Management of complicated infections in the era of antimicrobial resistance: the role of tigecycline.

Expert Opin Pharmacother. 2009 May;10(7):1213-22

Authors: Nicolau DP

BACKGROUND: Increasing antimicrobial resistance and infection complications pose challenges to optimal antibiotic therapy. Paucity of new antibiotics (and the eventual bacterial resistance they face) highlights the critical need for more appropriate use of broadly effective agents, which may help to thwart the dramatic rise in global resistance. Single agents that can be combined effectively with others, if needed, promise the simplest overall utility. Approved in 2005 to treat complicated skin and intra-abdominal infections, tigecycline is a novel extended-spectrum minocycline derivative that circumvents bacterial resistance, as it is unaffected by efflux pumps and ribosomal protection. However, tigecycline should not be used as empiric monotherapy for treatment of health-care associated infections known or suspected to be owing to Pseudomonas aeruginosa or Proteus spp. OBJECTIVE: This article summarizes the demonstrated clinical utility of tigecycline so far. METHODS: A MEDLINE search examined authoritative published clinical studies, reviews and case reports detailing the clinical record of tigecycline since 2004. RESULTS/CONCLUSION: Tigecycline continues to maintain satisfactory profiles of safety, efficacy and antimicrobial resistance avoidance. Regardless, continued surveillance is needed to detect reduced susceptibility and resistance against both community and nosocomial pathogens. Judicious use of agents reserved for multidrug resistant pathogens is vital to preserve their effectiveness.

PMID: 19405794 [PubMed - indexed for MEDLINE]

Treatment strategies for Legionella infection.

Expert Opin Pharmacother. 2009 May;10(7):1109-21

Authors: Pedro-Botet ML, Yu VL

Given the nonspecific clinical manifestations of Legionnaires' disease and the high mortality of untreated Legionnaires' disease, we recommend routine use of Legionella testing, especially the Legionella urinary antigen test, for all patients with community-acquired pneumonia. This includes patients with ambulatory pneumonia and hospitalized children. Legionella cultures should be more widely available, especially in hospitals where the drinking water is colonized with Legionella. Azithromycin or levofloxacin can be considered as first-line therapy. Other antibiotics including tetracyclines, tigecycline, other fluoroquinolones and other macrolides (especially clarithromycin) are also effective. The clinical response of quinolones may be somewhat more favorable compared to macrolides, but the outcome is similar. If the Legionnaires' disease is hospital-acquired, culturing of the hospital drinking water for Legionella is indicated.

PMID: 19405787 [PubMed - indexed for MEDLINE]

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No more free drug samples?

PLoS Med. 2009 May 5;6(5):e1000074

Authors: Chimonas S, Kassirer JP

Susan Chimonas and Jerome Kassirer argue that giving out "free" drug samples is not effective in improving drug access for the indigent, does not promote rational drug use, and raises the cost of care.

PMID: 19434227 [PubMed - indexed for MEDLINE]

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Beta blockers for peripheral arterial disease.

Eur J Vasc Endovasc Surg. 2009 Jul;38(1):66-70

Authors: Paravastu SC, Mendonca DA, da Silva A

OBJECTIVES: To quantify the potential harm of beta blockers in patients with peripheral arterial disease. MATERIALS AND METHODS: All randomised controlled trials (RCTs) comparing beta blockers with placebo for the outcomes of claudication and maximal walking distance and time, calf blood flow, vascular resistance and skin temperature were searched using the Cochrane Controlled Trials Register, PubMed and CINAHL. Trials comparing different types of beta blockers were excluded. RESULTS: Six RCTs fulfilling the above criteria, with a total of 119 patients, were included. The beta blockers studied were atenolol, propranolol, pindolol and metoprolol. None of the trials showed a statistically significant worsening effect of beta blockers on the outcomes measured. There were no reports of any adverse events with the beta blockers studied. CONCLUSIONS: Currently, there is no evidence to suggest that beta blockers adversely affect walking distance in people with intermittent claudication. Beta blockers should be used with caution if clinically indicated, especially in patients with critical ischaemia where acute lowering of blood pressure is contraindicated.

PMID: 19359199 [PubMed - indexed for MEDLINE]

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Prasugrel for arterial coronary thrombosis.

Drugs Today (Barc). 2009 Feb;45(2):83-91

Authors: Serebruany V, Makarov L

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome undergoing percutaneous coronary intervention. Clopidogrel, in combination with aspirin, is associated with improvement in longterm vascular clinical outcomes in these patients and is currently the antiplatelet standard of care. However, a significant number of patients still experience secondary ischemic thrombotic events due to potential insufficient platelet inhibition or noncompliance. Therefore, the development of better and safer antiplatelet agents is of the utmost priority. Indeed, oral antiplatelet agents, such as aspirin in the ISIS-2 study and clopidogrel in the COMMIT mega trial, in moderate doses are among the very few classes of drugs that reduce absolute mortality in patients after acute vascular thrombotic events. Prasugrel (CS-747; LY-640315), an experimental third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate P2Y(12) receptor. Preclinical and early phase clinical studies have shown that prasugrel has greater antiplatelet potency, lower variability in platelet response and faster onset of inhibition than clopidogrel. However, the doses of the drug chosen for further prasugrel developments are much higher (about 2.5-2.7 times higher) than those of conventional clopidogrel regimen(s). The recent TRITON trial assessed head-to-head prasugrel versus clopidogrel, both in addition to aspirin, and led to numerous controversies with regard to the fairness of the trial design, interpretation of its results, and the suitability of the high maintenance prasugrel dose for chronic preventive human use. We critically review various aspects of prasugrel development, focusing on the discrepancies between the official interpretation of the results and actual findings. We conclude that the benefits of prasugrel are exaggerated and that the risks are underestimated. Very careful maintenance dose selection and a flawless long-term safety profile for the new agents will become the keys to the success of future oral antiplatelet drug development.

PMID: 19343228 [PubMed - indexed for MEDLINE]

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Renal toxicity of therapeutic drugs.

J Clin Pathol. 2009 Jun;62(6):505-15

Authors: John R, Herzenberg AM

A number of therapeutic agents can adversely affect the kidney, resulting in tubulointerstitial, glomerular or vascular disease. Drug-induced tubulointerstitial nephritis and acute tubular necrosis are common, and are often cause by antibiotics or non-steroidal anti-inflammatory drugs. Drug-induced glomerular and vascular disease is relatively rare. This review describes the morphological patterns of drug-induced disease in the kidney. The histopathological changes are often similar to disease that is idiopathic or due to other causes, so that awareness and clinical correlation are most helpful to arrive at the aetiology.

PMID: 19474353 [PubMed - indexed for MEDLINE]

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Transthoracic sonography for the detection of pulmonary embolism--a meta-analysis.

Ultraschall Med. 2009 Apr;30(2):150-6

Authors: Niemann T, Egelhof T, Bongartz G

PURPOSE: Radiation protection is a major issue since the implementation of MSCT technology and its widespread indication for the detection of various diseases. In a European-wide trial (SECT) meta-analyses of imaging alternatives to CT have been initiated. This paper focuses on the diagnostic performance of transthoracic ultrasound (TUS) for the diagnosis of pulmonary embolism (PE) (5 studies, 652 patients). MATERIALS AND METHODS: Medical literature (from 1990 to 2006) in PubMed and EMBASE databases was searched for articles on studies that used TUS as diagnostic tests for PE. Studies were included if they reported the positive and negative rates of PE diagnoses from TUS compared with the rates of PE in CT, MRI or a combination of diagnostic tests. Two readers assessed the quality of the studies. RESULTS: Pooled sensitivity and specificity of TUS for PE were 80 % (95 % CI: 75 %, 83 %) and 93 % (95 % CI: 89 %, 96 %), respectively. CONCLUSION: In the time of MSCT, TUS is an imaging modality that is no longer part of recent diagnostic algorithms for the diagnosis of PE. Considering the increasing number of requested CT examinations and therefore increasing collective radiation dose, this meta-analysis shows that TUS is a diagnostic alternative for special clinical settings in the work-up of suspected PE that seems to have fallen into oblivion.

PMID: 19253205 [PubMed - indexed for MEDLINE]

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Some medical inpatients with unhealthy alcohol use may benefit from brief intervention.

J Stud Alcohol Drugs. 2009 May;70(3):426-35

Authors: Saitz R, Palfai TP, Cheng DM, Horton NJ, Dukes K, Kraemer KL, Roberts MS, Guerriero RT, Samet JH

OBJECTIVE: Studies of alcohol brief intervention for medical inpatients have mixed results. We explored potential moderators of the effectiveness of brief intervention for unhealthy alcohol use among medical inpatients. METHOD: This is a secondary analysis of a randomized controlled trial of brief motivational counseling among 341 urban-hospital medical inpatients (99 women) with unhealthy alcohol use. Self-reported main outcomes were receipt of alcohol treatment by 3 months in subjects with dependence and change in the mean number of drinks per day 3 and 12 months after enrollment in all subjects. RESULTS: Among subjects with dependence, the effect of brief intervention on receipt of alcohol treatment differed significantly by gender and age (p = .02 for each interaction). In stratified analyses, brief intervention was associated with receipt of alcohol treatment in women (adjusted odds ratio [AOR] = 3.9, 95% confidence interval [CI]: 1.2-12.7), and younger (<44 years) subjects (AOR = 3.6, 95% CI: 1.3-10.1). Among subjects with nondependent, unhealthy alcohol use, brief intervention was significantly associated with fewer drinks per day and better physical health-related quality of life at 3 months. However, among those with dependence, intervention was associated with worse physical health-related quality of life and more hospital use, and no changes in drinking. In adjusted analyses among those with and without dependence, brief intervention was not associated with mental health-related quality of life, alcohol problems, or readiness to change. Effects of brief intervention on consumption outcomes were not consistently moderated by demographic characteristics, comorbidity/health, or readiness to change. CONCLUSIONS: Some medical inpatients with unhealthy alcohol use, particularly women, younger adults, and patients without dependence may benefit from brief intervention. Few factors that were expected to moderate brief intervention effects did so. Additional research should assess which medical inpatients, if any, can benefit from brief intervention.

PMID: 19371494 [PubMed - indexed for MEDLINE]

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A randomized, double-blind comparison of lorazepam and chlordiazepoxide in patients with uncomplicated alcohol withdrawal.

J Stud Alcohol Drugs. 2009 May;70(3):457-74

Authors: Kumar CN, Andrade C, Murthy P

OBJECTIVE: For important reasons, lorazepam (Ativan) and chlordiazepoxide (Librium) are both popular treatments for alcohol-withdrawal syndrome. Nevertheless, there is little literature directly comparing the two drugs. A formal comparison is desirable because of pharmacokinetic and other differences that could affect safety and efficacy considerations relevant to practice in developing countries. METHOD: One hundred consecutive consenting male inpatients in a state of moderately severe, uncomplicated alcohol withdrawal at screening were randomized to receive either lorazepam (8 mg/day) or chlordiazepoxide (80 mg/day) with dosing down-titrated to zero in a fixed-dose schedule across 8 treatment days. Double-blind assessments of withdrawal-symptom severity and impairing adverse events were obtained during treatment and for 4 days afterward. RESULTS: One chlordiazepoxide patient developed withdrawal delirium. Lorazepam and chlordiazepoxide showed similar efficacy in reducing symptoms of alcohol withdrawal as assessed using the revised Clinical Institute Withdrawal Assessment for Alcohol scale. During withdrawal, irritability and dizziness were more common with lorazepam, and palpitations were more common with chlordiazepoxide. No difficulties in drug discontinuation or differences in impairing adverse events were observed with either drug. CONCLUSIONS: With the treatment schedule used in this study, lorazepam is as effective as the more traditional drug chlordiazepoxide in attenuating uncomplicated alcohol withdrawal. Lorazepam, therefore, could be used with confidence when liver disease or the inability to determine liver function status renders chlordiazepoxide therapy problematic. The absence of clinically significant withdrawal complications with lorazepam in this large study contrasts with findings from previously published studies and suggests that higher doses of lorazepam than those formerly used may be necessary during alcohol withdrawal.

PMID: 19371497 [PubMed - indexed for MEDLINE]

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Prevention of venous thromboembolism in medical patients and outpatients.

Nat Rev Cardiol. 2009 May;6(5):356-63

Authors: Stashenko GJ, Tapson VF

The majority of fatal cases of pulmonary embolism in hospitalized patients occur in acutely ill, medically treated patients. Current guidelines, based on a large number of prospective, randomized, controlled trials evaluating the safety and efficacy of pharmacologic venous thromboembolism (VTE) prophylaxis in medical patients, now recommend using VTE prophylaxis in this population. Unfortunately, prophylaxis rates in medical patients are unacceptably low, despite efforts to develop strategies for improving implementation of prophylaxis regimens. Studies indicate that a substantial proportion of patients with VTE present after hospital discharge, but no clinical trials evaluating VTE prophylaxis for medical outpatients have yet been published. In this Review, we examine the literature on VTE prophylaxis in hospitalized medical patients, and evaluate the available data for the outpatient setting.

PMID: 19377498 [PubMed - indexed for MEDLINE]

Shared by Robert Mahoney
Link: http://www3.interscience.wiley.com/journal/122419566/abstract?CRETRY=1&SRETRY=0

Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in the diagnosis of heart failure.

J Intern Med. 2009 May 31;

Authors: Potocki M, Breidthardt T, Reichlin T, Hartwiger S, Morgenthaler NG, Bergmann A, Noveanu M, Freidank H, Taegtmeyer AB, Wetzel K, Boldanova T, Stelzig C, Bingisser R, Christ M, Mueller C

Objectives. The concentration of atrial natriuretic peptide (ANP) in the circulation is approximately 10- to 50- fold higher than B-type natriuretic peptide (BNP). We sought to compare the accuracy of midregional pro-atrial natriuretic peptide (MRproANP) measured with a novel sandwich immunoassay with N-terminal pro-B-type natriuretic peptide (NTproBNP) in the diagnosis of heart failure. Design. The diagnosis of heart failure was adjudicated by two independent cardiologists using all available clinical data (including BNP levels) in 287 consecutive patients presenting with dyspnoea to the emergency department (ED). MRproANP and NTproBNP levels were determined at presentation in a blinded fashion. Results. Heart failure was the adjudicated final diagnosis in 154 patients (54%). Median MRproANP was significantly higher in patients with heart failure as compared to patients with other causes of dyspnoea (400 vs. 92 pmol L(-1), P < 0.001). The diagnostic accuracy of MRproANP was very high with an area under the receiver operating characteristic curve of 0.92 and was comparable with that of NTproBNP (0.92, P = 0.791). Moreover, MRproANP provided incremental diagnostic information to BNP and NTproBNP in patients presenting with BNP levels in the grey zone between 100 and 500 pg mL(-1). Conclusion. Midregional pro-atrial natriuretic peptide is as accurate in the diagnosis of heart failure as NTproBNP. MRproANP seems to provide incremental information on top of BNP or NT-proBNP in some subgroups and should be further investigated in other studies.

PMID: 19570053 [PubMed - as supplied by publisher]

Shared by Robert Mahoney
Link: http://content.nejm.org/cgi/content/abstract/361/1/22

Epidemiologic study of in-hospital cardiopulmonary resuscitation in the elderly.

N Engl J Med. 2009 Jul 2;361(1):22-31

Authors: Ehlenbach WJ, Barnato AE, Curtis JR, Kreuter W, Koepsell TD, Deyo RA, Stapleton RD

BACKGROUND: It is unknown whether the rate of survival after in-hospital cardiopulmonary resuscitation (CPR) is improving and which characteristics of patients and hospitals predict survival. METHODS: We examined fee-for-service Medicare data from 1992 through 2005 to identify beneficiaries 65 years of age or older who underwent CPR in U.S. hospitals. We examined temporal trends in the incidence of CPR and the rate of survival after CPR, as well as patient- and hospital-level predictors of survival to discharge. RESULTS: We identified 433,985 patients who underwent in-hospital CPR; 18.3% of these patients (95% confidence interval [CI], 18.2 to 18.5) survived to discharge. The rate of survival did not change substantially during the period from 1992 through 2005. The overall incidence of CPR was 2.73 events per 1000 admissions; the incidence was higher among black and other nonwhite patients. The proportion of patients undergoing in-hospital CPR before death increased over time and was higher for nonwhite patients. The survival rate was lower among patients who were men, were older, had more coexisting illnesses, or were admitted from a skilled-nursing facility. The adjusted odds of survival for black patients were 23.6% lower than those for similar white patients (95% CI, 21.2 to 25.9). The association between race and survival was partially explained by hospital effects: black patients were more likely to undergo CPR in hospitals that have lower rates of post-CPR survival. Among patients surviving in-hospital CPR, the proportion of patients discharged home rather than to a health care facility decreased over time. CONCLUSIONS: Survival after in-hospital CPR did not improve from 1992 through 2005. The proportion of in-hospital deaths preceded by CPR increased, whereas the proportion of survivors discharged home after undergoing CPR decreased. Black race was associated with higher rates of CPR but lower rates of survival after CPR.

PMID: 19571280 [PubMed - in process]

Shared by Robert Mahoney
Link: http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH09-01-0048

Accuracy of complete compression ultrasound in ruling out suspected deep venous thrombosis in the ambulatory setting. A prospective cohort study.

Thromb Haemost. 2009 Jul;102(1):166-72

Authors: Sevestre MA, Labarère J, Casez P, Bressollette L, Taiar M, Pernod G, Quéré I, Bosson JL

Evidence on the safety of complete compression ultrasound for ruling out deep venous thrombosis (DVT) is derived from studies conducted in tertiary care centers, although most patients with suspected DVT are managed in the ambulatory office setting. It was the objective of this study to estimate the rate of venous thromboembolism when anticoagulant therapy is withheld from ambulatory patients with normal findings on a single complete compression ultrasound. As part of a prospective cohort study, 3,871 ambulatory patients with clinically suspected DVT were enrolled by 255 board-certified vascular medicine physicians practicing in private offices in France. Compression ultrasound of the entire lower extremities was performed using a standardised examination protocol. Anticoagulant therapy was withheld from patients with negative findings on compression ultrasound, and 1,254 of them were randomly selected for follow-up. The main outcome measure was the three-month incidence of symptomatic venous thromboembolic events confirmed by objective testing. DVT was detected in 1,023 patients (26.4%), including 454 (11.7%) and 569 (14.7%) cases of proximal and isolated distal DVT, respectively. Of the 1,254 patients with negative results sampled for follow-up, six received anticoagulant therapy during follow-up and five were lost to follow-up. Five of 1,243 patients (0.4%, 95% confidence interval [CI], 0.1-0.9) experienced non-fatal symptomatic venous thromboembolic events (pulmonary embolism in two patients and DVT in three patients) and eight of 1,254 patients (0.6%, 95% CI, 0.3-1.2) died during the three-month follow-up. In conclusion, anticoagulant therapy can be safely withheld after negative complete compression ultrasound without further testing in the ambulatory office setting.

PMID: 19572082 [PubMed - in process]

Shared by Robert Mahoney
Link: http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH09-01-0003

Association of anaemia and mortality in patients with acute pulmonary embolism.

Thromb Haemost. 2009 Jul;102(1):153-8

Authors: Jiménez D, Escobar C, Martí D, Díaz G, César J, García-Avello A, Sueiro A, Yusen RD

This study aimed to evaluate the relationship between anaemia and pulmonary embolism (PE) prognosis. We analysed a cohort of 764 patients with acute PE referred to a single center for diagnosis and management. Patients were divided into groups by quartiles of haemoglobin (Hb): Hb < 11.7 g/dl; Hb 11.7 to 12.9 g/dl; Hb 13.0 to 14.1 g/dl; Hb > 14.1 g/dl. Patients had a mean Hb of 12.9 g/dl, and values ranged from to 4.3 to 19.5 g/dl. Lower Hb was associated with recent bleeding, an impaired haemodynamic profile and higher creatinine. Patients in the lower Hb quartiles more commonly had female gender (p < 0.001), a diagnosis of cancer (p < 0.001), and an indication for an inferior vena cava (IVC) filter (p < 0.002), compared to patients in the higher Hb quartiles. Patients in higher Hb quartiles had higher survival at three months (75%, 86%, 90% and 91% for lowest to highest quartiles, respectively). On multivariate analysis, adjusting for known PE prognostic factors, low Hb proved to be an independent predictor of mortality (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05 to 1.28 for each decrease of 1 g/dl). Hb level remained an independent predictor of all-cause mortality when cancer patients were excluded from the analysis (adjusted HR 0.81; 95% CI, 0.66 to 0.99; p = 0.04). Moreover, patients with anaemia showed a higher risk of fatal PE (unadjusted HR 1.19, 95% CI 1.04 to 1.37). In conclusion, in patients with acute symptomatic PE, anaemia severity is associated with worsened survival.

PMID: 19572080 [PubMed - in process]

Shared by Robert Mahoney
Link: http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH08-10-0653

Differential inhibition of thrombin generation by vitamin K antagonists alone and associated with low-molecular-weight heparin.

Thromb Haemost. 2009 Jul;102(1):42-8

Authors: Gerotziafas GT, Dupont C, Spyropoulos AC, Hatmi M, Samama MM, Kiskinis D, Elalamy I

Vitamin K antagonists (VKA) treatment starts with co-administration of low-molecular-weight heparin (LMWH). The anticoagulation induced by the two drugs is still not well determined. In the present study we used thrombin generation assay to evaluate the hypo-coagulation induced by treatment with VKA and by the combination of VKA with LMWH. Tissue factor triggered thrombin generation in platelet-poor plasma was assessed in samples from 15 healthy volunteers, 97 samples from patients treated with VKA and 41 samples from patients receiving enoxaparin and VKA. Patients were classified according to international normalised ratio (INR) level (<2, 2-3 and >3). In plasma samples from patients treated with VKA having INR 2-3 the inhibition of thrombin generation reached 50% compared to controls. In samples with INR>3 this inhibition was 80%. In samples from patients receiving both LMWH and VKA, thrombin generation was significantly decreased compared to the controls and VKA group. In samples with an INR 2-3 obtained from patients treated with LMWH and VKA, the inhibition of thrombin generation was similar to that observed in samples with an INR>3 obtained from VKA treated patients. Thrombin generation assay is sensitive to detect the global the anticoagulant effect produced by the association of LMWH and VKA. For equal INR dual anticoagulant treatment induces significantly more profound inhibition of thrombin generation compared to treatment with VKA alone. The clinical relevance of this observation merits to be studied in prospective studies in patients with defined indications of anticoagulant therapy.

PMID: 19572066 [PubMed - in process]