Safety of Fluoroquinolone Use in Patients with Hepatotoxicity Induced by Anti-Tuberculosis Regimens.

Clin Infect Dis. 2009 Apr 27;

Authors: Ho CC, Chen YC, Hu FC, Yu CJ, Yang PC, Luh KT

Background. Fluoroquinolones are frequently used to replace agents in first-line anti-tuberculosis (anti-TB) regimens in patients with TB who have drug-induced hepatic dysfunction. We investigated the safety of using fluoroquinolone in an area where TB is endemic and where there is a high incidence of drug-induced liver injury. Methods. From September 2003 through August 2006, patients who had aspartate aminotransferase and/or alanine aminotransferase levels >3 times the upper limit of normal in the presence of hepatitis symptoms or who had aspartate aminotransferase and/or alanine aminotransferase levels >5 times the upper limit of normal after receipt of anti-TB treatment were enrolled. The control group received ethambutol, with or without streptomycin; study groups received either (1) ethambutol plus levofloxacin, with or without streptomycin; or (2) ethambutol plus moxifloxacin, with or without streptomycin. The outcome measurement was the time from onset of hepatitis to normalization of liver functions. Results. One hundred thirty-four (11.3%) of 1191 patients received a diagnosis of hepatotoxicity and needed to stop anti-TB treatment. The risk factor was abnormal baseline transaminase levels. Twenty-two of the 134 patients received the control medication, 40 received levofloxacin, and 45 received moxifloxacin; the remaining patients were excluded from the study. There were no significant prestudy differences between groups. Time to liver function normalization was almost the same for all groups (mean +/- standard deviation, [Formula: see text], [Formula: see text], and [Formula: see text] days, respectively). Conclusions. Abnormal baseline transaminase levels are the independent risk factors for anti-TB therapy-induced hepatitis. Levofloxacin and moxifloxacin caused no additional hepatotoxicity when they were used by patients with hepatitis induced by first-line anti-TB drugs.

PMID: 19400686 [PubMed - as supplied by publisher]

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Rationale for Revised Penicillin Susceptibility Breakpoints versus Streptococcus pneumoniae: Coping with Antimicrobial Susceptibility in an Era of Resistance.

Clin Infect Dis. 2009 Apr 28;

Authors: Weinstein MP, Klugman KP, Jones RN

In January 2008, the Clinical and Laboratory Standards Institute published revised susceptibility breakpoints for penicillin and Streptococcus pneumoniae, and shortly thereafter, the United States Food and Drug Administration similarly revised its breakpoints via changes in the package insert for penicillin. The revised susceptibility breakpoint is 2 mug/mL for nonmeningeal infections treated with parenteral penicillin at a dosage of 12 million units-24 million units per day. The susceptibility breakpoint of 0.06 mug/mL remains unchanged for pneumococcal meningitis treated with parenteral penicillin at a dosage of 18 million units per day. Herein, we review the scientific basis for the revisions to the breakpoints, which were supported by microbiologic, pharmacokinetic and/or pharmacodynamic, and clinical data. Clinicians, once again, should feel comfortable prescribing penicillin for pneumococcal pneumonia and other pneumococcal infections outside the central nervous system.

PMID: 19400744 [PubMed - as supplied by publisher]

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Romiplostim Management of Immune Thrombocytopenic Purpura (May).

Ann Pharmacother. 2009 Apr 28;

Authors: Ipema HJ, Jung MY, Lodolce AE

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of romiplostim, the first drug approved for use in patients with immune thrombocytopenic purpura (ITP). DATA SOURCES: Articles were identified through searches of MEDLINE (1966- January 2009) and International Pharmaceutical Abstracts (1970-January 2009) using the key words romiplostim and AMG 531. Searches were limited to articles published in English. The manufacturer was contacted for additional data. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and pharmacokinetic data were selected for review. DATA SYNTHESIS: Romiplostim is a second-generation thrombopoietic receptor agonist that exerts its therapeutic effect by stimulating megakaryopoiesis. Subcutaneous therapy results in a dose-dependent increase in platelets; however, interindividual variability exists. Time to peak concentration is approximately 14 hours, and the elimination half-life is approximately 3.5 days (range 1-34). Romiplostim undergoes endothelial recirculation and is eliminated by the reticuloendothelial system. The results of 2 Phase 3, randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of romiplostim for increasing platelet counts in patients with ITP refractory to other therapies, including splenectomy. Effects on platelets were transient and decreased within 2 weeks of discontinuing the drug. Interim results of an open-label extension study revealed that romiplostim has sustained efficacy and tolerability for up to 156 weeks at a dosage range of 1-17 microg/kg/wk (mean 5.9 +/- 3.9). The most common adverse effects include headache, fatigue, epistaxis, and contusion. Romiplostim is also under investigation for treatment of thrombocytopenia associated with myelodysplastic syndrome. The drug must be ordered directly from the manufacturer through a limited access program, and weekly subcutaneous injections are given in the clinic setting. CONCLUSIONS: Romiplostim is effective for the management of ITP in adults refractory to other therapies, including splenectomy.

PMID: 19401474 [PubMed - as supplied by publisher]

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WHO raises level of alert on flu pandemic.

BMJ. 2009;338:b1777

Authors: O’Dowd A

PMID: 19401319 [PubMed - in process]

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Newer aspects of the pathophysiology of sickle cell disease vaso-occlusion.

Hemoglobin. 2009;33(1):1-16

Authors: Conran N, Franco-Penteado CF, Costa FF

Sickle cell disease is an inherited disorder of hemoglobin (Hb) synthesis, caused by a single nucleotide substitution (GTG>GAG) at the sixth codon of the beta-globin gene, leading to the production of a defective form of Hb, Hb S. When deoxygenated, Hb S polymerizes, damaging the sickle erythrocyte and it is this polymerization that is the primary indispensable event in the molecular pathogenesis of sickle cell disease. Hb S polymerization results in a series of cellular alterations in red cell morphology and function that shorten the red cell life span and leads to vascular occlusion. Sickle cell disease vaso-occlusion is now known to constitute a complex multifactorial process characterized by recurrent vaso-occlusion, ischemia-reperfusion injury, and oxidative stress with consequent vascular endothelial cell activation that induces a chronic inflammatory state in sickle cell disease individual and is propagated by elevated levels of circulating inflammatory cytokines. Activation of the endothelium results in the induction of endothelial adhesion molecule expression that mediates red and white cell adhesion to the vessel wall and the formation of heterocellular aggregates, followed by secondary red cell trapping, all of which contribute to reduced blood flow and eventually obstruction of the micro-circulation. Reduced nitric oxide bioavailability, caused principally by its consumption by cell-free Hb, liberated during intravascular hemolysis, contributes to this process by facilitating vasoconstriction and adhesion molecule activity.

PMID: 19205968 [PubMed - indexed for MEDLINE]

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Pathogenesis of venous thromboembolism: when the cup runneth over.

Semin Thromb Hemost. 2008 Nov;34(8):747-61

Authors: Lippi G, Franchini M

A comprehensive understanding of the pathogenesis of venous thrombosis is essential for identifying patients at increased risk and who may therefore benefit from more aggressive preventive and therapeutic measures. As for other pathologies, the pathogenesis of venous thromboembolism is multifactorial. All risk factors, either congenital or acquired, are relatively “innocent” when considered alone. However, when an individual is unlucky enough to inherit one or more abnormality, compounded in many cases by environmental hazards, that person may be propelled over a threshold that precipitates the development of thrombosis. An appropriate analogy is that where “the last drop makes the cup run over.” A reinterpretation of the traditional Virchow’s triad (abnormal vessel wall, abnormal blood flow, and abnormal blood constituents) was provided by Eberhard Mammen throughout his research, and this has contributed greatly to the understanding of the pathogenesis of this serious disorder. Mammen postulated immobility as the leading event, because it reduced blood flow as a result of decreased muscle contraction. The subsequent “stasis of flow” led to accumulation of blood within the intramuscular sinuses, especially of the calf, triggering hypercoagulability due to local accumulation of activated clotting factors and coagulation activation products and the simultaneous consumption of blood coagulation inhibitors. On Mammen’s “hit list” nearly 20 years ago were included (among inherited abnormalities) decreased protein C, protein S, antithrombin III, plasminogen, and tissue plasminogen activator, and increased plasminogen activator inhibitor-1, whereas (among acquired predisposing conditions) surgery, trauma, previous thromboembolism, prolonged immobility and paralysis, malignancy, congestive heart failure, obesity, advanced age, pregnancy and puerperium, varicose veins, and oral contraceptives were also identified. Some two decades later, the situation has perhaps not changed so much, although studies continue to expand our knowledge of this topic, clarifying the relative contribution of each single risk factor in the pathogenesis of venous thrombosis.

PMID: 19214913 [PubMed - indexed for MEDLINE]

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Incidence and Prognostic Significance of Thrombocytopenia Developed During Acute Coronary Syndrome in Contemporary Clinical Practice.

Circulation. 2009 Apr 27;

Authors: Wang TY, Ou FS, Roe MT, Harrington RA, Ohman EM, Gibler WB, Peterson ED

BACKGROUND: -Prior studies examining thrombocytopenia among patients with acute coronary syndromes (ACS) evaluated highly selected patients in a clinical trial setting using varying definitions of thrombocytopenia. The incidence, severity, and prognostic significance of acquired thrombocytopenia during ACS in community practice have not been well defined. Methods and Results-We examined 36 182 patients with non-ST-segment elevation ACS enrolled at 379 US hospitals participating in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) quality improvement initiative between June 2004 and December 2006. Patients with baseline platelet counts <150×10(9)/L were excluded. Overall, 4697 patients (13%) developed new thrombocytopenia, defined as nadir platelet count <150×10(9)/L (referenced lower limit of normal), during their ACS hospitalization. Risks of in-hospital mortality and bleeding correlated directly with severity of thrombocytopenia; even mild thrombocytopenia (nadir 100 to 149×10(9)/L) was associated with increased risks of mortality (adjusted odds ratio [OR], 2.01; 95% CI, 1.69 to 2.38) and bleeding (adjusted OR, 3.76; 95% CI, 3.43 to 4.12). Each 10% drop in platelet count was associated with increased mortality and bleeding risks (adjusted ORs, 1.39 [95% CI, 1.33 to 1.46] and 1.89 [95% CI, 1.83 to 1.95], respectively). A >/=50% drop in platelet count was associated with higher risk of adverse outcomes regardless of the nadir count. A novel combined definition of acquired thrombocytopenia-nadir <150×10(9)/L or platelet count drop >/=50%-identifies a population of ACS patients at higher risk of mortality and major bleeding (adjusted ORs, 2.58 [95% CI, 2.23 to 2.98] and 4.32 [95% CI, 3.97 to 4.70], respectively). Conclusions-Thrombocytopenia, a common complication of ACS, is associated with increased mortality and bleeding risks. Even mild thrombocytopenia or a platelet count drop >/=50% in the setting of normal nadir values is clinically significant. Application of a combined definition for thrombocytopenia using both absolute and relative thresholds permits increased sensitivity for patients at high risk of adverse outcomes.

PMID: 19398666 [PubMed - as supplied by publisher]

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Effect of an electronic medication reconciliation application and process redesign on potential adverse drug events: a cluster-randomized trial.

Arch Intern Med. 2009 Apr 27;169(8):771-80

Authors: Schnipper JL, Hamann C, Ndumele CD, Liang CL, Carty MG, Karson AS, Bhan I, Coley CM, Poon E, Turchin A, Labonville SA, Diedrichsen EK, Lipsitz S, Broverman CA, McCarthy P, Gandhi TK

BACKGROUND: Medication reconciliation at transitions in care is a national patient safety goal, but its effects on important patient outcomes require further evaluation. We sought to measure the impact of an information technology-based medication reconciliation intervention on medication discrepancies with potential for harm (potential adverse drug events [PADEs]). METHODS: We performed a controlled trial, randomized by medical team, on general medical inpatient units at 2 academic hospitals from May to June 2006. We enrolled 322 patients admitted to 14 medical teams, for whom a medication history could be obtained before discharge. The intervention was a computerized medication reconciliation tool and process redesign involving physicians, nurses, and pharmacists. The main outcome was unintentional discrepancies between preadmission medications and admission or discharge medications that had potential for harm (PADEs). RESULTS: Among 160 control patients, there were 230 PADEs (1.44 per patient), while among 162 intervention patients there were 170 PADEs (1.05 per patient) (adjusted relative risk [ARR], 0.72; 95% confidence interval [CI], 0.52-0.99). A significant benefit was found at hospital 1 (ARR, 0.60; 95% CI, 0.38-0.97) but not at hospital 2 (ARR, 0.87; 95% CI, 0.57-1.32) (P = .32 for test of effect modification). Hospitals differed in the extent of integration of the medication reconciliation tool into computerized provider order entry applications at discharge. CONCLUSIONS: A computerized medication reconciliation tool and process redesign were associated with a decrease in unintentional medication discrepancies with potential for patient harm. Software integration issues are likely important for successful implementation of computerized medication reconciliation tools.

PMID: 19398689 [PubMed - in process]

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UN warns that swine flu outbreak could turn into pandemic.

BMJ. 2009;338:b1751

Authors: Charatan F

PMID: 19398472 [PubMed - in process]

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Avian influenza virus.

Comp Immunol Microbiol Infect Dis. 2009 Jul;32(4):301-10

Authors: Lee CW, Saif YM

Avian influenza viruses do not typically replicate efficiently in humans, indicating direct transmission of avian influenza virus to humans is unlikely. However, since 1997, several cases of human infections with different subtypes (H5N1, H7N7, and H9N2) of avian influenza viruses have been identified and raised the pandemic potential of avian influenza virus in humans. Although circumstantial evidence of human to human transmission exists, the novel avian-origin influenza viruses isolated from humans lack the ability to transmit efficiently from person-to-person. However, the on-going human infection with avian-origin H5N1 viruses increases the likelihood of the generation of human-adapted avian influenza virus with pandemic potential. Thus, a better understanding of the biological and genetic basis of host restriction of influenza viruses is a critical factor in determining whether the introduction of a novel influenza virus into the human population will result in a pandemic. In this article, we review current knowledge of type A influenza virus in which all avian influenza viruses are categorized.

PMID: 18457876 [PubMed - indexed for MEDLINE]

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Highly pathogenic H5N1 avian influenza virus: cause of the next pandemic?

Comp Immunol Microbiol Infect Dis. 2009 Jul;32(4):287-300

Authors: Pappaioanou M

Since 1997, when human infections with a highly pathogenic (HP) avian influenza A virus (AIV) subtype H5N1 – previously infecting only birds – were identified in a Hong Kong outbreak, global attention has focused on the potential for this virus to cause the next pandemic. From December 2003, an unprecedented H5N1 epizootic in poultry and migrating wild birds has spread across Asia and into Europe, the Middle East, and Africa. Humans in close contact with sick poultry and on rare occasion with other infected humans, have become infected. As of early March 2007, 12 countries have reported 167 deaths among 277 laboratory-confirmed human infections to WHO. WHO has declared the world to be in Phase 3 of a Pandemic Alert Period. This paper reviews the evolution of HP AIV H5N1, molecular changes that enable AIVs to infect and replicate in human cells and spread efficiently from person-to-person, and strategies to prevent the emergence of a pandemic virus.

PMID: 19318178 [PubMed - indexed for MEDLINE]

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Ceftobiprole: first cephalosporin with activity against methicillin-resistant Staphylococcus aureus.

Pharmacotherapy. 2009 May;29(5):511-25

Authors: Vidaillac C, Rybak MJ

Ceftobiprole medocaril is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received an approvable letter from the United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftobiprole exerts its antibacterial activity by inhibiting the penicillin-binding proteins (PBPs) involved in cell wall synthesis. It has an established stability against hydrolysis by many gram-positive beta-lactamases and a higher affinity for various PBPs (such as PBP2a of MRSA or PBP2x of Streptococcus pneumoniae), which leads to a wider spectrum of activity compared with older beta-lactams. Ceftobiprole activity does not cover extended-spectrum beta-lactamase-producing Enterobacteriaceae and some other pathogens, including Enterococcus faecium or Acinetobacter baumanii. Generally well tolerated, with nausea and taste disturbance being the most common adverse events, ceftobiprole appeared noninferior to empiric therapy in several clinical trials. Ceftobiprole is available only for intravenous administration; recommended dosage regimens have not been approved by the FDA as of this writing. However, based on the Canadian package insert, expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of complicated skin and skin structure infections caused by certain gram-positive pathogens, and 500 mg as a 2-hour infusion every 8 hours when susceptible gram-negative or both gram-positive and susceptible gram-negative pathogens are involved. Dosage adjustments are indicated for patients with moderate or severe renal impairment, and dosage recommendations are expected to be 500 or 250 mg, respectively, as a 2-hour infusion every 12 hours. Several precautions regarding hypersensitivity and drug incompatibility are reported. Ceftobiprole represents a promising option for the treatment of mono- and polymicrobial infections caused by multidrug-resistant gram-positive and susceptible gram-negative pathogens, but further toxicity and safety studies are warranted.

PMID: 19397461 [PubMed - in process]

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Predictive factors in the quality of life of cancer inpatients.

J Psychosoc Oncol. 2008;26(4):75-90

Authors: Bruscia K, Shultis C, Dennery K, Dileo C

The purpose of the study was to determine whether sense of coherence (SOC), and demographic variables (age, gender, race, education, length of illness) predict quality of life (QOL) in cancer inpatients. SOC is the extent to which one finds life comprehensible, manageable, and meaningful. Participants were 49 inpatients (66% female) with various forms of cancer, mostly African American (71%), with a mean age of 54.5 years. The mean QOLS of cancer inpatients (84.6) was lower than a healthy population (90.0), however, their mean item scores indicated that they are mostly satisfied with most areas of QOL except for active forms of past-time and health. The mean SOC score (133.8) was also lower than other groups; however without appropriate norms, it cannot be concluded that cancer inpatients have a weak SOC. Multiple regressions showed that SOC was a significant predictor of QOL, and that the demographic variables were not predictive of QOL, except when combined with SOC. All findings may be limited by demographics of the sample (race, gender, age, severity of illness), and the inability of cross-sectional investigations to determine causality.

PMID: 19042273 [PubMed - indexed for MEDLINE]

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Investigation of the clinical efficacy and dosage of intravenous ciprofloxacin in patients with respiratory infection.

J Pharm Pharm Sci. 2008;11(2):111s-117s

Authors: Matsuo K, Azuma M, Kasai M, Hanji I, Kimura I, Kosugi T, Suga N, Satoh M

PURPOSE: Infection control is particularly vital in hospitals, and proper use of antimicrobial drugs is one of the most important roles of hospital pharmacists. In this study, we surveyed patients who had been prescribed single-use ciprofloxacin (CPFX), and evaluated the blood concentration of CPFX from the predictive AUC (area under the concentration curve). METHODS: This study was performed retrospectively to 112 adult patients diagnosed as having respiratory infections who had been treated as inpatients with intravenous CPFX for more than 3 days at Toho University Omori Hospital in Tokyo. The predictive AUC of each patient was obtained from the modified formulae reported by Forrest et al. (1993) [1]. The relation between the antimicrobial activity of CPFX and pharmacokinetic/pharmacodynamic (Cmax, AUC and AUC/MIC (minimum inhibitory concentration)) was studied. RESULTS: Although CPFX is excreted from the kidney, standard treatment with this drug does not take renal function into consideration. Our results indicated that CPFX was effective in less than 50% of the patients who received it. Moreover, the AUC/MIC ratio in both the effective group and the failure group was less than 125 when the clinical target was gram-negative bacteria. CONCLUSION: These results suggest that the clinical use of CPFX for the treatment of infectious diseases does not reach the target AUC/MIC ratio, and that the concentration of CPFX is not within the range to which many pathogens are susceptible in a large proportion of patients. To ensure the effective treatment of patients with infectious diseases and to prevent the development of resistance in bacteria, we recommend therapeutic drug monitoring (TDM) of CPFX in hospitals.

PMID: 19203473 [PubMed - indexed for MEDLINE]

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Is the Ordering of Imaging for Suspected Venous Thromboembolism Consistent With D-dimer Result?

Ann Emerg Med. 2009 Apr 23;

Authors: Teismann NA, Cheung PT, Frazee B

STUDY OBJECTIVE: We assessed whether the ordering of imaging studies in patients with suspected venous thromboembolism was consistent with the results of D-dimer testing. METHODS: We performed a retrospective chart review of consecutive cases in which a D-dimer assay was performed at an urban academic emergency department during a 13-month period. Measurements included D-dimer result and results of imaging for venous thromboembolism. The primary outcome measure was the percentage of patients in each D-dimer category (positive or negative result with a cutoff value of 500 ng fibrinogen equivalent units/dL) who underwent subsequent imaging within 48 hours. We also report the results of the imaging studies obtained. RESULTS: A total of 553 D-dimer tests were ordered, with 266 (48.1%) negative and 287 (51.9%) positive results. Of patients with a negative D-dimer result, 37 (14%; 95% confidence interval [CI] 10% to 19%) underwent at least 1 imaging study. Of patients with a positive D-dimer result, 137 (48%; 95% CI 42% to 54%) did not undergo imaging. CONCLUSION: Evaluation for venous thromboembolism occasionally proceeded despite a negative D-dimer result, whereas frequently no further evaluation occurred despite a positive result. These findings suggest that actual clinical practice differs from what is recommended by published algorithms that guide evaluation of patients with suspected venous thromboembolism.

PMID: 19394112 [PubMed - as supplied by publisher]

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