of septic shock. Methods In a randomised, multicentre, double-blind, placebo-controlled clinical trial in 105 hospitals in the USA and Canada, we randomly assigned 1879 patients a single infusion of 7·5 mg/kg TNFα MAb (n=949) or placebo (0·25% human serum albumin n=930). Our main outcome measurement was the rate of all-cause mortality at 28 days. Findings 382 (40·3%) of 948 patients who received TNFα MAb and 398 (42·8%) of 930 who received placebo had died at 28 days (95% CI −0·02 to 0·07, p=0·27). We found no association between therapy with TNFα MAb and increased rapidity in reversal of initial shock or prevention of subsequent shock. Similarly, baseline plasma interleukin-6 concentrations of more than 1000 pg/mL or detectable circulating TNF concentrations were not associated with improvement in survival after TNFα MAb therapy. Coagulopathy but not other organ or system failures, was significantly decreased in the TNFα MAb group compared with placebo (day 7, p Interpretation We did not find an improvement in survival after septic shock with TNFα MAb. Therapy not solely dependent on TNFα blockade may be required to improve survival.

Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study.

Linezolid, the first oxazolidinone, is active against gram-positive bacteria, including multidrug-resistant strains. This multinational, randomized, double-blind, controlled trial compared the efficacy, safety, and tolerability of linezolid with vancomycin in the treatment of nosocomial pneumonia. A total of 203 patients received intravenous linezolid, 600 mg twice daily, plus aztreonam, and 193 patients received vancomycin, 1 g intravenously twice daily, plus aztreonam for 7-21 days. Clinical and microbiological outcomes were evaluated at test of cure 12-28 days after treatment. Clinical cure rates (71 [66.4%] of 107 for linezolid vs. 62 [68.1%] of 91 for vancomycin) and microbiological success rates (36 [67.9%] of 53 vs. 28 [71.8%] of 39, respectively) for evaluable patients were equivalent between treatment groups. Eradication rates of methicillin-resistant Staphylococcus aureus and safety evaluations were similar between treatment groups. Resistance to either treatment was not detected. Linezolid is a well-tolerated, effective treatment for adults with gram-positive nosocomial pneumonia.

Linezolid in Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia: A Randomized, Controlled Study

BACKGROUND Post hoc analyses of clinical trial data suggested that linezolid may be more effective than vancomycin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. This study prospectively assessed efficacy and safety of linezolid, compared with a dose-optimized vancomycin regimen, for treatment of MRSA nosocomial pneumonia. METHODS This was a prospective, double-blind, controlled, multicenter trial involving hospitalized adult patients with hospital-acquired or healthcare-associated MRSA pneumonia. Patients were randomized to receive intravenous linezolid (600 mg every 12 hours) or vancomycin (15 mg/kg every 12 hours) for 7-14 days. Vancomycin dose was adjusted on the basis of trough levels. The primary end point was clinical outcome at end of study (EOS) in evaluable per-protocol (PP) patients. Prespecified secondary end points included response in the modified intent-to-treat (mITT) population at end of treatment (EOT) and EOS and microbiologic response in the PP and mITT populations at EOT and EOS. Survival and safety were also evaluated. RESULTS Of 1184 patients treated, 448 (linezolid, n = 224; vancomycin, n = 224) were included in the mITT and 348 (linezolid, n = 172; vancomycin, n = 176) in the PP population. In the PP population, 95 (57.6%) of 165 linezolid-treated patients and 81 (46.6%) of 174 vancomycin-treated patients achieved clinical success at EOS (95% confidence interval for difference, 0.5%-21.6%; P = .042). All-cause 60-day mortality was similar (linezolid, 15.7%; vancomycin, 17.0%), as was incidence of adverse events. Nephrotoxicity occurred more frequently with vancomycin (18.2%; linezolid, 8.4%). CONCLUSIONS For the treatment of MRSA nosocomial pneumonia, clinical response at EOS in the PP population was significantly higher with linezolid than with vancomycin, although 60-day mortality was similar.

Effect of clopidogrel on bleeding after coronary artery bypass surgery.

Objective Platelet dysfunction is a common cause of bleeding after coronary artery bypass graft surgery. This study explores the effects of clopidogrel on bleeding complications after coronary artery bypass graft surgery. Design Prospective observational study of patients undergoing coronary artery bypass graft. Setting Tertiary care center. Patients A total of 247 patients undergoing coronary artery bypass graft surgery. Interventions None. Measurements Primary end point was need for reexploration secondary to bleeding. Secondary end points included need for transfusion of blood products and chest tube output. Main results Eight (3.3%) of 247 patients required reexploration secondary to bleeding. Clopidogrel recipients had higher incidence of reexploration for bleeding (9.8 vs. 1.6, p = .01) with an odds ratio of 6.9 (95% confidence interval, 1.6–30). Clopidogrel also increased the percentage of patients receiving packed red blood cell transfusion (72.6 vs. 51.6%, p = .007), the number of packed red blood cell units (3 vs. 1.6, p =0.0004), and the number of cryoprecipitate units (2.4 vs. 1.2, p = .04) transfused after coronary artery bypass graft surgery. Among clopidogrel recipients, a trend for increased transfusion of platelet units (4.3 vs. 1.7, p = .05) and fresh frozen plasma units (1.1 vs. 0.6, p = .08) also was found. Conclusions Preoperative use of clopidogrel in combination with aspirin is associated with increased need for surgical reexploration as well as risk of packed red blood cell and cryoprecipitate transfusions after coronary artery bypass graft surgery.

High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm.

Levofloxacin demonstrates concentration-dependent bactericidal activity most closely related to the pharmacodynamic parameters of the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) and the ratio of peak plasma concentration (C(max)) to MIC. Increasing the dose of levofloxacin to 750 mg exploits these parameters by increasing peak drug concentrations, allowing for a shorter course of treatment without diminishing therapeutic benefit. This was demonstrated in a multicenter, randomized, double-blind investigation that compared levofloxacin dosages of 750 mg per day for 5 days with 500 mg per day for 10 days for the treatment of mild to severe community-acquired pneumonia (CAP). In the clinically evaluable population, the clinical success rates were 92.4% (183 of 198 persons) for the 750-mg group and 91.1% (175 of 192 persons) for the 500-mg group (95% confidence interval, -7.0 to 4.4). Microbiologic eradication rates were 93.2% and 92.4% in the 750-mg and 500-mg groups, respectively. These data demonstrate that 750 mg of levofloxacin per day for 5 days is at least as effective as 500 mg per day for 10 days for treatment of mild-to-severe CAP.

Continuation of a Randomized, Double-Blind, Multicenter Study of Linezolid Versus Vancomycin in the Treatment of Patients with Nosocomial Pneumonia

BACKGROUND The clinical efficacy and tolerability of linezolid were demonstrated in a previously published, randomized, double-blind, registration study comparing linezolid with vancomycin for the empiric treatment of 396 patients with nosocomial pneumonia. OBJECTIVES The aims of this study were to obtain additional experience with linezolid and vancomycin in patients with nosocomial pneumonia and to satisfy international regulatory requirements. METHODS Patients with pneumonia acquired after 48 hours in an inpatient facility were randomly assigned to receive either IV linezolid 600 mg or IV vancomycin 1 g every 12 hours for 7 to 21 consecutive days. Patients also received IV aztreonam 1 to 2 g every 8 hours, which could be discontinued if gram-negative pathogens were not identified. The primary efficacy variables were clinical and microbiologic outcomes in evaluable patients at the follow-up visit 15 to 21 days after the end of therapy. Results from the continuation study were analyzed separately and did not include patients from the previously reported study. RESULTS A total of 623 patients were enrolled: 321 in the linezolid group and 302 in the vancomycin group. Mean (SD) ages were 63.1 (19.1) years and 61.9 (19.3) years, respectively. Mean (SD) Acute Physiology and Chronic Health Evaluation II scores were 14.1 (5.8) and 14.1 (6.2), respectively. There were no significant differences between the linezolid and vancomycin groups at the follow-up visit in clinical cure rates (114/168 [67.9%] and 111/171 [64.9%]) or microbiologic success rates (47/76 [61.8%] and 42/79 [53.2%]) in evaluable patients (excluding those who had indeterminate or missing outcomes). There were also no significant differences in the rates of all drug-related adverse events (14.0% and 14.0%) or those that occurred in > 1% of patients, including diarrhea (3.7% and 3.0%), nausea (0.3% and 1.3%), and rash (0.6% and 1.7%) in the linezolid and vancomycin groups, respectively. CONCLUSION In the population studied, linezolid appeared to be as well tolerated and as effective as vancomycin, each in combination with aztreonam.

Validation of Cell-Cycle Arrest Biomarkers for Acute Kidney Injury Using Clinical Adjudication

RATIONALE We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).