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Mechanisms of drug-induced nephrotoxicity.

Handb Exp Pharmacol. 2010;(196):111-30

Authors: Nolin TD, Himmelfarb J

Drug-induced nephrotoxicity is a common complication of several medications and diagnostic agents. It is seen in both inpatient and outpatient settings with variable presentations ranging from mild, reversible injury to advanced kidney disease. Manifestations of drug-induced nephrotoxicity include acid-base abnormalities, electrolyte imbalances, urine sediment abnormalities, proteinuria, pyuria, hematuria, and, most commonly, a decline in the glomerular filtration rate. The mechanisms of drug-induced nephrotoxicity may differ between various drugs or drug classes, and they are generally categorized based on the histological component of the kidney that is affected. Aminoglycoside antibiotics, radiocontrast media, conventional nonselective nonsteroidal anti-inflammatory drugs, and selective cyclooxygenase-2 inhibitors, amphotericin B, and angiotensin-converting enzyme inhibitors have been frequently implicated. This chapter reviews the clinical presentation and basic mechanisms of drug-induced nephrotoxicity.

PMID: 20020261 [PubMed - indexed for MEDLINE]

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Strategies and new developments in the management of bacterial meningitis.

Infect Dis Clin North Am. 2009 Dec;23(4):925-43, viii-ix

Authors: Miranda J, Tunkel AR

The principles of antimicrobial therapy for acute bacterial meningitis include use of agents that penetrate well into cerebrospinal fluid and attain appropriate cerebrospinal fluid concentrations, are active in purulent cerebrospinal fluid, and are bactericidal against the infecting pathogen. Recommendations for treatment of bacterial meningitis have undergone significant evolution in recent years, given the emergence of pneumococcal strains that are resistant to penicillin. Clinical experience with use of newer agents is limited to case reports, but these agents may be necessary to consider in patients who are failing standard therapy.

PMID: 19909891 [PubMed - indexed for MEDLINE]

Clinical decisions. American Board of Internal Medicine maintenance of certification program.

N Engl J Med. 2010 Mar 11;362(10):948-52

Authors: Levinson W, King TE, Goldman L, Goroll AH, Kessler B

PMID: 20220192 [PubMed - in process]

Low diagnostic yield of elective coronary angiography.

N Engl J Med. 2010 Mar 11;362(10):886-95

Authors: Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS

BACKGROUND: Guidelines for triaging patients for cardiac catheterization recommend a risk assessment and noninvasive testing. We determined patterns of noninvasive testing and the diagnostic yield of catheterization among patients with suspected coronary artery disease in a contemporary national sample. METHODS: From January 2004 through April 2008, at 663 hospitals in the American College of Cardiology National Cardiovascular Data Registry, we identified patients without known coronary artery disease who were undergoing elective catheterization. The patients' demographic characteristics, risk factors, and symptoms and the results of noninvasive testing were correlated with the presence of obstructive coronary artery disease, which was defined as stenosis of 50% or more of the diameter of the left main coronary artery or stenosis of 70% or more of the diameter of a major epicardial vessel. RESULTS: A total of 398,978 patients were included in the study. The median age was 61 years; 52.7% of the patients were men, 26.0% had diabetes, and 69.6% had hypertension. Noninvasive testing was performed in 83.9% of the patients. At catheterization, 149,739 patients (37.6%) had obstructive coronary artery disease. No coronary artery disease (defined as <20% stenosis in all vessels) was reported in 39.2% of the patients. Independent predictors of obstructive coronary artery disease included male sex (odds ratio, 2.70; 95% confidence interval [CI], 2.64 to 2.76), older age (odds ratio per 5-year increment, 1.29; 95% CI, 1.28 to 1.30), presence of insulin-dependent diabetes (odds ratio, 2.14; 95% CI, 2.07 to 2.21), and presence of dyslipidemia (odds ratio, 1.62; 95% CI, 1.57 to 1.67). Patients with a positive result on a noninvasive test were moderately more likely to have obstructive coronary artery disease than those who did not undergo any testing (41.0% vs. 35.0%; P<0.001; adjusted odds ratio, 1.28; 95% CI, 1.19 to 1.37). CONCLUSIONS: In this study, slightly more than one third of patients without known disease who underwent elective cardiac catheterization had obstructive coronary artery disease. Better strategies for risk stratification are needed to inform decisions and to increase the diagnostic yield of cardiac catheterization in routine clinical practice.

PMID: 20220183 [PubMed - in process]

Thrombolysis for pulmonary embolism: Past, present and future.

Thromb Haemost. 2010 Mar 9;103(5)

Authors: Lankeit M, Konstantinides S

Patients with high-risk pulmonary embolism (PE), i.e. those with shock or hypotension at presentation, are at high risk of in-hospital death, particularly during the first hours after admission. A meta-analysis of trials which included haemodynamically compromised patients indicated that thrombolytic treatment significantly reduces the rate of in-hospital death or PE recurrence. Therefore, thrombolysis should be administered to patients with high-risk PE unless there are absolute contraindications to its use. Uncontrolled data further suggest that thrombolysis may be a safe and effective alternative to surgery in patients with PE and free-floating thrombi in the right heart. On the other hand, normotensive patients generally have a favourable short-term prognosis if heparin anticoagulation is instituted promptly, and they are thus considered to have non-high-risk PE. Generally, the bleeding risk of thrombolysis appears to outweigh the clinical benefits of this treatment in patients without haemodynamic compromise. However, within the group of normotensive patients with PE, some may have evidence of right ventricular dysfunction on echocardiography or computed tomography, or of myocardial injury based on elevated cardiac biomarkers (troponin I or T, heart-type fatty acid-binding protein). These patients have an intermediate risk of an adverse outcome in the acute phase of PE. Existing data suggest that selected patients with intermediate-risk PE may benefit from early thrombolytic treatment, particularly if they have a low bleeding risk. However, controversy will continue to surround the optimal treatment for this group until the results of a large ongoing thrombolysis trial are available in a few years.

PMID: 20216979 [PubMed - as supplied by publisher]

Improved susceptibility of Gram-negative bacteria in an intensive care unit following implementation of a computerized antibiotic decision support system.

J Antimicrob Chemother. 2010 Mar 9;

Authors: Yong MK, Buising KL, Cheng AC, Thursky KA

Objectives Emergence of multiresistant Gram-negative organisms in intensive care units (ICUs) throughout the world is a concerning problem. Therefore we undertook a study to follow the resistance patterns of the most common clinically isolated Gram-negative organisms within our ICU following an antibiotic stewardship intervention to evaluate whether a reduction in broad-spectrum antibiotics improves local antibiotic resistance patterns. Methods This prospective study was conducted over a 7 year period within an ICU at a tertiary teaching hospital in Melbourne, Australia. All clinically isolated Gram-negative organisms were identified and extracted from the hospital pathology system. Three monthly antibiograms were created. The pre-interventional period occurred between January 2000 and June 2002 (10 quarters) and the post-interventional period was defined from July 2002 to December 2006 (18 quarters). Segmented linear regression was used to analyse for a difference in the rates of change in susceptibility. Results A total of 2838 Gram-negative organisms were isolated from clinical sites from ICU patients during the study period. There was significant improvement in susceptibility of Pseudomonas to imipenem 18.3%/year [95% confidence interval (CI): 4.9-31.6; P = 0.009] and gentamicin 11.6%/year (95% CI: 1.8-21.5; P = 0.02) compared with the pre-intervention trend. Significant changes in the rates of gentamicin and ciprofloxacin susceptibility were also observed in the inducible Enterobacteriaceae group although these were less clinically significant. Conclusions This study demonstrates improved antibiotic susceptibility of ICU Gram-negative isolates including Pseudomonas following an intervention aimed at reducing broad-spectrum antibiotics.

PMID: 20215130 [PubMed - as supplied by publisher]

Propranolol and the risk of hospitalized myopathy: Translating chemical genomics findings into population-level hypotheses.

Am Heart J. 2010 Mar;159(3):428-433

Authors: Setoguchi S, Higgins JM, Mogun H, Mootha VK, Avorn J

BACKGROUND: A recent large-scale, chemical screening study raised the hypothesis that propranolol may increase the risk of myopathy. We tested this hypothesis in a large population to assess whether (1) propranolol use is associated with an increased risk of myopathy and (2) the concurrent use of propranolol with a statin may further increase risk of myopathy. METHODS: New users of propranolol and other beta-blockers (BBs) aged >/=65 were identified using data from Medicare and drug benefit programs in 2 states (1994-2005). The primary end point studied was hospitalization for myopathy or rhabdomyolysis. We used stratified Cox proportional hazards regression to estimate the multivariate-adjusted effect of propranolol compared to other BBs and controlled for demographic variables, risk factors for myopathy, other comorbidities, and health service use measures. We also assessed whether co-use of propranolol and statin further increases the risk, by including an interaction term for use of propranolol and statins. RESULTS: We identified 9,304 initiators of propranolol and 130,070 initiators of other BBs and found 30 cases of hospitalized myopathy in 15,477 person-years (PYs) of propranolol use and 523 in 343,132 PYs of other BB use. Comparing propranolol with other BB users, the adjusted hazard ratio was 1.45 (95% CI 1.00-2.11) for myopathy and 1.48 (95% CI 0.82-2.67) for rhabdomyolysis. We could not detect interaction between propranolol and statins due to limited power. Similar results were observed when propranolol users were compared to other antihypertensive drug users. CONCLUSIONS: Propranolol may be associated with a 45% increased risk of hospitalized myopathy in the elderly. Our study illustrates how results from in vitro chemical screens can be translated into hypotheses about drug toxicity at the population level.

PMID: 20211305 [PubMed - as supplied by publisher]

In-hospital management of patients with atrial flutter.

Am Heart J. 2010 Mar;159(3):370-376

Authors: Lapointe NM, Sun JL, Kaplan S

BACKGROUND: Little is known about the use of drugs or procedures for management of atrial flutter (AFl) in routine clinical practice. We describe the extent of use of conversion therapies during AFl hospitalizations. METHODS: We examined hospitalizations for primary diagnoses of AFl using hospital claims from January 2000 to December 2004. Patients who received antiarrhythmic drugs, ablation, and/or electrical cardioversion for AFl were categorized as receiving a conversion therapy. Characteristics associated with use of conversion therapy versus no conversion therapy were determined. RESULTS: The study cohort included 19,825 hospitalizations. Of these, 13,059 (65.9%) included in-hospital use of >/=1 conversion therapies. Care by a noncardiologist (adjusted odds ratio [OR] 0.37, 95% CI 0.33-0.41), female sex (adjusted OR 0.84, 95% CI 0.79-0.90), nonwhite race (adjusted OR 0.83, 95% CI 0.74-0.92), and increasing age >70 years (adjusted OR 0.88, 95% CI 0.85-0.91) were associated with lower odds of conversion versus no-conversion therapy. Cardiomyopathy (adjusted OR 1.33, 95% CI 1.17-1.51), heart failure (adjusted OR 1.17, 95% CI 1.06-1.28), coronary artery disease (adjusted OR 1.14, 95% CI 1.05-1.22), secondary diagnosis of atrial fibrillation (adjusted OR 1.28, 95% CI 1.18-1.38), and hospitalization in 2000 or 2001 versus later years (adjusted OR 1.22, 95% CI 1.12-1.33) were associated with greater odds of conversion therapy versus no conversion therapy. CONCLUSION: One or more methods of conversion to sinus rhythm were used in two thirds of the hospitalizations with a primary diagnosis of AFl. Greater use of conversion therapies in patients with other heart disease were expected; however, lower use among elderly persons, females, and racial minorities may indicate some disparities in use and warrant further study.

PMID: 20211297 [PubMed - as supplied by publisher]

Relation of Proton Pump Inhibitor Use After Percutaneous Coronary Intervention With Drug-Eluting Stents to Outcomes.

Am J Cardiol. 2010 Mar 15;105(6):833-838

Authors: Gaglia MA, Torguson R, Hanna N, Gonzalez MA, Collins SD, Syed AI, Ben-Dor I, Maluenda G, Delhaye C, Wakabayashi K, Xue Z, Suddath WO, Kent KM, Satler LF, Pichard AD, Waksman R

Recent evidence has shown that clopidogrel and proton pump inhibitors (PPIs) are metabolized by the same pathway and that patients taking both drugs have greater levels of platelet reactivity and more adverse outcomes than patients taking only clopidogrel. We sought to examine the effect of a PPI at discharge from the hospital after percutaneous coronary intervention with drug-eluting stents on the incidence of major adverse cardiac events (MACE) at 1 year. We compared 502 patients who were not prescribed a PPI at discharge and 318 patients who were prescribed a PPI. All patients were taking clopidogrel. We followed patients for 1 year with regard to MACE, including death, Q-wave myocardial infarction, target vessel revascularization, and stent thrombosis. We performed multivariate Cox regression to adjust for confounding variables, including compliance with clopidogrel, to assess the effect of a PPI at discharge on the 1-year outcomes. The baseline characteristics of patients discharged with a PPI were similar to those of patients discharged without a PPI. Univariate survival analysis of the outcomes showed a greater rate of MACE (13.8% vs 8.0%, p = 0.008) and overall mortality (4.7% vs 1.8%, p = 0.02) in the PPI group. After multivariate analysis, the adjusted MACE hazard ratio for PPI at discharge was 1.8 (95% confidence interval 1.1 to 2.7, p = 0.01). In conclusion, in patients undergoing percutaneous coronary intervention with drug-eluting stents and receiving clopidogrel, the prescription of a PPI at discharge was associated with a greater rate of MACE at 1 year.

PMID: 20211327 [PubMed - as supplied by publisher]

Results of Intracoronary Stem Cell Therapy After Acute Myocardial Infarction.

Am J Cardiol. 2010 Mar 15;105(6):804-812

Authors: Wöhrle J, Merkle N, Mailänder V, Nusser T, Schauwecker P, von Scheidt F, Schwarz K, Bommer M, Wiesneth M, Schrezenmeier H, Hombach V

To assess the effect of autologous bone-marrow cell (BMC) therapy in patients with acute myocardial infarction in a rigorous double-blind, randomized, placebo-controlled trial. Patients with reperfusion >6 hours after symptom onset were randomly assigned in a 2:1 ratio to receive intracoronary BMC or placebo therapy 5 to 7 days after symptom onset. The patients were stratified according to age, acute myocardial infarction localization, and left ventricular (LV) function. Rigorous double-blinding was ensured using autologous erythrocytes for the placebo preparation that was visually indistinguishable from the active treatment. Serial cardiac magnetic resonance imaging studies were performed before study therapy and after 1, 3, and 6 months. The primary end point was the difference in the LV ejection fraction from baseline to 6 months. The secondary end points included changes in the LV end-diastolic and end-systolic volume indexes and infarct size. A total of 42 patients were enrolled (29 in the BMC group and 13 in the placebo group) in the integrated pilot phase. A mean of 381 x 10(6) mononuclear BMCs were administered. The baseline clinical and cardiac magnetic resonance imaging parameters did not differ. Compared to baseline, the difference in LV ejection fraction for the placebo group versus BMC group was 1.7 +/- 6.4% versus -0.9 +/- 5.5% at 1 month, 3.1 +/- 6.0% versus 1.9 +/- 4.3% at 3 months, and 5.7 +/- 8.4% versus 1.8 +/- 5.3% at 6 months (primary end point; not significant). No difference was found in the secondary end points between the 2 groups, including changes in infarct size or LV end-diastolic and end-systolic volume indexes. In conclusion, in this rigorous double-blind, randomized, placebo-controlled trial, we did not observe an evidence for a positive effect for intracoronary BMC versus placebo therapy with respect to LV ejection fraction, LV volume indexes, or infarct size.

PMID: 20211323 [PubMed - as supplied by publisher]

Usefulness of Soluble Fas Levels for Improving Diagnostic Accuracy and Prognosis for Acute Coronary Syndromes.

Am J Cardiol. 2010 Mar 15;105(6):797-803

Authors: Cardinal H, Brophy JM, Bogaty P, Joseph L, Hébert MJ, Boyer L, Madore F

Although both inflammation and apoptosis occur in acute coronary syndromes (ACSs), previous studies have not tested the diagnostic and prognostic utility of an approach that measures circulating markers of these pathways. The aim of the present study was to assess whether measuring soluble Fas (sFas) and high-sensitivity C-reactive protein (hs-CRP), as markers of apoptosis and inflammation, improve ACS diagnostic and prognostic accuracy. In a prospective cohort of consecutive subjects admitted to the hospital for suspicion of ACS, we measured sFas, hs-CRP, and troponin T in those who had a final noncardiac chest pain diagnosis (n = 100), those who had an ACS diagnosis and experienced (n = 218) or did not experience (n = 170) recurrent cardiac events during 1 year of follow-up. sFas was strongly and independently associated with a discharge diagnosis of an ACS versus noncardiac chest pain during the index hospitalization (odds ratio 16.16 for the second vs first tertile, 95% confidence interval [CI] 7.07 to 36.91; and odds ratio 25.40 for the third vs first tertile, 95% CI 9.38 to 68.75). However, hs-CRP was not. sFas significantly improved the diagnostic accuracy for ACSs (C statistic increased from 0.85 to 0.93, difference +0.08, 95% CI for the difference 0.05 to 0.11). The sFas levels were high and did not vary with time in the subjects having early versus late measurements (beta 0.00 ln pg/ml/hour, 95% CI -0.01 to 0.01). In contrast, troponin increased with time since the beginning of the symptoms (beta 0.07 ln mug/L/hour, 95% CI 0.04 to 0.10). Baseline sFas and hs-CRP did not predict recurrent cardiac events. In conclusion, our results suggest that in suspected ACS cases, sFas, but not hs-CRP, helps to improve the diagnostic accuracy and timeliness over and above standard diagnostic criteria.

PMID: 20211322 [PubMed - as supplied by publisher]

Tirofiban for myocardial infarction.

Expert Opin Pharmacother. 2010 Apr;11(5):861-6

Authors: Juwana YB, Suryapranata H, Ottervanger JP, van 't Hof AW

Importance of the field: Inhibition of platelet aggregation plays a key role in treatment of coronary artery disease. Areas covered in this review: Studies on the effects of tirofiban in patients with either ST elevation or non-ST elevation myocardial infarction are reviewed. What the reader will gain: Tirofiban is a small-molecule glycoprotein IIb/IIIa receptor inhibitor. If discontinued, the action of tirofiban is faster reversed as abciximab. The dose varied between low (bolus of 0.4 mug/kg administered over 30 min followed by an infusion of 0.10 mug/kg/min), intermediate (bolus of 10 mug/kg administered over 3 min followed by an infusion of 0.15 mug/kg/min) and high (bolus of 25 mug/kg administered over 3 min followed by an infusion of 0.15 mug/kg/min). The high-dose administration especially may be beneficial in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI). There is no indication for tirofiban in patients treated with thrombolysis. Patients with non-ST elevation myocardial infarction requiring PCI are most likely to benefit from tirofiban if they have ongoing ischemia and/or dynamic ECG changes. The risk of serious bleeding with tirofiban is low and there is a very low risk of thrombocytopenia. Take home message: Use of tirofiban for myocardial infarction is effective and has an acceptable safety profile.

PMID: 20210689 [PubMed - in process]

Treatment of Acinetobacter infections.

Expert Opin Pharmacother. 2010 Apr;11(5):779-88

Authors: Michalopoulos A, Falagas ME

Importance of the field: Acinetobacter baumannii has emerged as a major cause of healthcare-associated infections. It commonly presents resistance to multiple antimicrobial agents, occasionally including carbapenems and polymyxins, and hence, it is considered the paradigm of multidrug-resistant (MDR) or pandrug-resistant (PDR) bacterium. MDR A. baumannii is a rapidly emerging pathogen, especially in the intensive care setting, causing infections including bacteremia, pneumonia/ventilator-associated pneumonia (VAP), meningitis, urinary tract infection, central venous catheter-related infection, and wound infection. Areas covered in this review: All potential antimicrobial agents that are available for the treatment of Acinetobacter infections are presented. Emphasis was given to the management of nosocomial infections due to MDR A. baumannii and its close relatives, spp. 3 and 13TU. Areas covered include bloodstream infections, pneumonia or VAP, meningitis, urinary tract infection, skin and soft-tissue or wound infections due to Acinetobacter. What the reader will gain: The antibiotics that are usually effective against A. baumannii infections include carbapenems, polymyxins E and B, sulbactam, piperacillin/tazobactam, tigecycline and aminoglycosides. Carbapenems (imipenem, meropenem, doripenem) are the mainstay of treatment for A. baumannii, though carbapenem-resistant Acinetobacter strains have increasingly been reported worldwide in recent years. However, although well-designed trials of new therapeutic approaches are certainly required, the most important factor necessary to guide clinicians in their choice of empirical or targeted therapy should be knowledge of the susceptibility patterns of strains present in their own geographical area. Take home message: Pooled data suggest that infections caused by A. baumannii, especially those with inappropriate treatment, are associated with considerable attributable mortality. The optimal treatment for A. baumannii nosocomial infections has not been established, especially for MDR strains. Therefore, well-designed clinical studies are necessary to guide clinicians on decisions regarding the best therapeutic approach for patients with MDR A. baumannii infections. In addition, new experimental studies are warranted to evaluate the activity and safety of peptides and other novel antibacterial agents for A. baumannii infections.

PMID: 20210684 [PubMed - in process]

Meta-Analysis of Trials Evaluating Parenteral Antimicrobial Therapy for Skin and Soft Tissue Infections.

Clin Infect Dis. 2010 Mar 8;

Authors: McClaine RJ, Husted TL, Hebbeler-Clark RS, Solomkin JS

Background. Many trials have been carried out to determine the effectiveness of antimicrobial agents in treating skin and soft tissue infections. The results of these studies are often utilized to make determinations about the use of these antimicrobials against other types of infections. Despite the importance of these trials in determining clinical care, we hypothesized that many of these studies failed to include a variety of infections of significant enough severity to effectively draw objective conclusions about antimicrobial efficacy. Methods. We conducted a modified PubMed search to identify studies of antimicrobial agents in treating soft tissue infections that were published from 1998 through 2008. We then evaluated these trials for specific recommended study criteria, which were based on published US Food and Drug Administration guidelines for the conduct of trials of antimicrobials for soft tissue infection. Results. Seventeen studies were identified for inclusion in the trial. Upon review, only 30% of trials required both local and systemic signs of infection for inclusion in the trial. One trial stratified results on the basis of operative intervention, less than half reported patient comorbidities, and only 53% provided a specific definition for "cure." Conclusions. Our meta-analysis of current trials evaluating antimicrobial therapy for skin and soft tissue infections revealed substantial shortcomings in the design of most of these trials. These data provide evidence for the importance of designing specialist panels to objectively evaluate studies and photographs of included infections to ensure that conclusions drawn from these trials concerning clinical practice are justified.

PMID: 20210644 [PubMed - as supplied by publisher]

Rates of Hospital-Acquired Respiratory Illness in Bangladeshi Tertiary Care Hospitals: Results from a Low-Cost Pilot Surveillance Strategy.

Clin Infect Dis. 2010 Mar 8;

Authors: Gurley ES, Zaman RU, Sultana R, Bell M, Fry AM, Srinivasan A, Rahman M, Rahman MW, Hossain MJ, Luby SP

Background. Patients hospitalized in resource-poor health care settings are at increased risk for hospital-acquired respiratory infections due to inadequate infrastructure. Methods. From 1 April 2007 through 31 March 2008, we used a low-cost surveillance strategy to identify new onset of respiratory symptoms in patients hospitalized for >72 h and in health care workers in medicine and pediatric wards at 3 public tertiary care hospitals in Bangladesh. Results. During 46,273 patient-days of observation, we recorded 136 episodes of hospital-acquired respiratory disease, representing 1.7% of all patient hospital admissions; rates by ward ranged from 0.8 to 15.8 cases per 1000 patient-days at risk. We identified 22 clusters of respiratory disease, 3 of which included both patients and health care workers. Of 226 of heath care workers who worked on our surveillance wards, 61 (27%) experienced a respiratory illness during the study period. The cost of surveillance was US$43 per month per ward plus 30 min per day in data collection. Conclusions. Patients on these study wards frequently experienced hospital-acquired respiratory infections, including 1 in every 20 patients hospitalized for >72 h on 1 ward. The surveillance method was useful in calculating rates of hospital-acquired respiratory illness and could be used to enhance capacity to quickly detect outbreaks of respiratory disease in health care facilities where systems for outbreak detection are currently limited and to test interventions to reduce transmission of respiratory pathogens in resource-poor settings.

PMID: 20210642 [PubMed - as supplied by publisher]