Michelle Weckmann, MD

  • Assistant Professor of Psychiatry
  • Roy J. and Lucille A. Carver College of Medicine
  • University of Iowa
  • Iowa City, Iowa

A 36-year-old woman recently treated for leukemia is admitted to the hospital with malaise medications vertigo purchase generic keppra line, chills medicine chest keppra 500mg free shipping, and high fever symptoms 8 days before period purchase 250mg keppra. The records of the patient reveal that she had a severe urticarial rash treatment for sciatica buy keppra with american express, hypotension treatment hepatitis b discount keppra 500 mg mastercard, and respiratory difficulty after oral penicillin V about 6 mo ago medicine show order keppra online from canada. A 52-year-old man (weight 70 kg) is brought to the hospital emergency department in a confused and delirious state. He has had an elevated temperature for more than 24 h, during which time he had complained of a severe headache and had suffered from nausea and vomiting. Lumbar puncture reveals an elevated opening pressure, and cerebrospinal fluid findings include elevated protein, decreased glucose, and increased neutrophils. Gram stain of a smear of cerebrospinal fluid reveals Gram-positive diplococci, and a preliminary diagnosis is made of purulent meningitis. The microbiology report informs you that for approximately 15% of S pneumoniae isolates in the community, the minimal inhibitory concentration for penicillin G is 20 mcg/mL. Treatment of this patient should be initiated immediately with intravenous administration of (A) Amoxicillin (B) Cephalexin (C) Ceftriaxone plus vancomycin (D) Nafcillin (E) Piperacillin 7. Resistance of pneumococci to penicillin G is due to (A) Alterations in porin structure (B) Beta-lactamase production (C) Changes in chemical structure of target penicillinbinding proteins (D) Changes in the d-Ala-d-Ala building block of peptidoglycan precursor (E) Decreased intracellular accumulation of penicillin G 8. If this patient had been 82 years old and the Gram stain of the smear of cerebrospinal fluid had revealed Gram-positive rods resembling diphtheroids, the antibiotic regimen for empiric treatment would include (A) Ampicillin (B) Cefoxitin (C) Ceftriaxone (D) Fosfomycin (E) Vancomycin 9. A patient needs antibiotic treatment for native valve, culturepositive infective enterococcal endocarditis. His medical history includes a severe anaphylactic reaction to penicillin G during the last year. The best approach would be treatment with (A) Amoxicillin-clavulanate (B) Aztreonam (C) Ceftriaxone (D) Piperacillin (E) Vancomycin 10. The beta-lactam antibiotics also activate autolysins, which break down the bacterial cell wall. Vancomycin inhibits transglycolase, preventing elongation of peptidoglycan chains. Treatments of choice for gonorrhea include a single dose of ceftriaxone (intramuscularly). Because of the high incidence of beta-lactamase-producing gonococci, the use of penicillin G or amoxicillin is no longer appropriate for gonorrhea. Alternative drugs (not listed) for gonorrhea include cefixime, azithromycin (see Chapter 44) or spectinomycin (see Chapter 45). The penile chancre, the enlarged nontender lymph nodes, and the microscopic identification of treponemes in fluid expressed from the lesion are essentials of diagnosis. Although a single dose of ceftriaxone may cure incubating syphilis, it cannot be relied on for treating primary syphilis. The most appropriate course of action in this patient is to administer a single intramuscular injection of 2. For penicillin-allergic patients, oral doxycycline or tetracycline for 15 d (not 7 d) is effective in most cases (see Chapter 44). First- and second-generation cephalosporins are not effective in meningitis because they do not readily enter the cerebrospinal fluid. Instability of penicillins in gastric acid does limit their oral absorption, renal elimination of amoxicillin is inhibited by probenecid, and ticarcillin has activity against several Gram-negative rods. All penicillins should be avoided in patients with a history of allergic reactions to any individual penicillin drug. Cephalosporins should also be avoided in patients who have had anaphylaxis or other severe hypersensitivity reactions after use of a penicillin. There is partial cross-reactivity between penicillins and the carbapenems such as imipenem and meropenem, but no cross-reactivity between the penicillins and aztreonam. Pneumococcal isolates with a minimal inhibitory concentration for penicillin G of greater than 2 mcg/mL are highly resistant. Such strains are not killed by the concentrations of penicillin G or ampicillin that can be achieved in the cerebrospinal fluid. Cefotaxime and ceftriaxone are the most active cephalosporins against penicillin-resistant pneumococci, and the addition of vancomycin is recommended in the case of highly resistant strains. Pneumococcal resistance to penicillins is due to changes in the chemical structures of the target penicillin-binding proteins located in the bacterial cytoplasmic membrane. A structural alteration in the d-Ala-d-Ala component of the pentapeptide side chains of peptidoglycans is the basis for a mechanism of resistance to vancomycin. Diphtheroid-like Gram-positive rods in the cerebrospinal fluid smear of an elderly patient are indicative of L monocytogenes. Listeria infections are more common in neonates, elderly patients, and those who have been treated with immunosuppressive agents. In patients who have had a severe reaction to a penicillin, it is inadvisable to administer a cephalosporin or a carbapenem such as meropenem. Aztreonam has no significant activity against Gram-positive cocci, so the logical treatment in this case is vancomycin, often with an aminoglycoside (eg, gentamicin) for synergistic activity against enterococci. Vancomycin is not absorbed after oral administration and is used by this route in the treatment of colitis caused by C difficile and staphylococci. Vancomycin is commonly considered the drug of first choice for parenteral use against methicillin-resistant staphylococci. Describe 3 mechanisms underlying the resistance of bacteria to beta-lactam antibiotics. Identify the prototype drugs in each subclass of penicillins, and describe their antibacte- rial activity and clinical uses. Identify the 4 subclasses of cephalosporins, and describe their antibacterial activities List the major adverse effects of the penicillins and the cephalosporins. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones the antimicrobial drugs reviewed in this chapter selectively inhibit bacterial protein synthesis. The mechanisms of protein synthesis in microorganisms are not identical to those of mammalian cells. Such differences form the basis for the selective toxicity of these drugs against microorganisms without causing major effects on protein synthesis in mammalian cells. Chloramphenicol, tetracyclines, and the aminoglycosides (see Chapter 45) were the first inhibitors of bacterial protein synthesis to be discovered. Because they had a broad spectrum of antibacterial activity and were thought to have low toxicities, they were overused. Many once highly susceptible bacterial species have become resistant, and most of these drugs are now used for more selected targets. Erythromycin, an older macrolide antibiotic, has a narrower spectrum of action but continues to be active against several important pathogens. Newer inhibitors of microbial protein synthesis, which include streptogramins, linezolid, telithromycin, and tigecycline (a tetracycline analog), have activity against certain bacteria that have developed resistance to older antibiotics. With the exception of tetracyclines, the binding sites for these antibiotics are on the 50S ribosomal subunit. Thus, the peptide at the donor site cannot be transferred to its amino acid acceptor. Macrolides, telithromycin, and clindamycin, which share a common binding site on the 50S ribosome, also block transpeptidation. They bind to the 50S ribosomal subunit, constricting the exit channel on the ribosome through which nascent polypeptides are extruded. Selective toxicity of these protein synthesis inhibitors against microorganisms may be explained by target differences. Tetracyclines have little effect on mammalian protein synthesis because an active efflux mechanism prevents their intracellular accumulation. Chloramphenicol (C) and macrolides (M) bind to the 50S subunit and block transpeptidation (step 2). Classification Drugs in this class are broad-spectrum bacteriostatic antibiotics that have only minor differences in their activities against specific organisms. Pharmacokinetics Oral absorption is variable, especially for the older drugs, and may be impaired by foods and multivalent cations (calcium, iron, aluminum). Doxycycline is excreted mainly in feces; the other drugs are eliminated primarily in the urine. The half-lives of doxycycline and minocycline are longer than those of other tetracyclines. Antibacterial Activity Tetracyclines are broad-spectrum antibiotics with activity against Gram-positive and Gram-negative bacteria, species of Rickettsia, Chlamydia, Mycoplasma, and some protozoa. Resistance mechanisms include the development of mechanisms (efflux pumps) for active extrusion of tetracyclines and the formation of ribosomal protection proteins that interfere with tetracycline binding. These mechanisms do not confer resistance to tigecycline in most organisms, with the exception of the multidrug efflux pumps of Proteus and Pseudomonas species. Primary uses-Tetracyclines are recommended in the treatment of infections caused by Mycoplasma pneumoniae (in adults), chlamydiae, rickettsiae, vibrios, and some spirochetes. Doxycycline is currently an alternative to macrolides in the initial treatment of community-acquired pneumonia. They are also used in the treatment of respiratory infections caused by susceptible organisms, for prophylaxis against infection in chronic bronchitis, in the treatment of leptospirosis, and in the treatment of acne. Selective uses-Specific tetracyclines are used in the treatment of gastrointestinal ulcers caused by Helicobacter pylori (tetracycline), in Lyme disease (doxycycline), and in the meningococcal carrier state (minocycline). Doxycycline is also used for the prevention of malaria and in the treatment of amebiasis (Chapter 52). Tigecycline-Unique features of this glycylcycline derivative of minocycline include a broad spectrum of action that includes organisms resistant to standard tetracyclines. Gastrointestinal disturbances-Effects on the gastrointestinal system range from mild nausea and diarrhea to severe, possibly life-threatening enterocolitis. Disturbances in the normal flora may lead to candidiasis (oral and vaginal) and, more rarely, to bacterial superinfections with S aureus or Clostridium difficile. Bony structures and teeth-Fetal exposure to tetracyclines may lead to tooth enamel dysplasia and irregularities in bone growth. Although usually contraindicated in pregnancy, there may be situations in which the benefit of tetracyclines outweighs the risk. Treatment of younger children may cause enamel dysplasia and crown deformation when permanent teeth appear. Hepatic toxicity-High doses of tetracyclines, especially in pregnant patients and those with preexisting hepatic disease, may impair liver function and lead to hepatic necrosis. Though not directly nephrotoxic, tetracyclines may exacerbate preexisting renal dysfunction. Photosensitivity-Tetracyclines, especially demeclocycline, may cause enhanced skin sensitivity to ultraviolet light. Vestibular toxicity-Dose-dependent reversible dizziness and vertigo have been reported with doxycycline and minocycline. Classification and Pharmacokinetics the macrolide antibiotics (erythromycin, azithromycin, and clarithromycin) are large cyclic lactone ring structures with attached sugars. The drugs have good oral bioavailability, but azithromycin absorption is impeded by food. Macrolides distribute to most body tissues, but azithromycin is unique in that the levels achieved in tissues and in phagocytes are considerably higher than those in the plasma. The elimination of erythromycin (via biliary excretion) and clarithromycin (via hepatic metabolism and urinary excretion of intact drug) is fairly rapid (half-lives of 2 and 6 h, respectively). Antibacterial Activity Erythromycin has activity against many species of Campylobacter, Chlamydia, Mycoplasma, Legionella, Gram-positive cocci, and some Gram-negative organisms. Azithromycin is also effective in gonorrhea, as an alternative to ceftriaxone and in syphilis, as an alternative to penicillin G. Resistance to the macrolides in Gram-positive organisms involves efflux pump mechanisms and the production of a methylase that adds a methyl group to the ribosomal binding site. In the case of methylase-producing microbial strains, there is partial cross-resistance with other drugs that bind to the same ribosomal site as macrolides, including clindamycin and streptogramins. Resistance in Enterobacteriaceae is the result of formation of drugmetabolizing esterases. Clinical Uses Erythromycin is effective in the treatment of infections caused by M pneumoniae, Corynebacterium, Campylobacter jejuni, Chlamydia trachomatis, Chlamydophila pneumoniae, Legionella pneumophila, Ureaplasma urealyticum, and Bordetella pertussis. Azithromycin has a similar spectrum of activity but is more active against H influenzae, Moraxella catarrhalis, and Neisseria. Because of its long half-life, a single dose of azithromycin is effective in the treatment of urogenital infections caused by C trachomatis, and a 4-d course of treatment has been effective in community-acquired pneumonia. Clarithromycin has almost the same spectrum of antimicrobial activity and clinical uses as erythromycin. The drug is also used for prophylaxis against and treatment of M avium complex and as a component of drug regimens for ulcers caused by H pylori. Fidaxomicin is a narrow-spectrum macrolide antibiotic that inhibits protein synthesis and is selectively active against Grampositive aerobes and anaerobes. Fidaxomicin has proved to be as effective as vancomycin for the treatment of C difficile colitis, possibly with a lower relapse rate. Toxicity Adverse effects, especially with erythromycin, include gastrointestinal irritation (common) via stimulation of motolin receptors, skin rashes, and eosinophilia. A hypersensitivity-based acute cholestatic hepatitis may occur with erythromycin estolate. Hepatitis is rare in children, but there is an increased risk with erythromycin estolate in the pregnant patient.

Korppi medications routes order keppra 500 mg on-line, "Serum C-reactive protein cannot differentiate bacterial and viral aetiology of community-acquired pneumonia in children in primary healthcare settings symptoms nausea safe keppra 500 mg," Scandinavian Journal of Infectious Diseases medicine ketoconazole cream discount generic keppra uk, vol treatment 7th feb bournemouth cheapest keppra. Assendelft symptoms during pregnancy purchase 500mg keppra visa, "Diagnostic value of C reactive protein in infections of the 400 Infectious Diseases: An Evidence based Approach 22 medicine head keppra 250mg free shipping. Combes, "New diagnostic and prognostic markers of ventilator-associated pneumonia," Current Opinion in Critical Care, vol. Anker, "Pyrexia, procalcitonin, immune activation and survival in cardiogenic shock: the potential importance of bacterial translocation," International Journal of Cardiology, vol. 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Jacobs, "C-reactive protein and procalcitonin concentrations in bronchoalveolar lavage fluid as a predictor of ventilator-associated pneumonia," Annals of Clinical Biochemistry, vol. Murdoch, "Diagnostic markers of infection: comparison of procalcitonin with C reactive protein and leucocyte count," Archives of Disease in Childhood, vol. Hansson, "Procalcitonin and C-reactive protein levels in community-acquired pneumonia: correlation with etiology and prognosis," Infection, vol. Eckardt, "Elevations in procalcitonin but not C-reactive protein are associated with pneumonia after cardiopulmonary resuscitation," Resuscitation, vol. Soto, "Diagnostic strategies for nosocomial pneumonia," Current Opinion in Pulmonary Medicine, vol. Cravoisy, "Soluble form of the triggering receptor expressed on myeloid cells-1 as a marker of microbial infection," Clinical Medicine & Research, vol. Pineda, "Triggering receptors expressed on myeloid cells in pulmonary aspiration syndromes," Intensive Care Medicine, vol. Bollaert, "Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia," the New England Journal of Medicine, vol. Suter, "Rapid diagnosis of gram negative pneumonia by assay of endotoxin in bronchoalveolar lavage fluid," Thorax, vol. Findlay, "Diagnosis of Gram negative, ventilator associated pneumonia by assaying endotoxin in bronchial lavage fluid," Journal of Clinical Pathology, vol. Damas, "Correlation between endotoxin level and bacterial count in bronchoalveolar lavage fluid of ventilated patients," Critical Care Medicine, vol. Robertson, "Antidiuretic hormone: normal and disordered function," Endocrinology and Metabolism Clinics of North America, vol. Bergmann, "Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin," Clinical Chemistry, vol. Dunser, "Copeptin: clinical use of a new biomarker," Trends in Endocrinology and Metabolism, vol. Teixeira, "Copeptin, a novel prognostic biomarker in ventilatorassociated pneumonia," Critical Care, vol. Teixeira, "Prognostic value of midregional pro-atrial natriuretic peptide in ventilator-associated pneumonia," Intensive Care Medicine, vol. Maisel, "Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea," Journal of the American College of Cardiology, vol. Bouillon, "Clinical review 95: acute and prolonged critical illness as different neuroendocrine paradigms," Journal of Clinical Endocrinology & Metabolism, vol. Suboptimal clinical evaluation can result in missed diagnoses and excess morbidity and mortality. We estimate the sensitivity of pneumonia diagnosis and investigate its determinants among children in Malawi. We calculated sensitivity of pneumonia diagnosis and used multilevel logbinomial regression to assess factors associated with diagnostic sensitivity. Advanced practice clinicians were more likely than other providers to diagnose pneumonia correctly (adjusted relative risk 2. Clinical quality was strongly associated with correct diagnosis: sensitivity was 23% in providers at the 75th percentile for guideline adherence compared with 14% for those at the 25th percentile. Contextual factors, facility structural readiness, and training or supervision were not associated with sensitivity. Conclusions Care quality for Malawian children is poor, with low guideline adherence and missed diagnosis for four of five children with pneumonia. Existing interventions such as training and supportive supervision are associated with higher guideline adherence, but are insufficient to meaningfully improve sensitivity. Innovative and scalable Distribution and Determinants of Pneumonia Diagnosis Using. Furthermore, research from sub-Saharan Africa has revealed that children often receive suboptimal assessments for pneumonia at health facilities, such as inadequate history-taking and physical examination, resulting in delayed or inadequate diagnosis and increased morbidity and mortality. Previous studies on assessment and management of pneumonia using nationally representative data have identified gaps in clinical assessment and poor prescribing practices. We then assessed potential determinants of correct diagnosis of pneumonia to identify opportunities for intervention to further reduce under-five mortality in Malawi. Outcome Definition and Assessment Re-examinations of sick children included assessment of cough, respiratory rate (if cough was reported), anaemia, temperature and responsiveness. These guidelines are in accordance with the Malawi national guidelines in place at the time of the survey. Given the information available from the re-examination, we defined pneumonia cases as children with cough and fast breathing on re-examination. Providers were asked the diagnosis they assigned following each patient visit as part of the direct clinical observation; results are thus not subject to potentially poor data quality of medical records. Due to limited information from the re-examination, including no indication of stridor, we could not definitively identify children who did not meet the case definition of pneumonia; we thus did not assess specificity of diagnosis. Covariates We identified multiple levels influencing sensitivity of pneumonia diagnosis: contextual factors such as poverty, facility characteristics, provider characteristics and child/visit characteristics. Facility characteristics were defined as infrastructural and environmental factors that might be associated with diagnosis, such as location, facility management, facility type and structural quality, and provider factors such as professional level and technical quality score. Child characteristics considered included child age (infant or not), sex and case severity, where severe case was defined as fever (temperature 37. Among children who met the case definition for pneumonia but did not receive a pneumonia diagnosis, we assessed the proportion who received common alternative diagnoses. We calculated level of sensitivity across the binary and categorical covariates and tested significance of any differences using F tests corrected for the design effect Distribution and Determinants of Pneumonia Diagnosis Using. We then compared average structural and technical quality between children who were correctly and incorrectly diagnosed, determining significance using F tests again clustered by facility. We constructed multivariable models to test the association of the key covariates at each of the levels defined above with sensitivity, controlling for confounding by higher-level factors. Model 1 tested broad facility factors: location (urban or not), management type and facility type; we consolidated facility types into hospitals and non-hospitals following the tiers of the health system in Malawi. Model 3 and Model 4 incorporated provider capacity, including provider cadre and the technical quality of the care received, respectively. We identified child characteristics as factors that might be associated with pneumonia diagnosis, but that should not affect facility or visit characteristics; we tested each for inclusion as a control variable in unadjusted models with sensitivity using a criterion of P <0. We conducted a similar analysis to select contextual factors such as poverty and urban versus rural location due to the small sample size, controlling only for those related to the outcome at P <0. To test whether technical quality was differentially associated with sensitivity in better-equipped facilities, we assessed the association between technical quality and sensitivity of diagnosis only for children who received care in facilities with above-average structural quality for child care. All other analyses, which pertain to the subsample of children with pneumonia symptoms, are unweighted. Other symptoms include diarrhoea, vomit, feeding problem, convulsions, sleeping problem and other. The Harvard University Human Research Protection Program deemed this analysis exempt from human subjects review (protocol no. In total, care was observed for 3248 children under 5 years of age; 112 of these were children under 2 months who were excluded from analysis. Table 1 describes characteristics of facilities providing sick-child care and children receiving care. Children in the sample were 51% male and 49% female, with 64% from 12 to 59 months of age. Children most frequently received care from advanced practice clinicians or paramedical professionals, such as assistant medical officers or clinical officers, in public facilities in rural areas. The majority of sick-child visits (61%) occurred at non-hospitals, such as health centres or clinics, in areas where the proportion Distribution and Determinants of Pneumonia Diagnosis Using. Considerable gaps were evident in structural capacity to provide care: facilities scored an average of just under two-thirds on both general service readiness and childspecific service readiness. Only 118 children (21%) of these children were correctly diagnosed with pneumonia (table 2). Sensitivity was lower in children 12 months to 59 months old, with 78 of 428 (18% sensitivity) diagnosed with pneumonia compared with 40 of 145 cases (28% sensitivity) in children under one. Healthcare workers were more likely to assign the correct diagnosis when children presented with fever, high respiration or both as well as cough: sensitivity among these children (n=206) was 28%. Although prevalence of confirmed fever was equal across age groups, caretakers of children over one were more likely to report fever as a cause for the visit (76. All children 2 months through 59 months Clinician Dx+ 118 241 359 Clinician Dx- 455 2322 2777 573 2563 3136 418 Infectious Diseases: An Evidence based Approach Sensitivity 20. Children 12 months through 59 months Clinician Dx+ 78 122 Clinician Dx- 350 1526 428 1648 Sensitivity 18. Children 2 months through 11 months Clinician Dx+ 40 119 Clinician Dx- 105 796 145 915 Sensitivity 27. Among client demographics and facility characteristics, sensitivity of diagnosis was significantly higher for children <12 months of age, those with fever and/or high respiration, and those seen by clinicians as compared with nurses and other providers. Children seen in dispensaries were less likely to be correctly diagnosed than those seen in hospitals, health centres and clinics; the difference did not reach statistical significance. Analysis of case severity using presence of fever and/or high respiration did not identify differences in the case mix presenting by facility type or clinician qualification (see online supplementary table A1). Average technical quality was significantly higher for children receiving a correct diagnosis of pneumonia (0. Fever and/or tachypnoea confirmed by re-examination Severe case: child has fever and/or tachypnoea Less severe case: child has neither fever nor tachypnoea 28% 16% 0. Child age above and below 1 year, case severity and urban versus rural location met our screening criterion but child sex and poverty did not; we thus controlled for age, severity and location in all models. As shown in column 2 of table 4, probability of correct diagnosis among children with pneumonia symptoms was higher in rural areas and privately managed facilities, but not significantly so. Sensitivity did not vary significantly by general and child-specific structural quality (model 2). In model 3, clinicians were twice as likely to provide the correct diagnosis to children with pneumonia symptoms as nurses and other providers (adjusted relative risk 2. Clinician includes clinical officers, assistant medical officers and medical officers; other includes counsellors and social workers. Service readiness is an index from 0 to 1 comprising basic amenities, equipment, infection prevention, diagnostics and medications. Child service readiness is an index from 0 to 1 comprising staff and training, guidelines, and child-specific equipment and medication. Consistent with prior studies in low-income and middle-income countries, Distribution and Determinants of Pneumonia Diagnosis Using. Missed diagnoses were common irrespective of surrounding poverty level, urban versus rural location and facility type. Providers under-diagnosed pneumonia at both well-equipped and poorly equipped facilities. This evidence suggests a critical quality gap in formal healthcare services in Malawi, one that contributes to excess morbidity and avertable child deaths. Patient factors, such as child age and presenting with fever and/or tachypnoea, were associated with correct diagnosis in bivariable analysis. This is consistent with previous research19 36 and may suggest a lower threshold for diagnosing pneumonia in infants, who experience higher pneumonia incidence and mortality. Healthcare providers may be predisposed to look for pneumonia in infants and malaria in older children; given the incompleteness of physical examinations conducted (five of six children did not have respiratory rate assessed), caretaker report and expected prevalence of disease may form much of the basis for diagnosis.

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Regarding the anticipated actions of levodopa medicine norco generic keppra 500 mg amex, the patient need not be informed that (A) Dizziness may occur symptoms sinus infection buy keppra with amex, especially when standing (B) He should take the drug in divided doses to avoid nausea (C) Livedo reticularis is a possible side effect (D) the drug will probably improve his symptoms for a period of time but not indefinitely (E) Uncontrollable muscle jerks may occur 2 treatment zit purchase keppra amex. He suffers from irregular symptoms xxy buy cheap keppra 500mg on line, involuntary muscle jerks that affect the proximal muscles of the limbs medications and grapefruit juice buy keppra 500 mg visa. A 51-year-old patient with parkinsonism is being maintained on levodopa-carbidopa with adjunctive use of low doses of tolcapone but continues to have off-periods of akinesia aquapel glass treatment order cheap keppra on line. A drug used to "rescue" the patient that provides temporary relief is (A) Apomorphine (B) Benztropine (C) Carbidopa (D) Pramipexole (E) Selegiline 6. A previously healthy 40-year-old woman begins to suffer from slowed mentation, lack of coordination, and brief writhing movements of her hands that are not rhythmic. The woman has no history of psychiatric or neurologic disorders but several relatives have had similar symptoms. Although further diagnostic assessment should be made, it is very likely that the most appropriate drug for treatment will be (A) Amantadine (B) Bromocriptine (C) Diazepam (D) Haloperidol (E) Levodopa 8. Which of the following drugs is most suitable for management of essential tremor in a patient who has pulmonary disease In prescribing levodopa, the patient should be informed about adverse effects, including gastrointestinal distress, postural hypotension, and dyskinesias. It is reasonable to advise the patient that therapeutic benefits cannot be expected to continue indefinitely. Livedo reticularis (a netlike rash) is an adverse effect of treatment with amantadine. The drug is not effective in antagonizing the akinesia, rigidity, and tremor caused by treatment with antipsychotic agents. Pramipexole is a dopamine D3 receptor activator and does not require bioactivation. Confusion, delusions, and hallucinations occur more frequently with dopamine receptor activators than with levodopa. The use of dopaminergic agents in combination with antimuscarinic drugs is common in the treatment of parkinsonism. The form and severity of dyskinesias resulting from levodopa may vary widely in individual patients. With continued treatment, dyskinesias may develop at a dose of levodopa that was previously well tolerated. They occur more commonly in patients treated with levodopa in combination with carbidopa or with other dopamine receptor agonists. Apomorphine, via subcutaneous injection, is used for temporary relief of off-periods of akinesia (rescue) in parkinsonian patients on dopaminergic drug therapy. Pretreatment with the antiemetic trimethobenzamide for 3 days is essential to prevent severe nausea. The non-ergot dopamine agonists (pramipexole, ropinirole) are sometimes used prior to levodopa in mild parkinsonism. The mydriatic action of levodopa may increase intraocular pressure; the drug should be used cautiously in patients with open-angle glaucoma and is contraindicated in those with angle-closure glaucoma. Antimuscarinic drugs may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. Drugs that are partly ameliorative include agents that deplete dopamine (eg, tetrabenazine) or that block dopamine receptors (eg, haloperidol). Pramipexole is a non-ergot agonist at dopamine receptors and has greater selectivity for D3 receptors in the striatum. Pramipexole (or the D2 receptor agonist ropinirole) is often chosen for monotherapy of mild parkinsonism, and these drugs sometimes have value in patients who have become refractory to levodopa. Adverse effects of these drugs include dyskinesias, postural hypotension, and somnolence. Increased activation of adrenoceptors has been implicated in essential tremor, and management commonly involves administration of propranolol. However, the more selective 1 blocker metoprolol may be equally effective and is more suitable in a patient with pulmonary disease. Adverse effects referable to activation of peripheral dopamine (or beta adrenoceptors in the case of levodopa) include postural hypotension, tachycardia (possible arrhythmias), mydriasis, and emetic responses. Adverse effects referable to antagonism of peripheral muscarinic receptors include dry mouth, mydriasis, urinary retention, and tachycardia. Identify the mechanisms by which levodopa, dopamine receptor agonists, selegiline, tolcapone, and muscarinic blocking drugs alleviate parkinsonism. Antipsychotic Agents & Lithium the antipsychotic drugs are used in schizophrenia and are also effective in the treatment of other psychoses and agitated states. The efficacy of these drugs has led to several hypotheses linking specific transmitter disorders to the etiology of schizophrenia. Older (first generation) drugs have high affinity for dopamine D2 receptors, thus an early hypothesis postulated a disorder of dopamine transmission as a primary factor. Unfortunately, protracted therapy (years) is often needed and can result in severe toxicity in some patients. Bipolar disorder (formerly called manic-depressive disorder) may be related to schizoaffective disorder on a continuum. In bipolar affective disorder, although lithium has been the mainstay of treatment for many years, the use of newer antipsychotic agents and of several antiseizure drugs is increasing. Classification the first generation antipsychotic drugs constitute several chemical subgroups including the phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine), the thioxanthenes (eg, thiothixene), and the butyrophenones (eg, haloperidol). The established second generation drugs have varied heterocyclic structures and include clozapine, loxapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Some very recently approved second generation agents are listed in the Drug Summary table. In some patients, these atypical antipsychotic drugs may be somewhat more effective and are often less toxic than the older drugs. These drugs require metabolism by liver enzymes before elimination and have long plasma halflives that permit once-daily dosing. In some cases, other drugs that inhibit cytochrome P450 enzymes can prolong the half-lives of antipsychotic agents. Parenteral forms of some agents (eg, fluphenazine, haloperidol, ziprasidone, olanzapine, and aripiprazole) are available for rapid initiation of therapy, use in uncooperative patients, or depot treatment. Dopamine hypothesis-The dopamine hypothesis of schizophrenia proposes that the disorder is caused by a relative excess of functional activity of the neurotransmitter dopamine in specific neuronal tracts in the brain. First, many antipsychotic drugs block brain dopamine receptors (especially D2 receptors). Second, dopamine agonist drugs (eg, amphetamine, levodopa) exacerbate schizophrenia. Third, an increased density of dopamine receptors has been detected in certain brain regions of untreated schizophrenics. The dopamine hypothesis of schizophrenia is not fully satisfactory because antipsychotic drugs are only partly effective in most patients and many effective drugs have a higher affinity for other receptors, than for D2 receptors. The D2 receptor, found in the caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus, is negatively coupled to adenylyl cyclase. The therapeutic efficacy of the older antipsychotic drugs correlates with their relative affinity for the D2 receptor. Unfortunately, there is also a correlation between blockade of D2 receptors and extrapyramidal dysfunction. Other receptors-Most of the second generation (atypical) antipsychotic agents have higher affinities for other receptors than for the D2 receptor. The receptor-binding characteristics of the newer antipsychotic drugs have led to a serotonin hypothesis as an alternative to the dopamine hypothesis of the nature of schizophrenia. Most of the atypical drugs cause less extrapyramidal dysfunction than the first generation agents. With the exception of haloperidol, all antipsychotic drugs block H1 receptors to some degree. Dopaminergic tracts in the brain include the mesocorticalmesolimbic pathways (regulating mentation and mood), nigrostriatal tract (extrapyramidal function), tuberoinfundibular pathways (control of prolactin release), and chemoreceptor trigger zone (emesis). Mesocortical-mesolimbic dopamine receptor blockade presumably underlies antipsychotic effects, and a similar action on the chemoreceptor trigger zone leads to the useful antiemetic properties of some antipsychotic drugs. Adverse effects resulting from receptor blockade in the other dopaminergic tracts, a major problem with first generation drugs, include extrapyramidal dysfunction and hyperprolactinemia (see later discussion). Note that almost all antipsychotic agents block both 1 and histamine H1 receptors to some extent. Treatment of schizophrenia-Antipsychotic drugs reduce some of the positive symptoms of schizophrenia, including hyperactivity, bizarre ideation, hallucinations, and delusions. Consequently, they can facilitate functioning in both inpatient and outpatient environments. Overall efficacy of the antipsychotic drugs is, for the most part, equivalent in terms of the management of the floridly psychotic forms of the illness, although individual patients may respond best to a specific drug. However, clozapine is effective in some schizophrenic patients resistant to treatment with other antipsychotic drugs. First generation drugs are still commonly used, partly because of their low cost compared with newer agents. However, none of the traditional drugs has much effect on negative symptoms of schizophrenia. Newer atypical drugs are reported to improve some of the negative symptoms of schizophrenia, including emotional blunting, social withdrawal, and lack of motivation. Other psychiatric and neurologic indications-The newer antipsychotic drugs are often used with lithium in the initial treatment of mania. Several second-generation drugs (as well as benzodiazepines) are approved for treatment of acute mania; two of these (aripiprazole and olanzapine) are also approved for maintenance prevention of the manic phase of bipolar disorder. Several are also approved for the prevention of bipolar depression (quetiapine, lurasidone, olanzapine). Molindone is used mainly in Tourette syndrome; it is rarely used in schizophrenia. Nonpsychiatric indications-With the exception of thioridazine, most phenothiazines have antiemetic actions; prochlorperazine is promoted solely for this indication. H1-receptor blockade, most often present in short side-chain phenothiazines, provides the basis for their use as antipruritics and sedatives and contributes to their antiemetic effects. This toxicity may be reversed by a decrease in dose and may be antagonized by concomitant use of muscarinic blocking agents. Extrapyramidal toxicity occurs most frequently with haloperidol and the more potent piperazine side-chain phenothiazines (eg, fluphenazine, trifluoperazine). Parkinsonism occurs infrequently with clozapine and is much less common with the other second generation drugs than with first generation agents. Other reversible neurologic dysfunctions that occur more frequently with older agents include akathisia and dystonias; these usually respond to treatment with diphenhydramine or muscarinic blocking agents. Tardive dyskinesias-This important toxicity includes choreoathetoid movements of the muscles of the lips and buccal cavity and may be irreversible. Tardive dyskinesias tend to develop after several years of antipsychotic drug therapy but have appeared as early as 6 months. Antimuscarinic drugs that usually ameliorate other extrapyramidal effects generally increase the severity of tardive dyskinesia symptoms. There is no effective approved drug treatment for tardive dyskinesia although some investigational drugs appear promising (deutetrabenazine and valbenazine, see Chapter 28). Tardive dyskinesia may be attenuated temporarily by increasing neuroleptic dosage; this suggests that tardive dyskinesia may be caused by dopamine receptor sensitization. Autonomic effects-Autonomic effects result from blockade of peripheral muscarinic receptors and adrenoceptors and are more difficult to manage in elderly patients. Of the older antipsychotic agents, thioridazine has the strongest autonomic effects and haloperidol the weakest. Clozapine and most of the other atypical drugs have intermediate autonomic effects. Atropine-like effects (dry mouth, constipation, urinary retention, and visual problems) are often pronounced with the use of thioridazine and phenothiazines with aliphatic side chains (eg, chlorpromazine). These effects also occur with clozapine and most of the atypical drugs but not with ziprasidone or aripiprazole. Postural hypotension caused by blockade is a common manifestation of many of the older drugs, especially phenothiazines. In the elderly, measures must be taken to avoid falls resulting from postural fainting. The atypical drugs, especially clozapine and ziprasidone, also block receptors and can cause orthostatic hypotension. Endocrine and metabolic effects-Endocrine and metabolic effects include hyperprolactinemia, gynecomastia, the amenorrhea-galactorrhea syndrome, and infertility. Most of these adverse effects are predictable manifestations of dopamine D2 receptor blockade in the pituitary; dopamine is the normal inhibitory regulator of prolactin secretion. Significant weight gain and hyperglycemia due to a diabetogenic action occur with several of the second generation agents, especially clozapine and olanzapine. Aripiprazole and ziprasidone have little or no tendency to cause hyperglycemia, hyperprolactinemia, or weight gain. Neuroleptic malignant syndrome-Patients who are particularly sensitive to the extrapyramidal effects of antipsychotic drugs may develop a malignant hyperthermic syndrome. The symptoms include muscle rigidity, impairment of sweating, hyperpyrexia, and autonomic instability, which may be life threatening.

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Unstable angina is defined as new-onset angina symptoms 3 days dpo order keppra 250 mg on-line, angina at rest or angina after a heart attack symptoms stiff neck buy discount keppra 250 mg on-line. Heart attack or myocardial infarction When a plaque ruptures it can result in a blood clot forming around the site of rupture and this can partially or completely block the coronary artery symptoms thyroid cancer order 500 mg keppra free shipping. The section of heart muscle supplied by the artery is deprived of sufficient blood and oxygen and is said to be ischaemic treatment anal fissure cheap keppra 250 mg line. If the blood supply is not restored quickly alternative medicine buy discount keppra 250mg on-line, the myocardial muscle cells die treatment quadricep strain cheap 250 mg keppra free shipping, forming an infarct (area of dead tissue). The extent of the damage to the heart depends on the size and location of the artery that has been occluded. A large clot can block a large artery, which cuts off blood to a significant section of the heart muscle causing a major heart attack. Blood clot B is smaller, blocks a minor artery and affects a smaller area of tissue. Sometimes the ischaemic tissue can be rescued by collateral circulation, the blood supply from adjacent, unaffected arteries, keeping the tissue alive until the paramedics arrive. The brain fails to identify the precise source of the problem so that pain is perceived as emanating from a different area to the source. Heart failure the consequences of a heart attack can vary depending on the location of the thrombus, the area of heart tissue affected and most importantly, the time it takes for the paramedics to arrive. This is a complex process where the heart becomes more and more weakened as it attempts to maintain blood pressure and eventually becomes irreparably damaged, leading to complete failure and death. With more blood returning to the heart, end-diastolic volume is elevated which stretches the heart muscle, resulting in an increase in the force of contraction via the Frank-Starling law. Put simply, this law states that the more the heart muscle is stretched the more forcefully it contracts. This is fine for the healthy heart where an increase in contractility and stroke volume during exercise is necessary and beneficial. Ultimately, in heart failure, the constant over-stretching of the heart muscle not only fails to increase stroke volume, but also causes further damage. There is no effective treatment for heart failure and while medication may help, the prognosis for patients is not good. As these surgical procedures are common, it is worth outlining them to contextualise the drugs we shall shortly be describing. Here, a small balloon on the end of the catheter is expanded to open up the blocked artery. A small metal cage called a stent is often attached to the end of the catheter and as the balloon expands so does the stent, holding open the artery and allowing blood to flow freely. Drug-eluting stents have a drug such as paclitaxel incorporated into the stent that prevents the re-growth of surrounding tissue. The principal purpose of anti-angina drugs is to relieve the pain associated with the disease rather than treating the disease itself. The full treatment regime for anyone suffering from stable angina will include lifestyle changes such as giving up smoking, taking controlled exercise and eating a healthy diet that includes more fruit and vegetables, less saturated fat and less refined sugar. To reduce the rate at which atherosclerosis develops, statins such as atorvastatin may be prescribed to lower cholesterol levels in the blood. Angina sufferers also run the risk of clots forming in the coronary arteries, so aspirin may be prescribed on a long-term basis to prevent this. Several types of drugs are available to reduce angina pain and these include nitrates, beta-blockers and calcium channel blockers. The general aim of these drugs is to reduce the workload of the heart or dilate the coronary arteries, so delivering more oxygenated blood to the heart muscle. In this section of the chapter we will concentrate on the action of nitrates and beta-blockers and leave any detailed discussion of the calcium channel blockers until Chapter 5, when we examine their role as antihypertensive drugs. It is available as tablets or as a spray, both of which are used under the tongue from where the drug speedily enters the bloodstream and quickly relieves angina pain. The action of nitrates on cells is complex but their main effect is to release nitric oxide, a potent vasodilator that causes relaxation of the smooth muscle cells surrounding blood vessels and so produces vasodilation. Venodilation (dilation of the veins) reduces pressure in the veins which in turn reduces the amount of blood returning to the heart. Less blood in the ventricles when they are contracting reduces the workload of the heart. Vasodilation of coronary arteries increases blood flow to the heart muscle, bringing with it more oxygen. Vasodilation of arteries and larger arterioles lowers blood pressure lowers blood pressure and reduces the amount of effort needed by the heart to pump blood out of the ventricles. Nitrate tolerance can be a problem with these drugs as their effectiveness diminishes with long-term use. Nitric oxide has many complex regulatory actions in the body including vasodilation and the inhibition of platelet aggregation. This results in relaxation of the muscle cell and vasodilation of the blood vessel. They have been in the pharmacopoeia for over 40 years and earned their inventor, Sir James Black, the Nobel Prize for Medicine in 1989 for the synthesis of propranolol. Examples of this group used in the treatment of angina include acebutolol, atenolol, bisoprolol, carvedilol, metoprolol, nadolol, oxprenolol, pindolol, propranolol and timolol. Selected members of this group of drugs are also used for hypertension and arrhythmias and heart failure. The sympathetic neurons release the neurotransmitter noradrenaline and this stimulates 1 adrenoceptors on the heart pacemaker cells and the heart muscle. This increases both the heart rate and contractility which in turn increases the workload of the heart and so the probability of angina-induced pain. Beta-blockers also reduce blood pressure by a complex mechanism that is by no means fully understood (see Chapter 5). This is because these drugs can block 2 adrenaline receptors in the bronchioles of the lungs and these receptors are the targets for bronchodilators such as salbutamol. If they are blocked by beta-blockers, then salbutamol cannot bind and activate its receptors, which could be potentially very serious for anyone having an asthma attack. We will meet them again in Chapter 5 when we discuss antihypertensive drugs, and we will examine in more detail how they reduce blood pressure. Slowing the heart rate reduces the workload of the heart and helps to ease angina pain. Nicorandil also dilates the coronary arteries thus increasing blood and oxygen supply to the myocardium. This means that even with partially blocked coronary arteries, sufficient oxygenated blood can be supplied to the myocardium to prevent the muscle cells producing the lactic acid that causes angina pain. The drug may also shift energy production in the heart away from lipids towards more efficient carbohydrate metabolism. This reduces pressure in the arteries, veins and ventricles and so reduces the workload of the heart. The coronary arteries are also dilated, supplying more blood and oxygen to the heart muscle. Beta-blockers such as atenolol block the effects of sympathetic stimulation on the heart, helping to reduce its workload. Miscellaneous anti-angina drugs include potassium channel openers such as nicorandil, funny channel blockers such as ivabradine and drugs that affect Na+ and Ca2+ balance such as ranolazine. Lipid-regulating drugs the regulation of lipid metabolism Cholesterol is a major constituent of the atherosclerotic plaques that develop in the coronary arteries. It is a lipid that is obtained from animal fats in the diet but can also be synthesised in the liver. Bile is the alkaline, detergentlike substance produced by the liver and secreted into the duodenum via the bile duct. Cholesterol is transported in the blood in small water-soluble spheres called lipoproteins. Being a lipid, cholesterol will not mix readily with blood which is watery in nature. In the centre of a lipoprotein sphere, however, the cholesterol is olated from the blood by the hydrophilic phospholipid shell. The density of the two lipoproteins refers to the relative amounts of protein in the spheres but essentially it is the different roles that interest us. In reality, patients often find it difficult to change their lifestyle and for those at high risk from cardiovascular disease, pharmacological intervention can help to regulate cholesterol levels. Molarity is the number of moles per litre of solution and 1 mole of a substance dissolved in 1 litre of water would be a 1 molar solution. The mole represents rather a lot of atoms so in biological chemistry you will generally find the millimole (mmol) rather than the mole. Put simply, the greater the molarity, the more of a substance there is in a solution. Drugs used to lower lipids: statins the most commonly prescribed drugs used to lower serum cholesterol for the prevention and management of cardiovascular disease are statins. There are a few other drugs such as anion-exchange resins and fibrates but statins are by far the most popular. Examples of this group include atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin. You might think that simply cutting down on fats in the diet would reduce cholesterol levels sufficiently but unfortunately, when cholesterol intake is reduced, the body can respond by manufacturing One mole cholesterol in the liver. This can result in elevated serum cholesterol despite a reduction in dietary intake. Remember that cholesterol is a useful substance as well as a potentially harmful one so when levels fall then the body responds by making more of it. This enzyme takes part in a reaction in the pathway that produces cholesterol in the hepatocytes (liver cells). Bile is the alkaline, detergent-like substance produced by the liver and secreted into the duodenum via the bile duct. A healthy diet, not smoking and taking plenty of exercise helps regulate cholesterol levels. When someone gets injured it is important that blood loss is minimised otherwise they may eventually lose so much blood that they go into shock, a state where blood pressure falls to the point where tissues are not supplied with sufficient oxygen. Animals have consequently evolved a mechanism that responds to injury involving damage to blood vessels by converting the blood in the area of damage from its normal fluid form into a solid clot. Having dealt with the immediate emergency, further mechanisms are then initiated by the body to make more permanent repairs to the injured area in a process called wound resolution. Saliva contains an enzyme called lysozyme that attacks and destroys bacteria and so prevents your injury becoming infected. In most situations, clotting is a desirable process that prevents the loss of blood from a wound but in the case of the formation of a clot in the blood vessels, this can result in serious consequences such as heart attacks, strokes and pulmonary embolisms. In this article we will examine the process more closely and find out what drugs there are available to prevent unwanted blood clots forming in the arteries and veins. If the thrombus detaches from the site where it forms and travels in the bloodstream it becomes known as an embolus. Eventually the embolised thrombus may lodge in an organ such as the lungs resulting in a thromboembolism. The platelets are small cell fragments that have the ability to bind to fibrin, a filament-like protein which then forms a web-like structure that traps red blood cells and forms a clot. Without them a clot will not form (a fact exploited by the many antiplatelet drugs). The conversion of fibrinogen into fibrin is the process targeted by anticlotting drugs. Around 300 million are found in each millilitre of blood with an average life of around ten days. Platelets are generally inactive as they circulate in the blood until they come into contact with proteins such as collagen in the wall of a damaged blood vessel. Thromboxane A2 is a mediator of the same family that plays a key role in inflammation (see Chapter 6). It is produced in the platelet via a short biochemical pathway with an intermediate reaction catalysed by the enzyme cyclo-oxygenase 1. On the floor are lots of skipping ropes (fibrin) and when the teacher blows a whistle all the children take their hands out of their pockets and grab hold of any two skipping ropes forming a kind of net. Hold onto this scenario as we will return to it later when discussing antiplatelet drugs.

However symptoms heart attack women order keppra on line amex, the primary mechanism of resistance to aminoglycosides medicine ball core exercises order keppra from india, especially in Gram-negative bacteria symptoms 2016 flu buy keppra 250mg with mastercard, involves the plasmidmediated formation of inactivating enzymes symptoms 0f a mini stroke buy keppra 500 mg. These enzymes are group transferases that catalyze the acetylation of amine functions and the transfer of phosphoryl or adenylyl groups to the oxygen atoms of hydroxyl groups on the aminoglycoside medications when pregnant keppra 250 mg cheap. For example medicine 2020 cheap keppra express, transferases produced by enterococci can inactivate amikacin, gentamicin, and tobramycin but not streptomycin. However, amikacin is often resistant to many enzymes that inactivate gentamicin and tobramycin. In addition, resistance to streptomycin, which is common, appears to be due to changes in the ribosomal binding site. They are polar compounds, not absorbed after oral administration, and must be given intramuscularly or intravenously for systemic effect. They have limited tissue penetration and do not readily cross the blood-brain barrier. Glomerular filtration is the major mode of excretion, and plasma levels of these drugs are greatly affected by changes in renal function. Dosage adjustments must be made in renal insufficiency to prevent toxic accumulation. Gentamicin, tobramycin, and amikacin are important drugs for the treatment of serious infections caused by aerobic Gram-negative bacteria, including Escherichia coli and Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, and Serratia species. These aminoglycosides also have activity against strains of Haemophilus influenzae, Moraxella catarrhalis, and Shigella species, although they are not drugs of choice for infections caused by these organisms. In most cases, aminoglycosides are used in combination with a beta-lactam antibiotic. When used alone, aminoglycosides are not reliably effective in the treatment of infections caused by Gram-positive cocci. Antibacterial synergy may occur when aminoglycosides are used in combination with cell wall synthesis inhibitors. Examples include their combined use with penicillins in the treatment of pseudomonal, listerial, and enterococcal infections. Streptomycin in combination with penicillins is often more effective in enterococcal carditis than regimens that include other aminoglycosides. This combination is also used in the treatment of tuberculosis, plague, and tularemia. Multidrug-resistant strains of Mycobacterium tuberculosis that are resistant to streptomycin may be susceptible to amikacin. Because of the risk of ototoxicity, streptomycin should not be used when other drugs will serve. Owing to their toxic potential, neomycin and kanamycin are usually restricted to topical or oral use (eg, to eliminate bowel flora). Netilmicin has been used for treatment of serious infections caused by organisms resistant to the other aminoglycosides. Its sole use is as a backup drug, administered intramuscularly as a single dose for the treatment of gonorrhea, most commonly in patients allergic to beta-lactams. Ototoxicity Auditory or vestibular damage (or both) may occur with any aminoglycoside and may be irreversible. Auditory impairment is more likely with amikacin and kanamycin; vestibular dysfunction is more likely with gentamicin and tobramycin. Ototoxicity risk is proportional to the plasma levels and thus is especially high if dosage is not appropriately modified in a patient with renal dysfunction. Because ototoxicity has been reported after fetal exposure, the aminoglycosides are contraindicated in pregnancy unless their potential benefits are judged to outweigh risk. This adverse effect, which is often reversible, is more common in elderly patients and in those concurrently receiving amphotericin B, cephalosporins, or vancomycin. Neuromuscular Blockade Though rare, a curare-like block may occur at high doses of aminoglycosides and may result in respiratory paralysis. It is usually reversible by treatment with calcium and neostigmine, but ventilatory support may be required. Skin Reactions Allergic skin reactions may occur in patients, and contact dermatitis may occur in personnel handling the drug. Which of the following statements about the clinical uses of the aminoglycosides is accurate Which statement is accurate regarding the antibacterial action of the aminoglycoside amikacin An adult patient (weight 80 kg) has bacteremia suspected to be due to a Gram-negative rod. Tobramycin is to be administered using a once-daily dosing regimen, and the loading dose must be calculated to achieve a peak plasma level of 20 mg/L. A 76-year-old man is seen in a hospital emergency department complaining of pain in and behind the right ear. Physical examination shows edema of the external otic canal with purulent exudate and weakness of the muscles on the right side of the face. Gram stain of the exudate from the ear shows many polymorphonucleocytes and Gram-negative rods, and samples are sent to the microbiology laboratory for culture and drug susceptibility testing. A 72-kg patient with creatinine clearance of 80 mL/min has a Gram-negative infection. Amikacin is administered intramuscularly at a dose of 5 mg/kg every 8 h, and the patient begins to respond. Assuming that no information is available about amikacin plasma levels, what would be the most reasonable approach to management of the patient at this point This drug has characteristics almost identical to those of gentamicin but has much weaker activity in combination with penicillin against enterococci. The most appropriate drug to use is (A) Azithromycin (B) Cefixime (C) Ceftriaxone (D) Ciprofloxacin (E) Doxycycline 10. Aminoglycosides are bactericidal inhibitors of protein synthesis binding to specific components of the 30S ribosomal subunit. Their actions include block of the formation of the initiation complex, miscoding, and polysomal breakup. In this case, the patient seems to be improving, so a decrease of the amikacin dose in proportion to decreased creatinine clearance is most appropriate. Because creatinine clearance is only one half of the starting value, a dose reduction should be made to one half of that given initially. Aminoglycoside antibiotics act at the ribosomal level and their intracellular accumulation by bacteria is oxygen dependent. The antibacterial action of aminoglycosides is concentration dependent rather than time dependent. Inhibitors of bacterial cell wall synthesis often exert synergistic effects with aminoglycosides, possibly by increasing the intracellular accumulation of the aminoglycoside. The loading dose of any drug is calculated by multiplying the desired plasma concentration (mg/L) by the volume of distribution (L). The diabetic patient with external otitis is at special risk because of the danger of spread to the middle ear and possibly the meninges, so hospitalization is advisable, especially in the elderly. Likely pathogens include E coli and Pseudomonas aeruginosa, and coverage must be provided for these and possibly other Gram-negative rods. The combination of an aminoglycoside plus a wider-spectrum penicillin is most suitable in this case and is synergistic against many pseudomonas strains. Imipenem-cilastatin is also possible, but resistant strains of P aeruginosa have emerged during treatment. The incidence of nephrotoxic effects with gentamicin is 2 to 3 times greater than the incidence of ototoxicity. With traditional dosage regimens, the first indication of potential nephrotoxicity is an increase in trough serum levels of aminoglycosides, which is followed by an increase in blood creatinine. Although aminoglycoside ototoxicity usually involves irreversible effects on vestibular function, hearing loss can also occur. Tobramycin is almost identical to gentamicin in both its pharmacodynamic and pharmacokinetic properties. However, for reasons that are unclear, it is much less active than either gentamicin or streptomycin when used in combination with a penicillin in the treatment of enterococcal endocarditis. Cephalosporins should be avoided in patients with a history of severe hypersensitivity to penicillins, and fluoroquinolones (see Chapter 46) should be avoided in pregnancy. Tetracyclines including doxycycline have been used in the past for gonorrhea, but not as single doses, and they too should be avoided in pregnancy. In "once-daily dosing" with aminoglycosides, the selection of an appropriate dose is particularly critical in patients with renal insufficiency. The aminoglycosides are eliminated by the kidney in proportion to creatinine clearance. List the major clinical applications of aminoglycosides and identify their 2 main Describe aminoglycoside pharmacokinetic characteristics with reference to their renal clearance and potential toxicity. Understand time-dependent and concentration-dependent killing actions of antibiotics and what is meant by postantibiotic effect. Sulfonamides continue to be used selectively as individual antimicrobial agents, although resistance is common. The combination of a sulfonamide with trimethoprim causes a sequential blockade of folic acid synthesis. This results in a synergistic action against a wide spectrum of microorganisms; resistance occurs but has been relatively slow in development. Resistance has emerged to the older antibiotics in this class, but has been offset to some extent by the introduction of newer fluoroquinolones with expanded activity against common pathogenic organisms. Classification and Pharmacokinetics the antifolate drugs used in the treatment of infectious diseases are the sulfonamides, which inhibit dihydropteroate synthase, a microbial enzyme involved in folic acid synthesis, and trimethoprim, a selective inhibitor of dihydrofolate reductase. Members of this group differ mainly in their pharmacokinetic properties and clinical uses. Pharmacokinetic features include modest tissue penetration, hepatic metabolism, and excretion of both intact drug and acetylated metabolites in the urine. Because of the solubility limitation, a combination of 3 separate sulfonamides (triple sulfa) has been used to reduce the likelihood that any one drug will precipitate. The sulfonamides may be classified as short-acting (eg, sulfisoxazole), intermediate-acting (eg, sulfamethoxazole), and long-acting (eg, sulfadoxine). Sulfonamides bind to plasma proteins at sites shared by bilirubin and by other drugs. It is a weak base and is trapped in acidic environments, reaching high concentrations in prostatic and vaginal fluids. Sulfonamides-The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. They can also act as substrates for this enzyme, resulting in the synthesis of nonfunctional forms of folic acid. Resistance Bacterial resistance to sulfonamides is common and may be plasmid-mediated. Clinical resistance to trimethoprim most commonly results from the production of dihydrofolate reductase that has a reduced affinity for the drug. Sulfonamides-The sulfonamides are active against Grampositive and Gram-negative organisms, Chlamydia, and Nocardia. Specific members of the sulfonamide group are used by the following routes for the conditions indicated: a. Toxoplasmosis-Oral sulfadiazine plus pyrimethamine (a dihydrofolate reductase inhibitor) plus folinic acid. Inhibition of 2 successive steps in the formation of tetrahydrofolic acid constitutes sequential blockade and results in antibacterial synergy. An intravenous formulation is available for patients unable to take the drug by mouth and is used for treatment of severe pneumocystis pneumonia and for Gram-negative sepsis. Hypersensitivity-Allergic reactions, including skin rashes and fever, occur commonly. Cross-allergenicity between the individual sulfonamides should be assumed and may also occur with chemically related drugs (eg, oral hypoglycemics, thiazides). Exfoliative dermatitis, polyarteritis nodosa, and Stevens-Johnson syndrome have occurred rarely. Hematotoxicity-Although such effects are rare, sulfonamides can cause granulocytopenia, thrombocytopenia, and aplastic anemia. Acute hemolysis may occur in persons with glucose-6-phosphate dehydrogenase deficiency. Nephrotoxicity-Sulfonamides may precipitate in the urine at acidic pH, causing crystalluria and hematuria. Drug interactions-Competition with warfarin and methotrexate for plasma protein binding transiently increases the plasma levels of these drugs. Sulfonamides can displace bilirubin from plasma proteins, with the risk of kernicterus in the neonate if used in the third trimester of pregnancy. Toxicity of Trimethoprim Trimethoprim can cause the predictable adverse effects of an antifolate drug, including megaloblastic anemia, leukopenia, and granulocytopenia. Pharmacokinetics All the fluoroquinolones have good oral bioavailability (antacids containing multivalent cations may interfere) and penetrate most body tissues. However, norfloxacin does not achieve adequate plasma levels for use in most systemic infections.

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