Keith A. Hecht, PharmD, BCOP

• Associate Professor, Department of Pharmacy Practice, School of Pharmacy, Southern Illinois University Edwardsville
• Clinical Pharmacy Specialist, Hematology/Oncology, Mercy Hospital St. Louis, St. Louis, Missouri

https://www.siue.edu/pharmacy/departments-faculty-staff/bio-hecht-keith.shtml

Antimycobacterial Drugs throughout the body dog arthritis medication jack hanna discount 200mg celebrex overnight delivery, with high concentrations in the skin treating arthritis of the back order celebrex visa. Patients typically develop a pink to brownish-black discoloration of the skin and should be informed of this in advance arthritis gout definition purchase 100mg celebrex amex. Thus arthritis leg pain cheap celebrex on line, erythema nodosum leprosum may not develop in patients treated with this drug rheumatoid arthritis epidemiology discount 100 mg celebrex mastercard. Other medications arthritis in the knee swelling buy cheap celebrex on-line, such as the protease inhibitors, may affect the concentration of rifabutin, requiring a dose adjustment. Rifampin is a potent inducer of cytochrome P450­dependent drug-metabolizing enzymes. The duration of action of methadone is dependent upon hepatic clearance, so enhanced drug metabolism will shorten the duration and increase the risk of withdrawal symptoms in individuals on methadone maintenance. He states he feels fine, but now is having difficulty reading his morning newspaper and feels he may need to get glasses. Clofazimine is a phenazine dye and will cause bronzing (the skin pigment color will change color, from pink to brownish-black), especially in fair-skinned patients. This occurs in a majority of patients, and generally is not considered harmful but may take several months to years to fade after discontinuing the medication. Optic neuritis, exhibited as a decrease in visual acuity or loss of color discrimination, is the most important side effect associated with ethambutol. Visual disturbances generally are dose related and more common in patients with reduced renal function. Mycotic infections may be superficial and involve only the skin (cutaneous mycoses extending into the epidermis), while others may penetrate the skin, causing subcutaneous or systemic infections. The characteristics of fungi are so unique and diverse that they are classified in their own kingdom. Unlike bacteria, fungi are eukaryotic, with rigid cell walls composed largely of chitin rather than peptidoglycan (a characteristic component of most bacterial cell walls). These structural characteristics are useful in targeting chemotherapeutic agents against fungal infections. Fungal infections are generally resistant to antibiotics, and, conversely, bacteria are resistant to antifungal agents. The incidence of fungal infections such as candidemia has been on the rise for the last few decades. During this same period, new therapeutic options have become available for the treatment of fungal infections. In spite of its toxic potential, amphotericin B remains the drug of choice for the treatment of several life-threatening mycoses. Mechanism of action: Amphotericin B binds to ergosterol in the plasma membranes of sensitive fungal cells. Pneumocystis jirovecii Blastomycosis Coccidioidomycosis Histoplasmosis Sporotrichosis Aspergillus spp. The pores disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death. Antifungal spectrum: Amphotericin B is either fungicidal or fungistatic, depending on the organism and the concentration of the drug. Drugs for Subcutaneous and Systemic Mycotic Infections Coccidioides immitis, Blastomyces dermatitidis, and many strains of Aspergillus. Resistance: Fungal resistance, although infrequent, is associated with decreased ergosterol content of the fungal membrane. Amphotericin B is insoluble in water and must be coformulated with either sodium deoxycholate (conventional) or a variety of artificial lipids to form liposomes. The liposomal preparations have the primary advantage of reduced renal and infusion toxicity. However, due to high cost, liposomal preparations are reserved mainly as salvage therapy for patients who cannot tolerate conventional amphotericin B. Low levels of the drug and its metabolites appear in the urine over a long period of time, and some are also eliminated via the bile. Dosage adjustment is not required in patients with hepatic dysfunction, but when conventional amphotericin B causes renal dysfunction, the total daily dose is decreased by 50%. Premedication with a corticosteroid or an antipyretic helps to prevent this problem. Renal impairment: Despite the low levels of the drug excreted in the urine, patients may exhibit a decrease in glomerular filtration rate and renal tubular function. Serum creatinine may increase, creatinine clearance can decrease, and potassium and magnesium are lost. Azotemia is exacerbated by other nephrotoxic drugs, such as aminoglycosides, cyclosporine, pentamidine, and vancomycin, although adequate hydration can decrease its severity. To minimize nephrotoxicity, sodium loading with infusions of normal saline and the lipid-based amphotericin B products can be used. Hypotension: A shock-like fall in blood pressure accompanied by hypokalemia may occur, requiring potassium supplementation. This combination of drugs is administered for the treatment of systemic mycoses and for meningitis caused by C. It is effective in combination with itraconazole for treating chromoblastomycosis (causes skin and subcutaneous infections) and in combination with amphotericin B for treating candidiasis and cryptococcosis. Flucytosine can also be used for Candida urinary tract infections when fluconazole is not appropriate; however, resistance can occur with repeated use. Excretion of both the parent drug and its minimal metabolites is by glomerular filtration, and the dose must be adjusted in patients with compromised renal function. Caution must be exercised in patients undergoing radiation or chemotherapy with drugs that depress bone marrow. Reversible hepatic dysfunction with elevation of serum transaminases and alkaline phosphatase may occur. Gastrointestinal disturbances (nausea, vomiting, and diarrhea) are common, and severe enterocolitis may also occur. Azole antifungals Azole antifungals are made up of two different classes of drugs- imidazoles and triazoles. In general, imidazoles are given topically for cutaneous infections, whereas triazoles are given systemically for the treatment or prophylaxis of cutaneous and systemic fungal infections. The inhibition of ergosterol biosynthesis disrupts membrane structure and function, which, in turn, inhibits fungal cell growth. Mechanisms of resistance include mutations in the C-14 -demethylase gene that lead to decreased azole binding. Additionally, some strains of fungi have developed efflux pumps that pump the azole out of the cell. Contraindications: Azoles are considered teratogenic, and they should be avoided in pregnancy unless the potential benefit outweighs the risk to the fetus. It is the least active of all triazoles, with most of its spectrum limited to yeasts and some dimorphic fungi. It is highly active against Cryptococcus neoformans and certain species of Candida, including C. It also is the drug of choice for Cryptococcus neoformans after induction therapy with amphotericin B and flucytosine and is used for the treatment of candidemia and coccidioidomycosis. It is well absorbed after oral administration and distributes widely to body fluids and tissues. Hepatotoxicity can also occur, and the drug should be used with caution in patients with liver dysfunction. It is rarely used for treatment of infections due to Candida and Aspergillus species because of the availability of newer and more effective agents. Itraconazole is available in two oral dosage forms, a capsule and an oral solution. The oral capsule should be taken with food, and ideally an acidic beverage, to increase absorption. In contrast, the solution should be taken on an empty stomach, as food decreases the absorption. Itraconazole is extensively metabolized by the liver, and the drug and inactive metabolites are excreted in the feces and urine. Adverse effects include nausea, vomiting, rash (especially in immunocompromised patients), hypokalemia, hypertension, edema, and headache. Hepatotoxicity can also occur, especially when given with other drugs that affect the liver. Itraconazole has a negative inotropic effect and should be avoided in patients with evidence of ventricular dysfunction, such as heart failure. Posaconazole is commonly used for the treatment and prophylaxis of invasive Candida and Aspergillus infections in severely immunocompromised patients. Due to its broad spectrum of activity, posaconazole is also used in the treatment of invasive fungal infections caused by Scedosporium and Zygomycetes. Even though posaconazole has a long half-life, the suspension is usually given in divided doses throughout the day due to saturable absorption in the gut, whereas the tablet is given once daily. The most common adverse effects include gastrointestinal disturbances (nausea, vomiting, and diarrhea) and headaches. Like other azoles, posaconazole can cause an elevation in serum hepatic transaminases. Drugs that affect the gastric pH (for example, proton pump inhibitors) may decrease the absorption of oral posaconazole and should be avoided if possible. Voriconazole has replaced amphotericin B as the drug of choice for invasive aspergillosis. It is also approved for treatment of invasive candidiasis, as well as serious infections caused by Scedosporium and Fusarium species. Adverse effects are similar to those of the other azoles; however, high trough concentrations are associated with visual and auditory hallucinations and an increased incidence of hepatotoxicity. Inhibitors and inducers of these enzymes may impact levels of voriconazole, leading to toxicity or clinical failure, respectively. Due to significant interactions, use of voriconazole is contraindicated with many drugs (for example, rifampin, rifabutin, carbamazepine, and the herb St. Echinocandins Echinocandins interfere with the synthesis of the fungal cell wall by inhibiting the synthesis of (1,3)-d-glucan, leading to lysis and cell death. The echinocandins have potent activity against Aspergillus and most Candida species, including those species resistant to azoles. All three agents are well tolerated, with the most common adverse effects being fever, rash, nausea, and phlebitis at the infusion site. They can also cause a histamine-like reaction (flushing) when infused too rapidly. Caspofungin is a first-line option for patients with invasive candidiasis, including candidemia, and a second-line option for invasive aspergillosis in patients who have failed or cannot tolerate amphotericin B or an azole. The dose of caspofungin does not need to be adjusted in renal impairment, but adjustment is warranted with moderate hepatic dysfunction. Caspofungin should not be coadministered with cyclosporine due to a high incidence of elevated hepatic transaminases with concurrent use. Micafungin and anidulafungin are first-line options for the treatment of invasive candidiasis, including candidemia. Micafungin and anidulafungin do not need to be adjusted in renal impairment or mild to moderate hepatic dysfunction. Anidulafungin can be administered in severe hepatic dysfunction, but micafungin has not been studied in this condition. Tinea infections are classified by the affected site (for example, tinea pedis, which refers to an infection of the feet). Common dermatomycoses, such as tinea infections that appear as rings or round red patches with clear centers, are often referred to as "ringworm. It is better tolerated, requires a shorter duration of therapy, and is more effective than either itraconazole or griseofulvin. Therapy is prolonged (usually about 3 months) but considerably shorter than that with griseofulvin. It may also be effective against Candida, Epidermophyton, and Scopulariopsis, but the efficacy in treating clinical infections due to these pathogens has not been established. Pharmacokinetics: Terbinafine is available for oral and topical administration, although its bioavailability is only 40% due to first-pass metabolism. Terbinafine accumulates in breast milk and should not be given to nursing mothers. The drug should be avoided in patients with moderate to severe renal impairment or hepatic dysfunction. Adverse effects: Common adverse effects of terbinafine include gastrointestinal disturbances (diarrhea, dyspepsia, and nausea), headache, and rash. Taste and visual disturbances have been reported, as well as transient elevations in serum hepatic transaminases. Naftifine 1% cream and gel are used for topical treatment of tinea corporis, tinea cruris, and tinea pedis. Like naftifine, butenafine 1% cream is used for topical treatment of tinea infections. It has been largely replaced by oral terbinafine for the treatment of onychomycosis, although it is still used for dermatophytosis of the scalp and hair. Duration of therapy is dependent on the rate of replacement of healthy skin and nails. Ultrafine crystalline preparations are absorbed adequately from the gastrointestinal tract, and absorption is enhanced by high-fat meals.

Risk factors for multidrug-resistant organisms: Infections with multidrug-resistant pathogens need broader antibiotic coverage when initiating empiric therapy arthritis pain diet mayo clinic order celebrex amex. Common risk factors for infection with these pathogens include prior antimicrobial therapy in the preceding 90 days arthritis pain emergency room discount 100 mg celebrex visa, hospitalization for greater than 2 days within the preceding 90 days name of arthritis in back discount celebrex 200mg on-line, current hospitalization exceeding 5 days rheumatoid arthritis prognosis discount celebrex 200 mg otc, high frequency of resistance in the community or local hospital unit (assessed using hospital antibiograms) arthritis relief plus order celebrex 200 mg amex, and immunosuppressive diseases and/or therapies arthritis relief for wrists buy celebrex 100 mg cheap. Safety of the agent Antibiotics such as the penicillins are among the least toxic of all drugs because they interfere with a site or function unique to the growth of microorganisms. Cost of therapy Often several drugs may show similar efficacy in treating an infection but vary widely in cost. Although choice of therapy usually centers on the site of infection, severity of the illness, and ability to take oral medications, it is also important to consider the cost of the medication. In hospitalized patients requiring intravenous therapy initially, the switch to oral agents should occur as soon as possible. Utilizing these properties to optimize antibiotic dosing regimens can improve clinical outcomes and possibly decrease the development of resistance. This effect is sometimes called concentration-independent or time-dependent killing. In this chapter, the list is used to illustrate the spectra of bacteria for which a particular class of antibiotics is therapeutically effective. Narrow-spectrum antibiotics Chemotherapeutic agents acting only on a single or a limited group of microorganisms are said to have a narrow spectrum. Administration of broadspectrum antibiotics can drastically alter the nature of the normal bacterial flora and precipitate a superinfection due to organisms such as Clostridium difficile, the growth of which is normally kept in check by the presence of other colonizing microorganisms. This strategy reduces the possibility of superinfections, decreases the emergence of resistant organisms, and minimizes toxicity. Advantages of drug combinations Certain combinations of antibiotics, such as -lactams and aminoglycosides, show synergism; that is, the combination is more effective than either of the drugs used separately. Because such synergism among antimicrobial agents is rare, multiple drugs used in combination are only indicated in special situations (for example, when an infection is of unknown origin or in the treatment of enterococcal endocarditis). Principles of Antimicrobial Therapy agent that is bactericidal may result in the first drug interfering with the action of the second. For example, bacteriostatic tetracycline drugs may interfere with the bactericidal effects of penicillins and cephalosporins. Another concern is the risk of selection pressure and the development of antibiotic resistance by giving unnecessary combination therapy. Genetic alterations leading to drug resistance Acquired antibiotic resistance requires the temporary or permanent gain or alteration of bacterial genetic information. Drug resistance due to altered targets Drug resistance due to decreased accumulation Permeability Aminoglycosides Chloramphenicol Clindamycin Fluoroquinolones b-Lactams Macrolides Rifampin Sulfonamides Tetracycline Trimethoprim Vancomycin Tetracycline b-Lactams enter gramnegative cells through porin channels. However, resistant organisms may also have altered porin channels through which cephalosporins do not pass. Tetracycline Tetracycline was e ective against gynecologic infection due to Bacteroides, but now these organisms are resistant due to the presence of plasmidmediated protein that promotes e ux of the drug. Neisseria gonorrhoeae is now largely resistant to penicillin because of penicillinase activity. Decreased accumulation: Decreased uptake or increased efflux of an antibiotic can confer resistance because the drug is unable to attain access to the site of its action in sufficient concentrations to injure or kill the organism. Also, the presence of an efflux pump can limit levels of a drug in an organism, as seen with tetracyclines. Enzymatic inactivation: the ability to destroy or inactivate the antimicrobial agent can also confer resistance on microorganisms. Examples of antibiotic-inactivating enzymes include 1) -lactamases ("penicillinases") that hydrolytically inactivate the -lactam ring of penicillins, cephalosporins, and related drugs; 2) acetyltransferases that transfer an acetyl group to the antibiotic, inactivating chloramphenicol or aminoglycosides; and 3) esterases that hydrolyze the lactone ring of macrolides. Because the indiscriminate use of antimicrobial agents can result in bacterial resistance and superinfection, prophylactic use is restricted to clinical situations in which the benefits outweigh the potential risks. The duration of prophylaxis should be closely observed to prevent the unnecessary development of antibiotic resistance. Hypersensitivity Hypersensitivity or immune reactions to antimicrobial drugs or their metabolic products frequently occur. For example, the penicillins, despite their almost absolute selective microbial toxicity, can cause serious hypersensitivity problems, ranging from urticaria (hives) to anaphylactic 4 Treatment prior to most surgical procedures can decrease the incidence of infection afterwards. E ective prophylaxis is directed against the most likely organism, not eradication of every potential pathogen. Direct toxicity High serum levels of certain antibiotics may cause toxicity by directly affecting cellular processes in the host. These infections usually require secondary treatments using specific anti-infective agents. Tobramycin (an aminoglycoside) is considered a pregnancy risk category D drug which means there is chance for potential harm to the fetus. Nitrofurantoin, amoxicillin (a penicillin), and cephalexin (a cephalosporin) are considered category B. Isoniazid is only active against Mycobacterium tuberculosis, while ceftriaxone, ciprofloxacin, and imipenem are considered broad spectrum due to their activity against multiple types of bacteria and risk for developing a superinfection. Clindamycin, linezolid, and vancomycin exhibit time-dependent killing, while daptomycin works best in a concentration-dependent fashion. Aminoglycosides, including gentamicin, possess a long post-antibiotic effect, especially when given as a high dose every 24 hours. Penicillin G, clindamycin, and vancomycin have a relatively short postantibiotic effect and require frequent dosing to maintain activity. Which of the following antibiotics requires close monitoring and dosing adjustment in this patient given his liver disease? Erythromycin is metabolized by the liver and should be used with caution in patients with hepatic impairment. Chloramphenicol and sulfonamides (sulfamethoxazole) can cause toxic effects in newborns due to poorly developed renal and hepatic elimination processes. Although the minimum inhibitory concentration will impact the effectiveness of the drug against a given bacteria, it does not affect the ability of a drug to penetrate into the brain. The lipid solubility, protein binding, and molecular weight all determine the likelihood of a drug to penetrate the blood­brain barrier and concentrate in the brain. Stevens-Johnson syndrome is a severe idiosyncratic reaction that can be life threatening, and these patients should never be rechallenged with the offending agent. A patient may be rechallenged if the benefits outweigh the risk (for example, pregnant patient with syphilis) or the patient could be exposed through a desensitization procedure. This is not an allergic reaction, and the patient can be rechallenged; however, the patient might be at risk for developing C. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms. The most important members of this group of drugs are the -lactam antibiotics (named after the -lactam ring that is essential to their activity), vancomycin, and daptomycin. The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, crosshypersensitivity, and susceptibility to bacterial degradative enzymes (-lactamases). Mechanism of action the penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses. Penicillin-binding proteins: Penicillins also inactivate numerous proteins on the bacterial cell membrane. Cell Wall Inhibitors prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria. Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity. Production of autolysins: Many bacteria, particularly the grampositive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Thus, the antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of the existing cell wall by autolysins. However, gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry. Natural penicillins: Natural penicillins (penicillin G and penicillin V) are obtained from fermentations of the fungus Penicillium chrysogenum. Semisynthetic penicillins, such as amoxicillin and ampicillin (also known as aminopenicillins), are created by chemically attaching different R groups to the 6-aminopenicillanic acid nucleus. Penicillins are susceptible to inactivation by -lactamases (penicillinases) that are produced by the resistant bacteria. Despite widespread use and increase in resistance to many types of bacteria, penicillin remains the drug of choice for the treatment of gas gangrene (Clostridium perfringens) and syphilis (Treponema pallidum). Penicillin V has a similar spectrum to that of penicillin G, but it is not used for treatment of bacteremia because of its poor oral absorption. Penicillin V is more acid stable than penicillin G and is often employed orally in the treatment of infections. Penicillinase-producing strains are treated using ceftriaxone, with azithromycin or spectinomycin as a backup. Infection often occurs in an institutional setting in individuals who are ill from other causes. Resistance to penicillin G has greatly increased worldwide due to mutations in one or more of the bacterial penicillinbinding proteins. A single treatment with penicillin is curative for primary and secondary syphilis. Resistance to these antibiotics is now a major clinical problem because of inactivation by plasmid-mediated penicillinases. Antimicrobial spectrum of ampicillin Gram (+) cocci Enterococci Gram (+) bacilli Listeria monocytogenes Gram (­) cocci Gram (­) rods Escherichia coli Haemophilus in uenzae Proteus mirabilis Salmonella typhi Anaerobic organisms Spirochetes Mycoplasma Chlamydia Other B. They are effective against many gram-negative bacilli, but not against Klebsiella because of its constitutive penicillinase. Formulation of ticarcillin or piperacillin with clavulanic acid or tazobactam, respectively, extends the antimicrobial spectrum of these antibiotics to include penicillinase-producing organisms (for example, most Enterobacteriaceae and Bacteroides species). Resistance Natural resistance to the penicillins occurs in organisms that either lack a peptidoglycan cell wall (for example, Mycoplasma pneumoniae) or have cell walls that are impermeable to the drugs. Acquired resistance to the penicillins by plasmid-mediated -lactamases has become a significant clinical problem. Multiplication of resistant strains leads to increased dissemination of the resistance genes. By obtaining resistance plasmids, bacteria may acquire one or more of the following properties, thus allowing survival in the presence of -lactam antibiotics. They are the major cause of resistance to the penicillins and are an increasing problem. Some of the -lactam antibiotics are poor substrates for -lactamases and resist hydrolysis, thus retaining their activity against -lactamase­producing organisms. The presence of an efflux pump can also reduce the amount of intracellular drug (for example, Klebsiella pneumoniae). Administration: the route of administration of a -lactam antibiotic is determined by the stability of the drug to gastric acid and by the severity of the infection. Penicillin V, amoxicillin, and dicloxacillin are available only as oral preparations. They are slowly absorbed into the circulation and persist at low levels over a long time period. Absorption: Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora. Food decreases the absorption of all the penicillinase-resistant penicillins because as gastric emptying time increases, the drugs are destroyed by stomach acid. Metabolism: Host metabolism of the -lactam antibiotics is usually insignificant, but some metabolism of penicillin G may occur in patients with impaired renal function. Excretion: the primary route of excretion is through the organic acid (tubular) secretory system of the kidney as well as by glomerular filtration. They are primarily metabolized in the liver and do not require dose adjustment for renal insufficiency. Adverse reactions Penicillins are among the safest drugs, and blood levels are not monitored. Hypersensitivity: Approximately 5% percent of patients have some kind of reaction, ranging from rashes to angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis. Cell Wall Inhibitors To determine whether treatment with a -lactam is safe when an allergy is noted, patient history regarding severity of previous reaction is essential. Diarrhea: Diarrhea is a common problem that is caused by a disruption of the normal balance of intestinal microorganisms. It occurs to a greater extent with those agents that are incompletely absorbed and have an extended antibacterial spectrum. Nephritis: Penicillins, particularly methicillin, have the potential to cause acute interstitial nephritis. Neurotoxicity: the penicillins are irritating to neuronal tissue, and they can provoke seizures if injected intrathecally or if very high blood levels are reached. Hematologic toxicities: Decreased coagulation may be observed with high doses of piperacillin, ticarcillin, and nafcillin (and, to some extent, with penicillin G). Cytopenias have been associated with therapy of greater than 2 weeks, and therefore, blood counts should be monitored weekly for such patients. Cephalosporins have the same mode of action as penicillins, and they are affected by the same resistance mechanisms.

For example arthritis disease buy celebrex 200 mg mastercard, some instruments can change the temperature at 20°C per s arthritis definition of order celebrex without a prescription, permitting instrument analysis of up to 32 samples in as little as 30 min arthritis fatigue discount celebrex online amex. Although a higher-capacity instrument may have a longer thermocycling time than a lower-capacity instrument rheumatoid arthritis definition symptoms cheap celebrex 100mg with amex, potentially more samples may be analyzed by the high-capacity instrument in a specific time period than by the low-capacity instrument arthritis during pregnancy order celebrex 100mg without a prescription. If target nucleic acid is present in extremely small amounts in a sample arthritis neck physical therapy exercises cheap celebrex 200 mg fast delivery, an instrument that permits higher-volume analysis may be preferred. A tungsten source lamp for excitation and selectable filters for excitation and emission wavelength detection are used in a number of instruments. Light-emitting diodes or laser excitation devices coupled with emission wavelength detection may also be used. Many manufacturers are coupling automated nucleic acid extraction instruments with amplification and detection systems to create high-throughput, fully automated nucleic acid analyzers. The GeneXpert system (Cepheid) represents the other end of the automation spectrum, in which a single sample is added to a disposable fluidic cartridge that fully automates and integrates sample preparation, amplification, and realtime detection. The instrument has a random-access design, amenable to on-demand molecular diagnostic testing. Other examples of simple, sample-in, answer-out systems designed to be performed on demand include FilmArray (BioFire) and AmpliVue (Quidel/BioHelix). A number of criteria need to be considered before selecting and implementing a new molecular microbiology instrument platform (144). These include vendor support by way of test menu, technical support, pricing, and kit configuration. The functionality of the instrument platform should be also be assessed by workflow, reliability, flexibility, and ease of use. Finally, the specifications for the instrument in terms of environmental conditions. Over time the methods have become more automated, the cost of testing has decreased, and clinical utility has been proven for the diagnosis and management of a variety of infectious diseases. As a result, molecular testing is now routinely performed in many clinical microbiology laboratories, and clinical applications will continue to expand in the future. A number of near-patient or point-of-care nucleic acid amplification tests for a variety of infectious diseases are commercially available or close to market. Initial Diagnosis With the development of molecular methods, the clinical microbiology laboratory is no longer reliant solely on the traditional culture methods for detection of pathogens in clinical specimens. Culture-based methods have long been the gold standard for infectious-disease diagnosis, but for several diseases, nucleic acid-based tests have replaced culture as the gold standard. In other diseases such as tuberculosis, nucleic acid amplification tests are useful adjuncts to culture that can provide more rapid initial diagnosis and permit timelier public health interventions. This technology has been used to best advantage in situations in which traditional methods are slow, insensitive, expensive, or not available. These techniques work particularly well with fragile or fastidious microorganisms that may die in transit or be overgrown by contaminating biota when cultured. Molecular Microbiology n 75 media, inappropriate transport conditions, or delays in transport can reduce the viability of the pathogen but may leave the nucleic acid still detectable. It is beyond the scope of this chapter to review all of the possible applications or to provide a compendium of methods for detection of various pathogens. Opportunities to actually replace culture for bacterial pathogens in routine practice are limited by the need to isolate the organisms for antibiotic susceptibility testing. In those applications in which culture has actually been replaced by nucleic acid testing, the pathogens are of predictable susceptibilities and, consequently, routine susceptibility testing is not performed, or the genetics of resistance are well defined and simple to detect, such as methicillin resistance in S. Since the last edition of this book, most clinical microbiology laboratories have replaced antigen detection with nucleic acid amplification methods for diagnosis of C. Molecular methods have had the biggest impact in clinical virology, in which the molecular approaches are often faster, more sensitive, and more cost-effective than the traditional methods. There are greater opportunities to replace the conventional methods in virology than in bacteriology because the culture-based methods are costly and antiviral susceptibility testing is not routinely performed. Until recently a major limitation of molecular tests for infectious diseases was the clinical need for simultaneous identification of multiple pathogens associated with defined syndromes such as respiratory tract infections, sepsis, gastroenteritis, and meningoencephalitis (150). This syndromic approach to molecular microbiology was facilitated by the technological developments of multiparametric or multiplex analysis described earlier in this chapter. It is likely that this trend in development and deployment of syndromic molecular microbiology tests on multiparametric platforms will increase in the future. Perhaps the greatest impact of molecular methods has been in the discovery of previously unrecognized or uncultivable pathogens. During the past 25 years, a number of infectious agents were first identified directly from clinical material by using molecular methods. This approach provides a new paradigm for discovery of unrecognized pathogens that is of value in other diseases with features that suggest an infectious etiology. Molecular methods are very powerful tools for the identification of emerging pathogens and are covered in detail in chapter 16. Within a few months of the recognized outbreak, the virus was identified and sequenced and the molecular assays were developed that played an essential role in diagnosing the infection and defining the epidemiology of the infection. Similarly, high-throughput shotgun sequencing offers important new opportunities for discovery of microbial pathogens. This approach has also been used to detect previously known and unknown viruses in feces of children with gastroenteritis and a novel Old World arenavirus that caused fatal disease in three recipients of organs from a single donor (157). The 16S gene sequence can be determined rapidly and provides objective results independent of phenotypic characteristics. As discussed in the preceding section, it can also be used to characterize previously unrecognized species. This gene is universally found in all fungi and contains sufficient variation to identify most fungi accurately to the species level. The major limitations of this approach to microbial identification include the high cost of automated nucleic acid sequencers, the lack of appropriate analysis software, and limited databases. Applied Biosystems has developed ribosomal gene sequencing kits for bacteria and fungi. The software analysis provides percent base pair differences between the unknown bacterium and the 20 most closely related bacteria, alignment tools to show differences between the related sequences, and phylogenetic tree tools to verify that the unknown bacterium actually clusters with the 20 closest bacteria in the database. Continued improvements in automation, refinements of analysis software, and decreases in cost should lead to more widespread use of nucleic acid sequence-based approaches to microbial identification. More recently, pyrosequencing, or sequencing by synthesis, has been used for the identification of infectious pathogens. Since the length of high-quality sequence generated is limited to 50 to 100 bp, it is very useful for singlenucleotide polymorphism analysis, but it has also been applied to taxonomic categorization of microorganisms. This approach requires identifying a variable region that contains a unique sequence for the different microorganisms within the group. Pyrosequencing has been successfully used to classify mycobacteria and nocardiae into clinically important groups and to identify yeast and filamentous fungi (163, 164). Targeted amplicon studies focus on one or a few marker genes and use these markers to reveal the composition and diversity of the microbiota. Others use a shotgun metagenomic approach in which genomic sequences are randomly obtained. A variety of sequencing technologies, including massively parallel sequencing, have been used for taxonomic profiling. Subsequent studies have confirmed that baseline viral load critically influences disease progression. Subtyping of respiratory syncytial viruses may provide information about the severity of infection in hospitalized infants, with those infected with group A viruses having poorer outcomes (168). Duration of and Response to Therapy Molecular methods have been developed to detect the genes responsible for resistance to single antibiotics or classes of antibiotics in bacteria and in many cases are superior to the phenotypic, growth-based methods. The detection of methicillin resistance in staphylococci, vancomycin resistance in enterococci, carbapenem resistance in Enterobacteriaceae, and rifampin resistance in M. However, it is difficult to imagine, given our current state of knowledge of the molecular genetics of antimicrobial resistance and the technological limitations, that a genotypic approach to routine antimicrobial susceptibility testing of bacteria could rival the phenotypic methods in terms of information content and cost in the near future. Molecular techniques are playing an increasing role in predicting and monitoring patient response to antiviral therapy. The laboratory may have a role in predicting response to therapy by detecting specific drug resistance mutations, determining viral load, and genotyping. Genotype is also used to determine the duration of therapy, with genotype 1 infection requiring a longer course of therapy than genotype 2 or 3 infections (180, 181). Recent studies have more closely Disease Prognosis Molecular techniques have created opportunities for the laboratory to provide important information that may predict disease progression. Molecular Microbiology n 77 defined duration of therapy based on the extent of the viral response. Patients who do not reach a 2-log10 drop in viral load at 12 weeks after initiating therapy are very unlikely to respond to pegylated interferon and ribavirin. Both drugs, boceprevir and telaprevir, are serine protease inhibitors to be used in conjunction with pegylated interferon and ribavirin. A number of other compounds encompassing at least five distinct drug classes are currently under development or in clinical trials (183). Currently, there is no clinical indication for viral resistance testing, but that may change as different classes of direct-acting antiviral agents are used for treatment. There are special concerns in the areas of specimen processing, workflow, quality assurance, and interpretation of test results. Specimen Collection, Transport, and Processing Proper collection, transport, and processing of clinical specimens are essential to ensure reliable results from molecular assays. Important issues to consider in specimen collection are the timing of specimen collection in relationship to disease state and the proper specimen type. Other factors that come into play include the use of the proper anticoagulant, transport and storage temperatures, and time to processing of the specimen. Once the plasma has been separated, it can be stored at 4°C for several days, but -70°C is recommended for long-term storage (191). Molecular methods have several advantages over conventional culture with regard to specimen collection. It may be easier to maintain the integrity of nucleic acid than the viability of an organism. Nucleic acid persists in specimens after initiation of treatment (192, 193), thus allowing detection of a pathogen even though the organism can no longer be cultured. Also, due to the increased sensitivity of molecular assays, it may be possible to test a smaller volume of specimen or use a specimen that is collected using a less invasive method. The major goals of specimen processing are to release nucleic acid from the organism, maintain the integrity of the nucleic acid, render the sample noninfectious, remove inhibiting substances, and in some instances concentrate the specimen. Complex specimen processing methods are time-consuming and may lead to the loss of target nucleic acid or result in contamination between specimens. Care must be taken to avoid carrying over inhibitory substances, such as phenol or alcohol, from the nucleic acid isolation step to the amplification reaction. Another factor to consider when deciding on a nucleic acid extraction method is the type of pathogen sought. Some pathogens, such as viruses, can be very easy to lyse, while mycobacteria, Gram-positive bacteria, and fungi can be very difficult to lyse. Enzyme digestion, harsh lysis conditions, or mechanical disruption may be required to disrupt the cell walls of these organisms. The lysate can be used directly in amplification assays, or additional steps may follow to purify the nucleic acid. These additional steps remove proteins and traces of organic solvents and concentrate the specimen. The Boom extraction method is also based on the lysing and nuclease-inactivating properties of guanidinium thiocyanate but utilizes the acid-binding properties of silica or glass particles to purify nucleic acid (197). Detection of target organisms that are present in small numbers in a large-volume clinical sample requires that target organisms be concentrated to a detectable level. One way to accomplish this is to isolate the particular nucleic acid of interest by binding it to a solid phase, which allows the support, with the target bound to it, to be separated from the original sample. Target capture techniques immobilize nucleic acids on magnetic beads by the use of a capture probe that attaches to the bead and to the target nucleic acid. A magnetic separation device is used to concentrate the target by drawing the magnetic beads to the sides of the sample tube, while the remainder of the sample is washed away and removed. Target capture techniques also remove materials in the sample that might otherwise interfere with amplification. Over the past several years, various manufacturers have developed commercially available reagents using one of these basic methods or a modification of these methods. Many of these methods rely on the use of spin column technology, are easy to use, and provide a rapid, reproducible method for purification of nucleic acid from a wide variety of clinical specimens. In recent years, further advances have been made with the introduction of magnetic silica particles that are coupled with instruments providing various degrees of automation, thus further simplifying nucleic acid extraction and purification. These reagents tend to be expensive, but the additional cost can be offset by labor savings. Laboratories are increasingly using automated systems for nucleic acid extraction, as they require less hands-on time, may reduce the risk of cross contamination between specimens, and provide more consistent yields. There are now many automated systems available for use in clinical laboratories; they should be thoroughly evaluated because not all isolate nucleic acids with the same efficiency and purity. The quality of the nucleic acid can have a significant impact on the performance of a molecular test. This can be accomplished by cutting the tissue into small pieces or mechanically homogenizing the tissue prior to proceeding with one of the above-described extraction methods. Preserved tissue specimens require removal of the paraffin with solvents and slicing into fine sections prior to processing. Removing inhibitors of amplification is a key function of the nucleic acid extraction process. The inhibition rate can be reduced to <1% by using a silicabased extraction method.

Syndromes

• Slow, sluggish, lethargic movement
• Uroporphyrin
• Lymph nodes in your chest may also be removed if your cancer has spread to them. The surgeon will remove them through a cut in the lower part of your neck.
• Trihexyphenidyl (Artane)
• Stroke
• New lumps in the breast

Stimulation of 2 receptors on the sympathetic presynaptic terminal reduces the release of norepinephrine rheumatoid arthritis ankle buy celebrex 100 mg fast delivery. Ephedrine is more lipophilic compared to the other drugs listed and therefore is more likely to cross the blood­brain barrier when administered systemically arthritis and sports order 100mg celebrex otc. Norepinephrine has more agonistic effects and activates mainly 1 rheumatoid arthritis in feet and hands purchase 200 mg celebrex with mastercard, 2 ultrasound for arthritis in dogs order 100 mg celebrex otc, and 1 receptors arthritis in dogs tail generic 100mg celebrex with visa. Dobutamine mainly activates 1 receptors and has no significant effects on 2 receptors can arthritis in neck cause lightheadedness generic celebrex 200mg fast delivery. Thus, epinephrine is the drug of choice in anaphylactic shock that can both stimulate the heart (1 activation) and dilate bronchioles (2 activation). Among the choices, the ideal drug to increase contractility of the heart in acute heart failure is dobutamine, since it is a selective 1-adrenergic agonist. Other drugs are nonselective adrenergic agonists that could cause unwanted side effects. Which of the following drugs would be the most appropriate to improve his cardiac function? Clonidine is an 2 agonist, albuterol is a 2 agonist, dobutamine is a 1 agonist, and norepinephrine is a nonselective adrenergic agonist. He is not on any asthma medications currently but is receiving a 1-selective blocker for his hypertension. The herbal remedy seems to relieve his asthma attacks, but his blood pressure seems to increase despite the -blocker therapy. Which of the following drugs is most likely present in the herbal remedy he is taking? Two drugs among the choices that could relieve asthma are ephedrine and salmeterol, as they activate 2 receptors in the bronchioles and cause bronchodilation. However, salmeterol is a selective 2 agonist and should not cause an increase in blood pressure. Ephedrine on the other hand stimulates the release of norepinephrine and acts as a direct agonist at - and -adrenergic receptors, thus causing an increase in blood pressure. Norepinephrine is a nonselective adrenergic agonist that does not have any stimulatory effects on 2 receptors. These drugs act by either reversibly or irreversibly attaching to the adrenoceptors, thus preventing activation by endogenous catecholamines. Numerous adrenergic antagonists have important roles in clinical medicine, primarily to treat diseases associated with the cardiovascular system. Because normal sympathetic control of the vasculature occurs in large part through agonist actions on -adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. The block is irreversible and noncompetitive, and the only way the body can overcome the block is to synthesize new adrenoceptors, which requires a day or longer. After the drug is injected, a delay of a few hours occurs before a blockade develops. Cardiovascular effects: By blocking receptors, phenoxybenzamine prevents vasoconstriction of peripheral blood vessels by endogenous catecholamines. Furthermore, the ability to block presynaptic inhibitory 2 receptors in the heart can contribute to an increased cardiac output. Epinephrine reversal: All -adrenergic blockers reverse the agonist actions of epinephrine. Therapeutic uses: Phenoxybenzamine is used in the treatment of pheochromocytoma, a catecholamine-secreting tumor of cells derived from the adrenal medulla. It may be used prior to surgical removal of the tumor to prevent a hypertensive crisis, and it is also useful in the chronic management of inoperable tumors. Phenoxybenzamine is sometimes effective in treating Raynaud disease and frostbite. Adverse effects: Phenoxybenzamine can cause postural hypotension, nasal stuffiness, nausea, and vomiting. Phenoxybenzamine should be used with caution in patients with cerebrovascular or cardiovascular disease. Catecholamine Untreated mine control 200 Isoproterenol ol (mm Hg) 0 200 e Epinephrine 0 200 Norepinephrine hrine 0 Pretreatment with an blocker Pretreatment with a blocker -Adrenergic blockers reverse the vasoconstrictive action of epinephrine. Like phenoxybenzamine, it produces postural hypotension and causes epinephrine reversal. Phentolamine-induced reflex cardiac stimulation and tachycardia are mediated by the baroreceptor reflex and by blocking the 2 receptors of the cardiac sympathetic nerves. The drug can also trigger arrhythmias and anginal pain, and phentolamine is contraindicated in patients with coronary artery disease. Phentolamine is useful to treat hypertensive crisis due to abrupt withdrawal of clonidine and from ingesting tyramine-containing foods in patients taking monoamine oxidase inhibitors. Metabolism leads to inactive products that are excreted in urine except for those of doxazosin, which appear in feces. Mechanism of action: All of these agents decrease peripheral vascular resistance and lower blood pressure by causing relaxation of both arterial and venous smooth muscle. These drugs, unlike phenoxybenzamine and phentolamine, cause minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Tamsulosin has the least effect on blood pressure because it is less selective for 1B receptors found in the blood vessels and more selective for 1A receptors in the prostate and bladder. Therapeutic uses: Individuals with elevated blood pressure treated with one of these drugs do not become tolerant to its action. Because of inferior cardiovascular outcomes as compared to other antihypertensives, 1 antagonists are not used as monotherapy for the treatment of hypertension (see Chapter 17). Adverse effects: 1-Blockers such as prazosin and doxazosin may cause dizziness, a lack of energy, nasal congestion, headache, drowsiness, and orthostatic hypotension (although to a lesser degree than that observed with phenoxybenzamine and phentolamine). By blocking receptors in the ejaculatory ducts and impairing smooth muscle contraction, 1 antagonists may cause inhibition of ejaculation and retrograde ejaculation. It is found as a component of the bark of the yohimbe tree and has been used as a sexual stimulant and in the treatment of erectile dysfunction. Its use in the treatment of these disorders is not recommended, due to lack of demonstrated efficacy. It is contraindicated in cardiovascular disease, psychiatric conditions, and renal dysfunction because it may worsen these conditions. Although all -blockers lower blood pressure, they do not induce postural hypotension, because the adrenoceptors remain functional. During exercise or stress, when the sympathetic nervous system is activated, -blockers attenuate the expected increase in heart rate. Cardiac output, workload, and oxygen consumption are decreased by blockade of 1 receptors, and these effects are useful in the treatment of angina (see Chapter 21). The reduction in cardiac output produced by all -blockers leads to decreased blood pressure, which triggers a reflex peripheral vasoconstriction that is reflected in reduced blood flow to the periphery. In patients with hypertension, total peripheral resistance returns to normal or decreases with long term use of propranolol. There is a gradual reduction of both systolic and diastolic blood pressures in hypertensive patients. Disturbances in glucose metabolism: blockade leads to decreased glycogenolysis and decreased glucagon secretion. Blocked action of isoproterenol: Nonselective -blockers, including propranolol, have the ability to block the actions of isoproterenol (1, 2 agonist) on the cardiovascular system. The actions of norepinephrine on the cardiovascular system are mediated primarily by receptors and are, therefore, unaffected. Hypertension: Propranolol does not reduce blood pressure in people with normal blood pressure. Angina pectoris: Propranolol decreases the oxygen requirement of heart muscle and, therefore, is effective in reducing chest pain on exertion that is common in angina. Myocardial infarction: Propranolol and other -blockers have a protective effect on the myocardium. Thus, patients who have had one myocardial infarction appear to be protected against a second heart attack by prophylactic use of -blockers. In addition, administration of a -blocker immediately following a myocardial infarction reduces infarct size and hastens recovery. The mechanism for these effects may be a blocking of the actions of circulating catecholamines, which would increase the oxygen demand in an already ischemic heart muscle. Migraine: Propranolol is effective in reducing migraine episodes when used prophylactically (see Chapter 36). Hyperthyroidism: Propranolol and other -blockers are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism. Adrenergic Antagonists -blockers may be lifesaving in protecting against serious cardiac arrhythmias. Pharmacokinetics: After oral administration, propranolol is almost completely absorbed. The volume of distribution of propranolol is quite large (4 L/kg), and the drug readily crosses the blood­brain barrier due to its high lipophilicity. Death by asphyxiation has been reported for patients with asthma whom were inadvertently administered the drug. Arrhythmias: Treatment with -blockers must never be stopped abruptly because of the risk of precipitating cardiac arrhythmias, which may be severe. On suspension of therapy, the increased receptors can worsen angina or hypertension. Sexual impairment: Because ejaculation in the male is mediated through -adrenergic activation, -blockers do not affect ejaculation or internal bladder sphincter function. Metabolic disturbances: Blockade leads to decreased glycogenolysis and decreased glucagon secretion. A major role of receptors is to mobilize energy molecules such as free fatty acids. These effects on the serum lipid profile may be less pronounced with the use of 1-selective antagonists such as metoprolol. Drug interactions: Drugs that interfere with, or inhibit, the metabolism of propranolol, such as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its antihypertensive effects. It is used topically in the treatment of chronic open-angle glaucoma and, occasionally, for systemic treatment of hypertension. Treatment of glaucoma: -blockers, such as topically applied timolol, betaxolol, or carteolol, are effective in diminishing intraocular pressure in glaucoma. When administered intraocularly, the onset is about 30 minutes, and the effects last for 12 to 24 hours. Prostaglandin-like analogues (topical) Latanoprost, travoprost, bimatoprost Increase of aqueous humor out ow Red eye and ocular irritation, increased iris pigmentation, and excessive hair growth of eye lashes. Transient myopia, nausea, diarrhea, loss of appetite and taste, and renal stones (oral drugs). Acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, and nebivolol: Selective 1 antagonists Drugs that preferentially block the 1 receptors minimize the unwanted bronchoconstriction (2 effect) seen with propranolol use in asthma patients. It is only available intravenously and is used to control blood pressure or heart rhythm during surgery or diagnostic procedures. In contrast to propranolol, the cardioselective -blockers have fewer effects on pulmonary function, peripheral resistance, and carbohydrate metabolism. In addition to its cardioselective blockade, nebivolol releases nitric oxide from endothelial cells and causes vasodilation. Therapeutic uses: the cardioselective -blockers are useful in hypertensive patients with impaired pulmonary function. These partial agonists stimulate the receptor to which they are bound, yet they inhibit stimulation by the more potent endogenous catecholamines, epinephrine and norepinephrine. They contrast with the other -blockers that produce initial peripheral vasoconstriction, and these agents are, therefore, useful in treating hypertensive patients for whom increased peripheral vascular resistance is undesirable. Therapeutic use in hypertension and heart failure: Labetalol is employed as an alternative to methyldopa in the treatment of pregnancy-induced hypertension. Intravenous labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure (see Chapter 17). These agents work by blocking the effects of sympathetic stimulation on the heart, which causes worsening heart failure over time (see Chapter 19). Adverse effects: Orthostatic hypotension and dizziness are associated with 1 blockade. However, due to the advent of newer and more effective agents with fewer side effects, these agents are seldom used therapeutically. Reserpine, a plant alkaloid, blocks the Mg2+/adenosine triphosphate­ dependent transport of biogenic amines (norepinephrine, dopamine, and serotonin) from the cytoplasm into storage vesicles in the adrenergic nerve terminals in all body tissues. Reserpine has a slow onset, a long duration of action, and effects that persist for many days after discontinuation. It has been used for the management of hypertension but has largely been replaced with newer agents with better side effect profiles and fewer drug interactions. Arrhythmia prophylaxis after myocardial infarction Propranolol and metoprolol reduce cardiac output and renin secretion. Angina pectoris Propranolol, nadolol, and other b-blockers reduce cardiac rate and force. Her blood pressure seems to be under control, but she complains of fatigue, drowsiness, and fainting when she gets up from the bed (orthostatic hypotension). The new drug is similar to which of the following drugs in terms of its pharmacological mechanism of action? Amphetamine is an indirect adrenergic agonist that mainly enhances the release of norepinephrine from peripheral sympathetic neurons. Since both and receptors are activated by amphetamine, -blockers or -blockers alone cannot relieve the symptoms of amphetamine poisoning. Norepinephrine activates both 1 and 1 receptors and causes an increase in heart rate and blood pressure. A drug that prevents the increase in blood pressure caused by norepinephrine should be similar to carvedilol that antagonizes both 1 and 1 receptors. Prazosin is an 1 antagonist, clonidine is an 2 agonist, and propranolol and metoprolol are antagonists, and these drugs cannot completely prevent the cardiovascular effects of norepinephrine.

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