Time and Concentration Dependent Effect of Antibiotics

b-lactam antibiotics and Vancomycin . . . . . .................. are antibiotics that exhibit time-dependent inhibition of microorganism.

Aminoglycosides, Fluoroquinolones, Daptomycin, Metronidazole, Azythromycin, Ketolides.................................................concenrtation dependent inhition

of microorganisms by these antibiotics.

Macrolides, Clindamycin, Streptogramins, Tetracyclines, and Linezolid . . . . .. . . . . ... . . .. ...............................The third group includes drugs that are predominantly bacteriostatic and produce moderate to prolonged Post antibiotic effects. Because of their prolonged Post antibiotic effects, their efficacy is determined less by time and more by AUC once concentrations exceed the MIC.

Drugs Approved by US-FDA in 2011: A Glance

Cardiology/Vascular Diseases

Brilinta (ticagrelor); AstraZeneca; For the reduction of thrombotic events in patients with acute coronary syndrome, Approved July 2011

Edarbi (azilsartan medoxomil); Takeda; For the treatment of hypertension, Approved February 2011

Edarbyclor (azilsartan medoxomil and chlorthalidone); Takeda Pharmaceutical; For the treatment of hypertension, Approved December of 2011

Xarelto (rivaroxaban); Janssen Pharmaceuticals; For the reduction in the risk of stroke and systemic embolism resulting from atrial fibrillation, Approved November 2011

Xarelto (rivaroxaban); Bayer; For the prophylaxis of deep vein thrombosis during knee or hip replacement surgery, Approved July 2011

Dermatology/Plastic Surgery

Firazyr (icatibant); Shire; For the treatment of acute attacks of hereditary angioedema, Approved August of 2011

Gralise (gabapentin); Abbott; For the treatment of postherpetic neuralgia, Approved February 2011

laViv (azficel-T); Fibrocell Science; For the improvement of nasolabial fold wrinkles in adults, Approved June 2011

Sylatron (peginterferon alfa-2b); Merck; For the treatment of melanoma, Approved April 2011

Yervoy (ipilimumab); Bristol-Myers Squibb; For the treatment of metastatic melanoma, Approved March 2011

Zelboraf (vemurafenib); Roche; For the treatment of BRAF + melanoma, Approved August of 2011

Endocrinology

Afinitor (everolimus); Novartis; For the treatment of advanced pancreatic neuroendocrine tumors, Approved May 2011

Juvisync (sitagliptin and simvastatin); Merck; For the treatment of type II diabetes, Approved October 2011

Sutent (sunitinib malate); Pfizer; For the treatment of pancreatic neuroendocrine tumors, Approved May 2011

Tradjenta (linagliptin); Boehringer Ingelheim; For the treatment of type II diabetes, Approved May 2011

Gastroenterology

Afinitor (everolimus); Novartis; For the treatment of advanced pancreatic neuroendocrine tumors, Approved May 2011

Dificid (fidaxomicin); Optimer Pharmaceuticals; For the treatment of Clostridium difficile-associated diarrhea, Approved May 2011

Duexis (ibuprofen and famotidine); Horizon Pharma; For the relief of rheumatoid arthritis and osteoarthritis and prevention of gastric ulcers, Approved April 2011

Incivek (telaprevir); Vertex; For the treatment of genotype 1 chronic hepatitis C, Approved May 2011

Rectiv (nitroglycerin) ointment 0.4%; ProStrakan; For the treatment of chronic anal fissure, Approved June 2011

Sutent (sunitinib malate); Pfizer; For the treatment of pancreatic neuroendocrine tumors, Approved May 2011

Victrelis (boceprevir); Merck; For the treatment of chronic hepatitis C genotype 1, Approved May 2011

Hematology

Adcretris (brentuximab vedotin); Seattle Genetics; For the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma, Approved August 2011

Erwinaze (asparaginase Erwinia chrysanthemi); Eusa Pharma; For the treatment of acute lymphoblastic leukemia, Approved November of 2011

Ferriprox (deferiprone); Apotex; For the treatment of transfusional iron overload due to thalassemia, Approved October 2011

Jakafi (ruxolitinib); Incyte; For the treatment of myelofibrosis, Approved November 2011

Soliris (eculizumab); Alexion; For the treatment of atypical hemolytic uremic syndrome, Approved September 2011

Xarelto (rivaroxaban); Bayer; For the prophylaxis of deep vein thrombosis during knee or hip replacement surgery, Approved July 2011

Immunology/Infectious Diseases

Arcapta (indacaterol maleate inhalation powder); Novartis; For the treatment of airflow obstruction resulting from chronic obstructive pulmonary disease, Approved July 2011

Benlysta (belimumab); Human Genome Sciences; For the treatment of systemic lupus erythematosus, Approved March 2011

Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate); Gilead; For the treatment of HIV-1 in treatment-naive adults, Approved August of 2011

Daliresp (roflumilast); Forest Pharmaceuticals; For the treatment of chronic obstructive pulmonary disease, Approved February 2011

Dificid (fidaxomicin); Optimer Pharmaceuticals; For the treatment of Clostridium difficile-associated diarrhea, Approved May 2011

Edurant (rilpivirine); Tibotec; For the treatment of HIV-1, Approved May 2011

Firazyr (icatibant); Shire; For the treatment of acute attacks of hereditary angioedema, Approved August of 2011

Gralise (gabapentin); Abbott; For the treatment of postherpetic neuralgia, Approved February 2011

Incivek (telaprevir); Vertex; For the treatment of genotype 1 chronic hepatitis C, Approved May 2011

Nulojix (belatacept); Bristol-Myers Squibb; For the prevention of organ rejection following kidney transplant, Approved June 2011

Victrelis (boceprevir); Merck; For the treatment of chronic hepatitis C genotype 1, Approved May 2011

Musculoskeletal

Actemra (tocilizumab); Genentech; For the treatment of systemic juvenile idiopathic arthritis, Approved April 2011

Duexis (ibuprofen and famotidine); Horizon Pharma; For the relief of rheumatoid arthritis and osteoarthritis and prevention of gastric ulcers, Approved April 2011

Nephrology/Urology

Anturol (oxybutynin) Gel; Antares Pharma; For the treatment of overactive bladder, Approved December 2011

Nulojix (belatacept); Bristol-Myers Squibb; For the prevention of organ rejection following kidney transplant, Approved June 2011

Soliris (eculizumab); Alexion; For the treatment of atypical hemolytic uremic syndrome, Approved September 2011

Neurology

Abstral (fentanyl sublingual tablets); ProStrakan; For the treatment of breakthrough cancer pain in opioid-tolerant patients, Approved January 2011

Exparel (bupivacaine liposome injectable suspension); Pacira Pharmaceuticals; For postsurgical analgesia, Approved November 2011

Gralise (gabapentin); Abbott; For the treatment of postherpetic neuralgia, Approved February 2011

Horizant (gabapentin enacarbil); GlaxoSmithKline; For the treatment of restless legs syndrome, Approved April 2011

Intermezzo (zolpidem tartrate sublingual tablet); Transcept Pharmaceuticals; For the treatment of insomnia, Approved November 2011

Lazanda (fentanyl citrate) nasal spray; Archimedes; For the management of breakthrough cancer pain, Approved June 2011

Onfi (clobazam); Lundbeck; For the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome, Approved October 2011

Oxecta (oxycodone HCl); Pfizer; For the management of acute and chronic moderate to severe pain, Approved June 2011

Potiga (ezogabine); Valeant Pharmaceuticals; For the treatment of partial-onset seizures, Approved June 2011

Viibryd (vilazodone hydrochloride); Clinical Data; For the treatment of major depressive disorder, Approved January 2011

Obstetrics/Gynecology

Makena (hydroxyprogesterone caproate injection); Hologic; For the prevention of risk of preterm birth, Approved February 2011

Oncology

Abstral (fentanyl sublingual tablets); ProStrakan; For the treatment of breakthrough cancer pain in opioid-tolerant patients, Approved January 2011

Adcretris (brentuximab vedotin); Seattle Genetics; For the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma, Approved August 2011

Afinitor (everolimus); Novartis; For the treatment of advanced pancreatic neuroendocrine tumors, Approved May 2011

Erwinaze (asparaginase Erwinia chrysanthemi); Eusa Pharma; For the treatment of acute lymphoblastic leukemia, Approved November of 2011

Lazanda (fentanyl citrate) nasal spray; Archimedes; For the management of breakthrough cancer pain, Approved June 2011

Sutent (sunitinib malate); Pfizer; For the treatment of pancreatic neuroendocrine tumors, Approved May 2011

Sylatron (peginterferon alfa-2b); Merck; For the treatment of melanoma, Approved April 2011

Vandetanib (vandetanib); Astra Zeneca; For the treatment of thyroid cancer, Approved April 2011

Xalkori (crizotinib); Pfizer; For the treatment of ALK+ non-small cell lung cancer, Approved August of 2011

Yervoy (ipilimumab); Bristol-Myers Squibb; For the treatment of metastatic melanoma, Approved March 2011

Zelboraf (vemurafenib); Roche; For the treatment of BRAF + melanoma, Approved August of 2011

Zytiga (abiraterone acetate); Centocor Ortho Biotech; For the treatment of prostate cancer, Approved May 2011

Ophthalmology

Eylea (aflibercept); Regeneron Pharmaceuticals; For the treatment of neovascular (wet) age-related macular degeneration, Approved November 2011

Otolaryngology

Vandetanib (vandetanib); Astra Zeneca; For the treatment of thyroid cancer, Approved April 2011

Pediatrics/Neonatology

Actemra (tocilizumab); Genentech; For the treatment of systemic juvenile idiopathic arthritis, Approved April 2011

Daliresp (roflumilast); Forest Pharmaceuticals; For the treatment of chronic obstructive pulmonary disease, Approved February 2011

Onfi (clobazam); Lundbeck; For the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome, Approved October 2011

Pharmacology/Toxicology

Oxecta (oxycodone HCl); Pfizer; For the management of acute and chronic moderate to severe pain, Approved June 2011

Psychiatry/Psychology

Intermezzo (zolpidem tartrate sublingual tablet); Transcept Pharmaceuticals; For the treatment of insomnia, Approved November 2011

Viibryd (vilazodone hydrochloride); Clinical Data; For the treatment of major depressive disorder, Approved January 2011

Pulmonary/Respiratory Diseases

Arcapta (indacaterol maleate inhalation powder); Novartis; For the treatment of airflow obstruction resulting from chronic obstructive pulmonary disease, Approved July 2011

Daliresp (roflumilast); Forest Pharmaceuticals; For the treatment of chronic obstructive pulmonary disease, Approved February 2011

Xalkori (crizotinib); Pfizer; For the treatment of ALK+ non-small cell lung cancer, Approved August of 2011

Rheumatology

Actemra (tocilizumab); Genentech; For the treatment of systemic juvenile idiopathic arthritis, Approved April 2011

Duexis (ibuprofen and famotidine); Horizon Pharma; For the relief of rheumatoid arthritis and osteoarthritis and prevention of gastric ulcers, Approved April 2011

Trauma/Emergency Medicine

Exparel (bupivacaine liposome injectable suspension); Pacira Pharmaceuticals; For postsurgical analgesia, Approved November 2011

Xanthelasmata Identified as Independent CV Risk Factor

A large new study from Denmark finds that xanthelasmata (raised yellow patches around the eyelids) but not arcus cornae (white or grey rings around the cornea) is an independent risk factor for cardiovascular disease.

In a paper in BMJ, Mette Christoffersen and colleagues report on 12,745 adults in Copenhagen without cardiovascular disease at baseline who were followed for a mean of 22 years. At baseline 4.4% had xanthelasmata and 24.8% had arcus corneae. Here are the main results, comparing the group without xanthelasmata to the group with xanthelasmata:

MI: 65 events versus 121 events per 10,000 person years (multifactorial adjusted HR for xanthelasmata: 1.48, CI 1.23-1.79).

Ischemic heart disease: 134 versus 226 events per 10,000 person years (multifactorial adjusted HR for xanthelasmata: 1.39, CI 1.20-1.60)

Ischemic stroke: 53 versus 64 events per 10,000 person years (multifactorial adjusted HR for xanthelasmata: 0.94, CI 0.73-1.21)

Ischemic cerebrovascular disease: 65 versus 74 events per 10,000 person years (multifactorial adjusted HR for xanthelasmata: 0.91, CI 0.72-1.15)

Total deaths: 293 versus 414 events per 10,000 person years (multifactorial adjusted HR for xanthelasmata: 1.14, CI 1.04-1.26)

The authors write that their results “suggest that xanthelasmata are a cutaneous marker of atherosclerosis independent of lipid concentrations and thus should be considered in clinical practice as an independent and additional risk factor for myocardial infarction and ischaemic heart disease.” They say the findings may be especially useful in places with limited access to laboratories.

In an accompanying editorial, Antonio Fernandez and Paul Thompson write that people with xanthelasmata “may have an enhanced biological propensity to deposition of cholesterol in vascular and soft tissue, which is not fully represented by their fasting lipid profiles. Because xanthelasmata are composed of foam cells similar to those present in atherosclerotic plaque, they may be a better marker than arcus corneae of the intra-arterial atherosclerotic process.” Therefore, they conclude, these patients “may therefore require more aggressive management of risk factors.”

Here is the press release from the BMJ:

Yellow patches around eyelids predict risk of heart problems

Research: Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study

Editorial: Eye markers of cardiovascular disease

Raised yellow patches of skin (xanthelasmata) around the upper or lower eyelids are markers of an individual’s increased risk of having a heart attack or suffering from heart disease, finds research published on bmj.com today.

The study, led by Professor Anne Tybjærg-Hansen at the University of Copenhagen, also concludes that white or grey rings around the cornea (arcus corneae) are not linked to an increased risk.

Previous research has established that both xanthelasmata and arcus corneae are deposits of cholesterol. However, around half of the individuals who have either or both condition will not test positively for high cholesterol in a blood test.

The researchers wanted to investigate links between xanthelasmata and/or arcus corneae and an increased risk of heart attack, heart disease, stroke, severe thickening of the arteries or premature death in the general population, as the evidence in this area is lacking.

Indeed, many patients are referred to dermatologists so that xanthelasmata can be removed.

The US Food and Drug Administration (FDA) approved a once-daily bronchodilator — indacaterol maleate (Arcapta Neohaler, Novartis Pharmaceuticals) — for chronic obstructive pulmonary disease (COPD). This bronchodilator may offer better patient adherence than twice-a-day bronchodilators on the market.

Indacaterol maleate is a new molecular entity in the ß2-adrenergic agonist class that helps relax muscles around lung airways to prevent COPD symptoms, such as wheezing and breathlessness. The FDA stated that the long-acting drug is not intended to treat asthma or COPD symptoms that come on fast and strong.

Common adverse effects (> 2% and more common than placebo) are runny nose, cough, sore throat, headache, and nausea.

Indacaterol maleate will carry a boxed warning that, like other long-acting ß2-adrenergic agonists (LABAs), may increase the risk for asthma-related death.

Without use of a long-term asthma control medication, indacaterol maleate and all LABAs are contraindicated in patients with asthma. Indacaterol maleate should not be started in patients with acutely deteriorating COPD, nor should it be used to relieve acute symptoms, which should be managed with concomitant short-acting ß2-agonists.

An FDA advisory panel in March recommended approval of indacaterol maleate after 6 confirmatory clinical trials demonstrated the drug's safety and efficacy. The trials included nearly 5500 patients 40 years and older with COPD who had smoked at least 1 pack of cigarettes for 10 years and exhibited moderate to severe decreases in lung function.

During the advisory panel meeting, John Walsh, the president of the nonprofit COPD Foundation, said that getting patients to faithfully take twice-daily LABAs is a challenge.

"The advantage of a once-daily LABA to increase compliance and impact adherence cannot be overstated," Walsh said.

Administration and Precautions

Indacaterol maleate is supplied as 75-µg inhalation powder hard capsules that should always be used with the Neohaler inhaler only, 75 µg inhaled once daily every day. The capsules are for oral inhalation only and are not to be swallowed. The recommended dose should not be exceeded because excessive use of indacaterol maleate, or use in conjunction with other LABA-containing medications, may cause clinically significant cardiovascular effects and may even be fatal.

Should life-threatening paradoxic bronchospasm occur, use of indacaterol maleate should immediately be discontinued. The inhaler should be used with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or sensitivity to sympathomimetic drugs.

Indacaterol maleate should be used with caution with other adrenergic drugs, as these may potentiate its effects. It should be used with caution with xanthine derivatives, steroids, diuretics, or non–potassium-sparing diuretics, as these medications may potentiate hypokalemia or electrocardiographic changes. Extreme caution is warranted when indacaterol maleate is used with monoamine oxidase inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval, as these may potentiate cardiovascular effects. Because ß-blockers may reduce the efficacy of indacaterol maleate, these should be used with caution and only when medically necessary.

Indacaterol maleate is pregnancy Category C, and it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because ß-agonists may interfere with uterine contractility, indacaterol maleate should be used during labor only in those patients in whom the benefits clearly outweigh the risks. Caution is warranted when indacaterol maleate is administered to breast-feeding women.

The safety and efficacy of indacaterol maleate in pediatric patients have not been determined; therefore, the drug is not indicated for use in children. No adjustment of dosage is warranted in geriatric patients, based on available data, nor in patients with mild and moderate hepatic impairment. Studies were not performed in patients with severe hepatic impairment nor in those with renal impairment, but the urinary pathway contributes very little to total body elimination.

More information on the FDA's approval of indacaterol maleate is available on the agency's Web site.

Laurie Barclay, MD, contributed to the synopsis.

Clinical Implications

The FDA approved indacaterol maleate as a once-daily bronchodilator to prevent COPD symptoms, such as wheezing and breathlessness. Dosage is 75 µg inhaled once daily every day, which should increase compliance relative to twice-daily inhalers. It is not intended for acute relief of COPD exacerbations.

Common adverse effects seen with use of indacaterol maleate are runny nose, cough, sore throat, headache, and nausea. It will carry a boxed warning that the risk for asthma-related death may be increased. There are several significant drug interactions.

Indacaterol maleate is pregnancy Category C. It should be used during labor only in those patients in whom the benefits clearly outweigh the risks, and caution is warranted when indacaterol maleate is administered to breast-feeding women. Indacaterol maleate is not indicated for use in children. No adjustment of dosage is warranted in geriatric patients nor in patients with mild and moderate hepatic impairment.

courtesy: NIH US-FDA