By Y. Goran. Westminster College, Salt Lake City.

Various techniques are being developed for producing arrays purchase baclofen with visa, and robot- controlled discount baclofen 10 mg with visa, pin-based or inkjet printing heads are the preferred tools for manufactur- ing protein arrays order genuine baclofen online. The emerg- ing future array systems will be used for high-throughput functional annotation of gene products cheap 10 mg baclofen with visa, their involvements in molecular pathways, and their response to medical treatment and become the physician’s indispensable diagnostics tools. Protein Biochips/Microarrays for Personalized Medicine Protein biochips/microarrays are well-established tools for research and some prod- ucts for in vitro diagnostics are available commercially. Profiling proteins on bio- chips will be useful for distinguishing the proteins of normal cells from early-stage cancer cells, and from malignant metastatic cancer cells. Of all the applications of protein microarrays, molecular diagnos- tics is most clinically relevant and would fit in with the coming trend in individual- ized treatment. Universal Free E-Book Store 56 2 Molecular Diagnostics in Personalized Medicine For example, different proteins such as antibodies, antigens, and enzymes can be immobilized within protein biochips. Protein microarrays are reliable tools for detec- tion of multiple biomarkers with only a minimal quantity of sample and have enor- mous potential in applications for personalized medicine (Yu et al. Microfluidics Microfluidics is the special behavior of fluids flowing in channels the size of a human hair. Fluids in this environment show very different properties than in the macro world. This new field of technology was enabled by advances in microfabrication – the etching of silicon to create very small features. Microfluidics allows the reduction in size with a corresponding increase in the throughput of handling, processing and analyzing the sample. Other advantages of microfluidics include increased reaction rates, enhanced detection sensitivity and control of adverse events. Applications of microfluidics, in relation to molecular diagnostics, include the following: • Genomic analyses • Protein analysis • Gene expression and differential display analysis Several commercial microfluidic technologies are available and a few examples are described in the following text. Moreover, the chip test is performed within hours whereas the conventional protocol required days. The rapid detection of chromosomal mutations will increase a physician’s ability to personalize treatment strategies to target indi- vidual cancers. An important limiting factor has been the difficulty of establishing molecular assays suitable for microfab- ricated formats. The power of the lab-on-a-chip concept lies primarily in its ability to detect and manipulate at the cellular and molecular level with sufficiently high throughputs. With careful design and scaling considerations, molecular and cellular detectors (or biosensors) facilitated by controlled microfluidic separation, purification, sorting, and mixing operations are more sensitive and specific. For proteins, an acoustic cavity mixer enables an order of magnitude increase in speed of detection 3. A novel microfluidic device based on dielectrophoresis enables the detection and sorting of biological cells based on their dielectric properties. LabChip Lab-on-a-chip (PerkinElmer’s LabChip), a miniaturized and integrated liquid han- dling and biochemical-processing device, is used for computer-aided analytical laboratory procedures that can be performed automatically in seconds. This as well as the Agilent 2100 bioanalyzer is being developed in collaboration with Agilent Technologies to integrate time-consuming and costly laboratory experiments onto a miniature chip. PerkinElmer’s genotyping system is designed to integrate each stage of the com- plete experiment in a volume of 1 nanoliter, a scale 10,000 to 100,000-fold smaller than currently used technology. Fluid is moved along these pathways by capillary action and centrifugal forces generated by disc rotation, allowing the processing of many different assay types. The combination of informatics, bioassays and minia- turization are what make this “laboratory on a disc” truly revolutionary. For instance, physicians will be able to run tests for multiple strains of hepatitis all at the same time, instead of ordering them separately. The ability to identify the strain of a virus can have profound implica- tions for clinical therapy. These studies provide an opportunities to explore pathomechanism of human diseases that are unbiased by previous hypotheses or assumptions about the nature of genes that influence complex diseases. Many genetic variants identified as risk factors for dis- eases by such studies have been localized to previously unsuspected pathways, to genes without a known function. In the absence of functional information about which polymorphisms are bio- logically significant, it is desirable to test the potential effect of all polymorphisms on drug response. Genotyping and Haplotyping A genotype is the genetic constitution of an organism as defined by genetic and molecular analysis and covers the complete set of genes. Genotyping can be used for determination of relevant genetic variation in each of the two parental chromosomes in an individual. Haplotypes are gene versions that represent the genetic variations as they occur on each pair of chromosome in an individual. Haplotypes are the most precise markers possible for a given gene because they contain all the variations in a gene. Haplotyping information makes it possible to highlight the structure of the genome, notably through haploblocks which correspond to segments of chromosomes unlikely to undergo a crossing-over event. Candidate gene-based haplotype approach has been applied to the pharmacoge- netics of drug response and adverse events. Clinical trials using haplotyped indi- viduals were the first genetically personalized medical treatments. Only two genomes were completely haplotyped: the reference human genome and Craig Venter’s genome, both of which relied on Sanger sequencing and clone mapping to resolve the haplotypes, which is a labor-intensive and costly process. Although the newer sequencing technologies enabled cost reductions and higher throughput, the shorter reads are not amenable to obtaining haplotype information, which will be critical in the fields of personalized medicine and population genetics. The first method was used to determine the haplotype-resolved genome of a South Asian individual (Kitzman et al. A single fosmid library was split into a modest number of pools, each providing ∼3 % physical coverage of the diploid genome. Sequencing of each pool yielded reads overwhelmingly derived from only one homologous chromosome at any given location. This method also facilitates the analysis of structural variation, for example, to anchor novel insertions to specific locations and haplotypes. The second method used a microfluidic device capable of separating and ampli- fying homologous copies of each chromosome from a single human metaphase cell (Fan et al. This approach has potential applications in personal genomics, single-cell genomics and statistical genetics. A method has been described for rapid and cost-effective long-range haplotyping (Kaper et al. Therefore, this strategy is suitable for haplotyping of a set of targeted regions as well as of the entire genome. The authors applied this method to determine allele-specific methylation patterns in a human genome and identify hundreds of differentially methylated regions that were previously unknown. Tools that facilitate access to phase information will lay the foundation for further advances throughout genomics and contribute to the development of personalized medicine. This model provides a powerful tool for elucidating the genetic variants of drug response and ultimately designing personalized medications based on each patient’s genetic constitution. These are described in more detail elsewhere (Jain 2015a) but some are described briefly in the text following Table 2. Desirable characteristics of a genotyping technology are: (1) robust performance and accuracy across a variety of circumstances; (2) high-throughput performance; and (3) low cost. The amplified fragments are then attached by one strand to a solid surface and the non-immobilized strands are removed by standard denaturation and washing. Genotyping of the individual samples shows that the average margin of error in frequency estimate is ~4 % when pools are used. These findings clearly demonstrate the potential of pooling techniques and their associated technologies as an initial screen in the search for genetic associations. BeadArray Technology BeadArray technology (Illumina) combines fiber optic bundles and specially pre- pared beads that self-assemble into an array. Each fiber optic bundle contains thousands to millions of individual fibers depending on the diameter of the bundle. Universal Free E-Book Store 64 2 Molecular Diagnostics in Personalized Medicine In a separate process, biosensors are created by affixing a specific type of molecule to each of the billions of microscopic beads in a given batch. Several conventional methods are then used, including fluorescence, optical density, electrophoresis and mass spectros- copy, to detect this single base extension. This technology allows researchers to perform “multiplex” assays (the ability to run assays that determine the presence or absence of multiple genetic mutations at the same time and on the same chip).

At first the knowledge of healing was regarded as a part of wisdom cheap 25mg baclofen amex,6 so that both the treatment of diseases and the study of natural things came into being under the same authorities purchase baclofen 10mg free shipping, (7) clearly because those who most required it [i purchase cheap baclofen on-line. For this reason purchase baclofen from india, as we hear, many of those who claimed expertise in wisdom were experienced in it [i. He presents Diocles, Praxagoras and Chrysippus, as well as Herophilus and Erasistratus, as men who exercised the art to such an extent that they developed different ways of healing, and he points out that ‘also, in the same period’ a divison of medicine took place into regimen, pharmacology, and surgery: Post quem Diocles Carystius, deinde Praxagoras et Chrysippus, tum Herophilus et Erasistratus, sic artem hanc exercuerunt ut etiam in diuersas curandi uias pro- cesserint. Primam diaithtikžn, secundam farmakeutikžn, tertiam ceirourg©an Graeci nomi- narunt. After him Diocles of Carystus, and later Praxagoras and Chrysippus, and then Herophilus and Erasistratus practised the art in such a way that they even pro- ceeded into diverse modes of treatment. However, Celsus then seems to suggest that within dietetics (eius autem quae uictu morbos curat) a renewed interest in theoretical speculation took place: for he says that there were ‘famous authorities’ who, out of a desire for deeper understanding, claimed that for this purpose knowledge of nature was indispensable, because without it medicine was truncated and impotent (trunca et debilis). Eius autem quae uictu morbos curat longe clarissimi auctores etiam altius quaedam agitare conati rerum quoque naturae sibi cognitionem uindicarunt, tamquam sine ea trunca et debilis medicina esset. Quem Apollonius et Glaucias et aliquanto post Hera- clides Tarentinus et aliqui non mediocres uiri secuti ex ipsa professione se empiricos appellauerunt. Yet as for that part of medicine which cures diseases by regimen, by far the most famous authorities also tried to deal with some things at even greater depth and also claimed for themselves a knowledge of the nature of things as if, without this, 7 Translation according to van der Eijk (2000a) 3–5. He was followed by Apollonius, Glaucias, and some time later by Heraclides of Tarentum and several other very distinguished men, who on the strength of the very claim they made gave themselves the name of Empiricists. After those who have just been dealt with, however, no one indeed added anything to what he had accepted from his precursors until Asclepiades made major changes to the method of healing. Four brief comments on this passage are in order here: (i) The art of medicine as practised by Hippocrates is presented by Celsus in a rather narrow sense of the art of healing (curare), namely treatment or therapy, which raises the question what place, if any, is left for anatomy, physiology, prognostics and pathology – areas which are well represented in the Hippocratic Corpus. It is unclear, however, what Celsus means by ‘the same times’, and whether this tripartition is identical to, or a consequence of, the differentiation mentioned in the previous sentence, or in other words, how the sentences Post quem. I shall be brief about point (i), for it may be, and often has been, argued that this perception of Hippocratic medicine reflects, to a much greater extent than the other three points, Celsus’ personal view of the priorities in medicine. The Hippocratic Corpus provides evidence of an increasingly self-conscious medical profession, which is re- flecting on and promulgating its own principles, setting high standards 8 OnCelsusasareporterofRationalistmedicineseevonStaden(1994b);onCelsus’viewofHippocrates see Serbat (1995) liii–lvii; Mudry (1977) 345–52; Castiglioni (1940) 862–6. Thus, as is well known, the author of the Hippocratic work On Ancient Medicine criticises what he calls ‘philosophy’9 and its influence on medical practice, and he refers disparagingly to the use of ‘postulates’ such as the elementary qualities hot and cold as all-pervading explanatory principles in the understanding and treatment of the human body. Interestingly, he counters the criticism that medicine is not in all cases capable of restoring health by pointing out that this is not due to lack of skill or poor performance of doctors (although this may of course be the case), but due either to lack of co-operation by the patient or to the fact that the disease is, or has become, incurable – and in such cases, he argues, it is actually to the doctor’s credit to be realistic and to refrain from treatment. For while the Hippocratic Corpus does not contain works specifically devoted to therapeutics as such, two lead- ing medical writers of the subsequent generation, Diocles of Carystus and Praxagoras of Cos, are both reported to have written extensively on ther- apeutics per se in works entitled On Treatments (perª qerapeiän), at least four books being attested in the case of Diocles and three for Praxagoras;12 and it may be noted that Aristotle, too, is credited with a work On Reme- dies (De adiutoriis, in Greek probably perª bohqhm†twn). To help, or to do no harm 107 On Treatments is provided by the Methodist writer Caelius Aurelianus, who is not a very sympathetic reporter of Diocles’ therapeutic views. Yet some fragments allow us to get some impression of the difference of emphasis between the two works. Quarto autem libro de curationibus ‘Iuuenes’, inquit, ‘atque habitudine robustos et magis, quibus dolor ad latera fertur phlebotomandos probo ex manu dextera interiore[m] uena[m] et submittendos in aquam calidam, fotis uentri inicere admixto sale clysterem et rursum in aquam calidam deponere et fouere. Non enim solos oportet iuuenes phlebotomari, sed etiam alios in aliis aetatibus constitutos, neque semper e dextera manu uel interiore uena, sed etiam ex sinistra atque exteriore facta. Then he gives them something to drink first and applies a clyster consisting of the seed of abrotanum mixed with oxymel, and of birthwort, cumin, nitre, fennel root decocted in wine mixed with sea water, or raisin wine, or more acid wine, or milk with a decoction of linseed and honey, or similar things. Again, in the fourth book on treatments he says: ‘For young people and those whose normal constitution is strong, and all the more for those in whom the pain stretches to the sides [of the body], I recom- mend venesection from the right hand, or from the internal vein, and bathing in hot water, and when they have got warm to inject in the belly a clyster mixed with salt, and then again to put them in hot water and to warm them. Then’, he says, ‘a convalescense cure should be applied’, of which he lists the materials, which it is superfluous to enumerate; for from the above it is evident that this mixture of stuffs is useless and unskilful. For one should venesect not only young people, but also people of other ages, and not always from the right hand or the interior vein, but also from the left hand and from the exterior vein. For after a withdrawal has been carried out, this gives relief to the swelling parts, but the use of clysters, due to their acid quality, causes the swelling parts to burn. Moreover, the drinking of drugs beforehand is irritating, for these are sharp and biting, and [are things] that do not soothe the acute state nor bring relief to the swelling parts. Swallowed lead, to be sure, presses and drives [the obstructing material] by its heaviness, but necessarily on contact cools and stretches the densely compacted intestines in an irritating manner. Broths are known to go off easily and to cause flatulency, and barley gruel to bring about the same effect; wine, too, is harmful when the disease is in its increasing phase. To help, or to do no harm 109 A comparison between the two accounts shows that the therapeutic in- structions derived from On Treatments are much more detailed and show greater differentiation according to the individual patient. The fact that a lead pill is not mentioned in the report of the therapeutic section of Affection, Cause, Treatment may be a matter of coincidence, or of Caelius’ selectivity in reporting, but it may be significant that such a pill is also men- tioned in another testimony where the two works are compared, in Caelius’ discussion of Diocles’ treatment of epilepsy (Chronic Affections 1. Yet for those who have incurred this affection because of the usual state of their body, he recommends the withdrawal of a thick humour, which he called phlegma. He also applies drugs that stimulate the urinary passages, which people call diuretica, and also walking and being carried around. Yet even if these were real remedies, because of the smallness of their number and of their power it could hardly be said that they are strong enough against this great affection, or that they are sufficient for its destruction. Again, in the book of treatments he applies venesection and uses as medicine a pill which turns the stomach and causes vomiting after dinner by filling the head with exhalations. He gives vinegar to drink, and by causing sneezing before the patients fall asleep he troubles the sensory passages at a highly untimely moment. He also gives wormwood, centaury, ass’s milk, and the scab of horses or mules not indicating the time these measuresshouldbeappliedbutafflictingthepatientswithdreadfulthings’(ItemDiocles libro,quode passionibusscripsit,inhis,quiexuinolentiauelcarnaliciboistampassionemconceperint,phlebotomiam probat, antecedentes potius quam praesentes intuens causas. Item libro curationum phlebotomans utitur medicamine catapotio, quod stomachum euertit atque post cenam uomitum facit, exhalationibus implens caput. On the relative infrequence of the use of pills in early Greek medicine see Goltz (1974) 206–7. He also gives raisin wine mixed with water to drink to children or to those who have contracted the affection because of a wound. He also prohibits the giving of food and he prescribes the application of vapour baths to the [parts] that are stiffened by the affection and to make them flexible. Again, in the third book On Treatments, he similarly uses a clyster and gives sweet wine to drink and applies vapour baths, sometimes dry ones, sometimes wet ones, and he anoints the affected parts with wax-salve and covers them with wool’ (Diocles libro, quo passiones atque causas atque curationes scripsit, tetanicis inquit adhibenda mictoria medicamina, quaeappellauitdiuretica,tumuentremdeducendumatqueuacuandum. Further titles and fragments of Diocles’ works indicate that he wrote separate works on regimen in health, anatomy, physiology (digestion), external remedies, toxicology, prognostics, gynae- cology, fevers, catarrhs, evacuations, bandages, surgery, vegetables, rootcut- ting, and possibly cookery and sexuality. Apart from the titles mentioned, there is also a work by Diocles entitled Archidamos (fr. But many commentators have expressed uncertainty about the precise meaning of this phrase; cf. Smith (1989, 76): ‘I am uncertain what differences Celsus may have had in mind’ and Serbat (1995, xxxix: ‘observation assez enigmatique’), and the translations by´ Spencer: ‘so practiced this art that they made advances even towards various methods of treatment’; Serbat: ‘pratiquerent cet art en le faisant meme progresser dans des voies therapeutiques differentes’;` ˆ ´ ´ and Mudry (1982, 67): ‘pratiquerent cet art de telle sorte qu’ils avancerent encore dans des voies` ` differentes’). To help, or to do no harm 111 However, on this interpretation it is slightly strange to introduce a new paragraph at section 9, as Mudry does,22 for this suggests that a new issue is to be discussed, whereas both sentences seem to be expressing more or less the same idea: progress leading to different methods of treatment and divi- sion of the art of medicine into three areas which are also defined by the way in which they provide treatment (quae uictu. It is important to see for what purpose Celsus has inserted the tripartition of healing into his argument. Thus interpreted, Celsus’ report is consistent with the fact (which there was no reason for him to ignore) that the Hippocratic Corpus itself already provides evidence of a division of therapeutic activities roughly correspond- ing to the tripartition into dietetics, surgery and pharmacology. To help, or to do no harm 113 distinguishes between treatment by drugs, venesection and clystering,35 and elsewhere between regimen, fomentations and drugs;36 and the author of On Internal Affections distinguishes on one occasion between treatment by fomentations, drugs, foods and exercises,37 and on another occasion between treatment by drugs, drink, food and exercises. The verb diaitan (diaitŽn) is often used by Hippocratic authors to describe a treatment consisting of measures characteristic of what we would call dietetics, such as foods and drinks, walking, baths, exercise and sleep. But sometimes it just seems to be equivalent to ‘treatment’, as in a well-known statement of the doctor’s primary requirements in Epidemics 3. It could be argued that it should rather be defined more generally as a care for the body both – and perhaps predominantly – in healthy states as well as (perhaps secondarily) in unhealthy states, or on the interface between the two, as seems to be the position of the author of On Regimen. If Celsus is correct in portraying dietetics as a relatively late development in Greek therapeutics,45 this must refer to dietetic medicine, the application of dietetic principles to the treatment of diseases. Rather than thinking that dietetics was originally a part of medicine and was only later, under the influence of changing social and cultural circumstances,46 divided into a therapeutic part (the treatment of diseases) and a hygienic part (the preservation of health and hygiene), one may also defend the view that dietetics as a way of looking after the body was of an older origin and had, by the fifth century bce, developed into an established corpus of knowledge primarily based on experience which was subsequently applied to the treatment of diseases. For the ambivalence just noted – preser- vation of health, or treatment of disease, or providing palliative care – is, in a way, characteristic of Hippocratic approaches to health and disease as a whole. Here the need for terminological clarification makes itself particu- larly felt, for neither the Greek qerape©a nor its English derivative ‘therapy’ is specific with regard to this question about the aim(s) to be achieved. This brings us to a consideration of the terms in which the doctor’s activities are referred to in the Hippocratic Corpus. As Nadia van Brock has shown,48 among the various words used to signify the doctor’s activity – such as «¦sqai (‘cure’), qerapeÅein (‘treat’), meletŽn (‘care’), Ýfele±n (‘help, benefit’), bohqe±n (‘remedy, assist’), meleda©nein (‘care’), metaceir©zesqai (‘treat’), ful†ssein (‘protect’) – perhaps ˆpal- l†ssein (‘set free, release’), Ëgi†zein (‘make healthy’), and the passive Ëg©hv 43 See On Regimen in Acute Diseases 41 (2. But the former is the starting-point, and came before the latter (ˆrcŸ d• –ke©nh ¡ pr»teron genom”nh).

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Vancomycin can stimulate the production of platelet-reactive antibodies that can cause thrombocytopenia and severe bleeding (51) buy genuine baclofen on-line. Sulfonamides buy baclofen 10 mg otc, rifampin 10 mg baclofen mastercard, and rarely b-lactams (including penicillin cheap baclofen 25mg with mastercard, ampicillin, methicillin, cefazolin, and cefoxitin) have also been reported to induce platelet destruction (45,52). Chloramphenicol-induced thrombocytopenia is usually dose-related and, if not associated with aplastic anemia, is reversible following discontinuation of the drug. Coagulation Malnutrition, renal failure, hepatic failure, malignancy, and medications can all predispose critically ill patients to bleeding. Although many studies have found an association between antibiotics and clinical bleeding (53), in-depth, statistically validated investigations may be necessary to establish causation in complex patients with multiple underlying diseases (54). Dysfunctional platelet aggregation, an important mechanism by which selected antibiotics may cause bleeding, is mostly noted with penicillins. Among penicillins, it is most likely with penicillin G and advanced-generation penicillins (55). The problem is dose- related, may be exacerbated by renal failure, and is additive to other factors seen in critically ill patients that could, in their own right, be associated with dysfunctional platelet aggregation (55,56). Most commonly, the reason for dysfunctional platelet aggregation is that carboxyl groups on the acyl side chain block binding sites located on the platelet surface resulting in the inability of platelet agonists such as adenosine diphosphate to affect aggregation (55). All of these products contain an N-methylthiotetrazole side chain that can interfere with hepatic prothrombin synthesis (59). Sulfonamides can displace warfarin from its binding site on albumin and thereby enhance its bioavailability. Virtually any antimicrobial agent may cause a rash, but this problem occurs most commonly with b-lactams, sulfonamides, fluoroquinolones, and vancomycin (60). Factors that should lead the clinician to suspect a serious drug reaction include facial edema, urticaria, mucosal involvement, palpable or extensive purpura, blisters, fever, or lymphaden- opathy. Maculopapular eruptions associated with antibiotics are especially common, usually occurring within one to two weeks after starting the offending agent and often becoming generalized and pruritic. In patients with thrombocytopenia or other coagulopathies, hemorrhage into the skin may modify the appearance of the rash. In some instances, the likely offending agent can be continued and the rash will stabilize or disappear. In patients with penicillin-induced mild or moderately severe maculopapular rashes, it is generally safe to use cephalosporins (61). If the rash is severe or associated with mucosal lesions or exfoliation, the offending agent should almost always be discontinued. The most commonly implicated antibiotics are the aminopenicillins and sulfonamides. Clinically, the rash can present as symmetrical target lesions, maculopapular and urticarial plaques, and/or vesicular lesions. Stevens–Johnson syndrome can involve mucosae of the eyes, mouth, entire gastrointestinal tract, and the genitourinary tract. Infections (for which the offending antibiotic may have been prescribed), including pneumococcal, mycoplasmal, and staphylococcal infections can cause a similar rash. Stevens–Johnson syndrome can evolve into toxic epidermal necrolysis; mortality of this condition is 30% (62). Sulfonamides are the antibiotics most often associated with toxic epidermal necrolysis. Although the benefits of corticosteroid therapy are unproven, these products are often used for treatment. Severe cases have been associated with angioedema, hypotension, chest pain, and rarely, severe cardiac toxicity and death (20). Incidence may be as high as 47% in patients and is substantially higher in human volunteers (64). One study documented a dose-related increase in circulating histamine concentrations that correlated with the severity of the reaction (65). Histamine antagonists may abort the syndrome in patients who require 548 Granowitz and Brown vancomycin and who continue to have red man syndrome despite slow administration of the drug (63,66). Both may be associated with redness, heat, tenderness and a “cord” at the peripheral catheter site. Therapy for the former is removal of the catheter and appropriate antibacterial agents, while the latter is treated with catheter removal and moist heat. Presence of lymphangitic streaking or purulent drainage from the catheter site generally indicates infection. Antibiotics most likely to cause phlebitis include potassium penicillin, cephalosporins, vancomycin, streptogramins, and amphotericin B. Although routine audiography has been promulgated for some hospitalized patients given potentially ototoxic drugs (67), in practice such testing is not routinely employed. Therefore, the clinician must recognize the circumstances that could result in ototoxicity and take steps to decrease its likelihood. Erythromycin and azithromycin can cause bilateral hearing loss and/or labyrinthine dysfunction that is usually reversible within two weeks of discontinuating the agent (68,69). These complications are dose- related and usually occur in the presence of renal and/or hepatic dysfunction (71). A prospective study in patients with pneumonia documented sensorineural hearing loss in approximately 25% of patients treated with 4 g of erythromycin daily, while no patients who received lesser doses or control agents developed this condition (68). Aminoglycosides cause ototoxicity or vestibular dysfunction in 10% to 22% of patients and it can be permanent (24,72). Cumulative dose is important and clinicians should be wary of administering repeated courses of aminoglyco- sides. Use of an early vancomycin preparation was associated with sensorineural hearing loss (76). Other Neurotoxicities Antibiotics can also occasionally cause peripheral nerve or acute central nervous system dysfunction (e. Most peripheral neuropathies occur with prolonged administration of selected antibiotics (e. Hallucinations, twitching, and seizures can be caused by penicillin, imipenem/cilastatin, ciprofloxacin, and rarely by other b-lactam antibiotics (78,79). Seizures may be the result of b-lactams interfering with the function of the inhibitory neurotransmitter g-aminobutyric acid (80). Intravenous aqueous penicillin G may cause central nervous system toxicity when normal-sized adults are given more than 20 to 50 million units per day (78). Patients with abnormal renal function, hyponatremia, or preexisting brain lesions can experience neuro- toxicity at lower doses. The maximum recommended dose of imipenem-cilastatin in adults with normal renal function is 4 g/day. Animal studies confirm that neurotoxicity with imipenem/cilastatin may be noted at substantially lower blood levels than with other b-lactams (80). Our practice has been to virtually never employ imipenem/cilastatin in doses of >2 g/day unless treating Pseudomonas aeruginosa infections. Seizures have not been noted in more than two decades of regular use at the authors’ institution. Fluoroquinolone use has been associated with central nervous system adverse effects including headache and seizures in 1% to 2% of recipients (83). Hallucinations, slurred speech, Adverse Reactions to Antibiotics in Critical Care 549 and confusion have been noted; these generally resolve rapidly once the offending agent is discontinued. The presence of an underlying nervous system disorder may predispose to neurotoxicity. Serotonin syndrome is due to impaired serotonin metabolism and is characterized by agitation, neuromuscular hyperactivity, fever, hypotension and even death. Although linezolid itself does not cause serotonin syndrome, combining this drug with other monoamine oxidase inhibitors can result in toxicity. A small percentage (<5%) of patients on selective serotonin reuptake inhibitors who are given linezolid develop serotonin syndrome (84–88). If it is necessary to start linezolid in a patient requiring a selective serotonin reuptake inhibitor, the patient should be watched for signs of serotonin syndrome and the responsible medications promptly discontinued if signs develop. Neuromuscular blockade has been reported with aminoglycosides (78) and polymyxins. Clinical presentation is acute paralysis and apnea that develop soon after drug administration. Because of this potential toxicity, aminoglycosides should be avoided in patients with myasthenia gravis. With the first dose, approximately one-third of patients receiving voriconazole usually experience transient visual changes.

The distribution of the drug throughout the various compartments and tissues that are accessed result in an equilibrium concentration discount baclofen 10 mg with mastercard, and from that point buy 25mg baclofen otc, the elimination of the drug proceeds in a consistent fashion order 25 mg baclofen free shipping. A semilogarithm plot is used for the concentration at each time point and this yields a linear configuration to the elimination plot order baclofen 10 mg with visa. Extrapolation of the semilogarithm elimination plot to time-zero permits calculation of the volume of distribution (Vd) of the drug in this specific set of clinical circumstances. The volume of distribution equals the total dose of drug given (D) divided by 6 the time-zero theoretical concentration (T0), or D/(T0) ¼ Vd. Thus, 1 g of an antibiotic (1 Â 10 mg) with an extrapolated (T0) ¼ 50 m/mL results in a Vd ¼ 20,000 m, or 20 L. The linear configuration of drug elimination over time permits calculation of the biological elimination half-life (T1/2). The T1/2 is the period of time required for the equilibrated plasma concentration of the drug to decline by 50%. The expectation is that the plasma concentration reflects the dynamic processes of equilibration of the central pool (i. Antibiotics are generally considered to have a single T1/2 that describes elimination of the drug, but some may have a second T1/2 that describes clearance at low concentrations. Antibiotic Kinetics in the Multiple-System Trauma Patient 523 Figure 1 Illustrates the clearance curve of a theoretical antibiotic. Vd is a theoretical calculation that can be influenced by factors other than the actual body water of drug distribution. Knowledge of the Vd and T1/2 allows the design of dose and dosage intervals for the antibiotic. If our theoretical drug in Figure 1 was deemed to have toxicity at concentrations above 80 m/mL then it would be desirable to have the concentration below that threshold for the treatment interval. Thus, a rational configuration of the use of this drug would be a 1 g dose that was re- dosed every eight hours. Antibiotics with a significant post-antibiotic effect can have treatment intervals that are greater than would be predicted by the above model. Nevertheless, the above strategy is generally used for the design of the therapeutic application of drugs in clinical trials. The design is derived from studies in healthy volunteers and clinical trials are generally performed in patients without critical illness. Biotransformation is the process by which the parent drug molecule is metabolized following infusion. Biotransformation may occur via a number of pathways, although hepatic metabolism is most common. It may occur within the gastrointestinal tract, the kidney epithelium, the lungs, and even within the plasma itself. Hepatic biotransformation may result in the metabolite being released within the blood, resulting commonly in attenuation of action and facilitation of 524 Fry elimination via the kidney. Hepatic metabolism may result in the inactivated metabolite being eliminated within the bile. Clearly, abnormalities within the organ responsible for biotransformation will affect the process. The cytochrome P-450 system requires molecular oxygen, so poor perfusion or oxygenation of the liver from any cause will impact hepatic metabolism of specific drugs. Some drugs are eliminated unchanged by the kidney into the urine, or excreted by the liver into the bile. Excretion of unchanged drug via the biliary tract, which in turn can be reabsorbed, may create an enterohepatic circulation that results in prolonged drug presence in the patient. When either the intact drug or metabolic product is dependent on a specific organ system for elimination, intrinsic disease becomes an important variable in the overall pharmacokinetic profile. Extensive torso and extremity injuries result in soft tissue injuries that activate the human systemic inflammatory response. This systemic inflammatory response requires extensive volume resuscitation for maintenance of intravascular volume and tissue perfusion. Blunt chest trauma requires intubation and prolonged ventilator support, and exposure of the lung to environmental contamination. The patients are immunosuppressed from the extensive injuries, transfusions, and protein-calorie malnutrition. Following the injury itself, infection becomes the second wave of activation of systemic inflammation. Infection becomes a complication at the sites of injury, at the surgical sites of therapeutic interventions, and as nosocomial complications at sites remote from the injuries. Fever and hypermetabolism are common and add an additional compounding variable at a time when antimicrobial treatment is most important in the patient’s outcome. Antibiotics are invariably used in the febrile, multiple-injury patient, but they are dosed and re-dosed using the model of the healthy volunteer initially employed in the development of the drug. Are antibiotics dosed in accordance with the pathophysiologic changes of the injury and febrile state? Extensive tissue injury and invasive soft-tissue infection share the common consequence of activating local and systemic inflammatory pathways. The initiator events of human inflammation include (i) activation of the coagulation cascade, (ii) activation of platelets, (iii) activation of mast cells, (iv) activation of the bradykinin pathway, and (v) activation of the complement cascade. The immediate consequence of the activation of these five initiator events is the vasoactive phase of acute inflammation. The release of both nitric oxide–dependent (bradykinin) and independent (histamine) pathways result in relaxation of vascular smooth muscle, vasodilation of the microcirculation, increased vascular capacitance, increased vascular permeability, and extensive movement of plasma proteins and fluid into the interstitial space (i. The expansion of intravascular capacitance and the loss of oncotic pressure mean that the Vd for many drugs will be expanded. Shock, injury, and altered tissue perfusion have been associated with the loss of membrane polarization, and the shift of sodium and water into the intracellular space. At a theoretical level, there is abundant reason to anticipate that the conventional dosing of antibiotics may be inadequate in these circumstances (Fig. The vascular changes in activation of the inflammatory cascade also result in the relaxation of arteriolar smooth muscle and a reduction in systemic vascular resistance. The reduction in systemic vascular resistance becomes a functional reduction in left ventricular afterload, which combined with an appropriate preload resuscitation of the severely injured patient leads to an increase in cardiac index. The hyperdynamic circulation of the multiple- trauma patients leads to the “flow” phase of the postresuscitative patient. Increased perfusion of the kidney and liver results in acceleration of excretory functions and potential enhancement Antibiotic Kinetics in the Multiple-System Trauma Patient 525 Figure 2 Illustrates the influence upon the clearance curve of the theoretical antibiotic in Figure 1 of an increase in extracellular and/or intracellular water in a trauma patient that has fever secondary to invasive infec- tion. The peak concentration [A ]* and the equilibrated peak concentration [B ] are less* than those concentrations observed under normal circumstances. Subsequent organ failure from the ravages of sustained sepsis results in impairment of drug elimination and prolongation of T1/2. Severe injury results in the infiltration of the soft tissues with neutrophils and monocytes as part of the phagocytic phase of the inflammatory response. Proinflammatory cytokine signals are released from the phagocytic cells, from activated mast cells, and from other cell populations. The circulation of these proinflammatory signals leads to a febrile response with or without infection. The febrile response is associated with systemic hypermetabolism and autonomic and neuroendocrine changes that further amplify the systemic dyshomeostasis. Pro-inflammatory signaling up-regulates the synthesis of acute-phase reactants and down- regulates the synthesis of albumen, which further impacts the restoration of oncotic pressure and predictable drug pharmacokinetics. The summed effects of injury, fever, and the sequela of systemic inflammation result in pathophysiologic alterations (Table 1) that compromise the effectiveness of antibiotic therapy because of suboptimal dosing. A review of the literature identifies a paucity of clinical studies in the 526 Fry multiple-injury patient, despite the fact that antibiotics are used for a wide array of indications in these patients. The effects of pathophysiologic changes upon antibiotic therapy will be cited among studies of critically ill and severely septic patients in the intensive care unit, and not exclusively in multiple-trauma patients. Preventive Antibiotics in the Injured Patient Preventive antibiotics have been used for over 30 years in trauma patients (1). The recognized principals of preoperative administration of an antibiotic with activity against the likely pathogens to be encountered have been the hallmark of utilization in this setting. However, trauma patients have blood loss and large volumes of resuscitation in the period of time leading up to, and during, the operative intervention. The sequestration of the resuscitation volume into injured tissue results and the obligatory expansion of the extracellular water volume all contribute to a vastly expanded Vd.

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