Primaquine

Gary Michael Felker, MD

• Professor of Medicine
• Member in the Duke Clinical Research Institute

https://medicine.duke.edu/faculty/gary-michael-felker-md

Rarely symptoms miscarriage primaquine 15 mg generic, severe forms of the disease can occur with atypical manifestations (see Section 3B) treatment 32 buy primaquine overnight. However treatment croup order genuine primaquine line, an increase in crude death rates was reported during the 20042008 epidemics in India and Mauritius symptoms liver cancer primaquine 15 mg for sale. Infant with maculo-papular rash symptoms pneumonia purchase 7.5 mg primaquine, petechial spots and erythema of upper and lower limbs associated with edema of the extremities 12 Clinical presentation medications with aspirin order 15 mg primaquine fast delivery. Swollen and stiff hands in a 55-year-old man who was infected 5 years earlier Credits: (C), (D), (I), (K), (L), (M)Pr. These manifestations can be due to the direct effects of the virus, immunologic response to the virus, or drug toxicity. For instance, meningoencephalitis and vesiculobullous dermatosis are observed more frequently in children and infants, respectively. Clinical presentation is thought to vary by age, however, with the very young (neonates) and the elderly being at greater risk for more severe disease. Infants are typically asymptomatic at birth and then develop fever, pain, rash, and peripheral edema. Those infected during the intrapartum period may also develop neurologic disease. Individuals >65 years had a 50-fold higher mortality rate when compared to younger adults (<45 years old). Diseases that can be considered in the differential diagnoses may vary based on pertinent epidemiologic features such as place of residence, travel history, and exposure (Table 3). Disease or agent Presentation Periodicity of fever and alteration of Malaria consciousness Fever and two or more of the following, retro-orbital or ocular pain, headache, rash, myalgia, arthralgia, leucopenia, or Dengue fever hemorrhagic manifestations. See section and table below for more information on dengue Severe myalgia localized to calf muscles with conjunctival congestion/or subconjunctival Leptospirosis hemorrhage with or without jaundice or oliguria. Post-infectious arthritis Rheumatic fever is seen more commonly (including rheumatic in children as migratory polyarthritis fever) predominantly affecting large joints. Comparison of the clinical and laboratory features of chikungunya and dengue virus infections. Subacute and Chronic disease After the frst 10 days, most patients will feel an improvement in their general health and joint pain. Following this period, however, a relapse of symptoms can occur, with some patients complaining of various rheumatic symptoms, including distal polyarthritis, exacerbation of pain in previously injured joints and bones, and subacute hypertrophic tenosynovitis in wrists and ankles. In addition to physical symptoms, the majority of patients will complain of depressive symptoms, general fatigue, and weakness. The frequency of persons reporting persistent symptoms varies substantially by study and the time that had elapsed between symptom onset and follow-up. Studies from South Africa note that 12%18% of patients will have persistent symptoms at 18 months and up to 2 to 3 years later. Simone, Dept of Infectious Diseases and Tropical Medicine, Laveran Military Hospital, Marseilles, France, personal communication). Usually, there is no signifcant change in laboratory tests and x-rays of the affected areas. However, some individuals will go onto develop destructive arthropathy/arthritis resembling rheumatoid or psoriatic arthritis. In suspected fatal cases, virus detection can be attempted on available specimens. Selection of the appropriate laboratory test is based upon the source of the specimen (human or field-collected mosquitoes) and the time of sample collection relative to symptom onset for humans. Real time, closed system assays should be utilized, due to their increased sensitivity and lower risk of contamination. An acute phase serum should be collected immediately after the onset of illness and the convalescent phase serum 1014 days later. Therefore, to defnitively rule out the diagnosis, convalescent samples should be obtained on patients whose acute samples test negative. Collection, Storage, and Transportation of Samples Proper collection, processing, storage, and transportation of the specimens are essential aspects of the laboratory diagnosis. Collection of samples for serology, isolation and molecular diagnosis: Sample: Serum Time of collection: Acute, within the frst eight days of illness; convalescent, 1014 days after acute specimen collection. The following table (Table 5) outlines the ideal tests to be performed in various epidemiological settings. Furthermore, proficiency testing is planned to ensure testing quality in the Region. A contingency plan will be developed to ensure that all laboratories capable of performing testing in the Americas have an adequate supply of reagents and protocols. Symptomatic treatment is recommended after excluding more serious conditions like malaria, dengue, and bacterial infections. Patients should be advised to drink plenty of fuids to replenish fuid lost from sweating, vomiting, and other insensible losses. Although an older study suggested that chloroquine phosphate offered some beneft,45a recent double-blind, placebo-controlled randomized trial found it to be of no real value treating joint symptoms. In patients with refractory joint symptoms, alternative therapies such as methotrexate can be evaluated. In addition to pharmacotherapy, cases that have prolonged arthralgia and joint stiffness may beneft from a program of graduated physiotherapy. Movement and mild exercise tend to improve morning stiffness and pain, but heavy exercise may exacerbate symptoms. However, other modes of transmission, such as through respiratory droplets or particles, have not been documented. Health Care and Hospital Surge Capacity At the peak of one recent outbreak, 47,000 suspected cases were identifed in a single week among a population of 766,000. With that potential volume of cases per week, huge demands are likely to be placed on the health care system during outbreaks of the disease. Triage systems should be considered at various levels of health care to facilitate the fow of patients during an outbreak. Regardless of the level of medical care available at the triage location, a key measure that needs to be considered at all levels of health care is the institution of appropriate mosquito control measures in the immediate area. During a previous outbreak, up to one-third of health care workers became infected, further taxing already overburdened and stretched resources. If present, administer supportive care in a unit that can monitor vital signs on an hourly basis during the critical phase. Autopsies should be considered on all deceased pa tients, with involvement of pathologists. There are documented cases that include infection of laboratory personnel handling infected blood and of a health care worker drawing blood from an infected patient. This will require a preexisting platform and regulatory clearance, and is unlikely to be available in most areas. Similar measures should be considered for organ and tissue (grafts) transplantations. Early detection will allow for proper T response and characterization of the outbreak and identifcation of the viral strains circulating. A percentage of patients presenting with fever and arthralgia or fever and arthritis with no known etiology. To ensure adequate laboratory testing and surveillance capacity, laboratories should be aware of the laboratory network set up for testing and eventual distribution of supplies. Active, passive, and laboratory surveillance should be used to calculate and monitor indicators such as: incidence, rate of spread, rate of hospitalization (per infections), proportion of severe disease, mortality ratios, and disability rates. Sustained transmission Once the virus has been identifed throughout a country, scaling back of the level of testing and active surveillance can be considered. Any changes in surveillance at the national level should be readily communicated to other surveillance and prevention partners, such as vector control specialists, to ensure the quality and uniformity of the data collected. During an epidemic, all patients need not be subjected to confrmatory tests as above. In addition, other key partners, such as vector control management teams, should be notifed. Suspect case Laboratory Notifcation Alert vector control Negative Local Positive Health Offcer National Health Offce Exclusive and consider Confrmed Confrm outbreak other etiologies cases investigate and control 6E. Epidemiologic Reports Ideally, epidemiologic reporting should be established at the national level, with the support of local and regional public health offcials. The types and number of epidemiologic reports will likely evolve during the course of the outbreak to refect the types of surveillance that are performed in an area. Reporting should be coordinated at the national level by establishing a web-based line list, if possible, that contains a few required variables and additional variables as needed. A standardized case report form, including demographic, epidemiologic and laboratory information, should be developed quickly and shared with key partners to help facilitate the collection of information (See Appendix D for an example). At the national level, there should be clearly defned cutoffs in 47 terms of presenting and closing the data on a daily basis. In addition to case count by location and timing, reporting on disease severity (hospitalization, mortality), number of hospital beds occupied per day, and trends in cases based on syndromic surveillance can be considered as ways to present the data. The national level data should be communicated back to the collecting districts, as well as to the press and other public health and partner agencies that participate in the control efforts (see Section 8, Risk and Outbreak Communication for more detail). Once a country has identifed autochthonous transmission within its borders, it should activate its emergency operations center (sala de situacion) to serve as a source for rapid communication and decision making. Such an event would have a serious public health impact because of its potential to cause an epidemic with high attack rates among an immunologically naive population, and because vectors are suffciently abundant to potentially support permanent establishment of the virus and year-round transmission. The event would also be unusual for the Americas, since it would signal the appearance of a previously absent pathogen and a signifcant risk of international spread given the amount of travel between countries in the Region. Some jurisdictions outside the Americas have instituted mosquito abatement activities at international airports and spraying adulticides in the passenger cabins of arriving international fights as part of efforts aimed at preventing dengue importation. However, virus-infected mosquitoes arriving in passenger aircraft are not considered as signifcant sources of most arboviral importations. For arboviruses with a human-mosquito-human transmission cycle, the most important source of viral importation is the viremic traveler. The exception would be if cases were being detected close to an international airport or seaport, or if suspected cases worked in or around these ports of entry. Therefore, vector control planning efforts should focus on suppression of both Ae. These species have distinct morphological features, and the identifcation of specimens collected during surveillance and control programs in the Americas can be readily accomplished. Successful control programs require well trained professional and technical staff and suffcient funding. The program must have the ability to systematically collect surveillance data on relative densities of Ae. Personal Protection Individuals may reduce the likelihood of infection by the use of personal repellents on skin or clothing. Infants and others sleeping or resting during the day should use bednets to avoid infection from Ae. Household Prevention the use of intact screens on windows and doors will reduce entry of vectors into the home, and mosquito proofng water storage vessels will reduce oviposition sites and local production. The number of adult mosquitoes in a home may be reduced by using commercially available pyrethroid-based aerosol sprays and other products designed for the home, such as mosquito coils and electronic mat vaporizers. Aerosol sprays may be applied throughout the home, but areas where adult mosquitoes rest (dark, cooler areas) must be targeted, including bedrooms, closets, clothing hampers, etc. Care should be taken to emphasize proper use of these products when advocating their application to the public, in order to reduce unnecessary exposure to pesticides. The program should be managed by experienced professional vector control biologists to assure that the program uses current pesticide recommendations, incorporates new methods of vector control, and includes resistance testing. Prevention programs should utilize the methods of vector control found in Appendix F, as appropriate. Vector control procedures must be intensifed to effectively reduce the abundance of infected vectors in order to halt transmission in the areas of the case(s). Initial efforts should focus on containing virus transmission and preventing expansion (Appendix G). If virus containment fails, or if cases are not detected until the outbreak has spread over a large geographic area, intensive vector control efforts will need to be expanded to a larger scale program. Risk Communication Strategies by Phase and Target Audience Appendix H gives an example of a model risk communication plan with strategies organized by preparedness, response, and recovery phases of an emergency. The plan defnes various target audiences that should be considered in developing a country-specifc risk communication plan. Risk communication should be organized across multiple agencies and should target the media, the public health community, community-based organizations, the private sector, and civil society institutions.

Mentally venlafaxine) medicine 5658 7.5mg primaquine with amex, monoamine oxidase inhibitors medications just like thorazine generic 15 mg primaquine overnight delivery, and tricyclic retarded individuals appear more likely than other patients to antidepressants (41 medicine 2015 lyrics cheap primaquine 7.5 mg free shipping,52) medicine 3605 purchase generic primaquine line. Two trials in children with partial seizures demon agement of attentional disorders and hyperactivity is not con strate the interaction between previous behavioral states and traindicated (41 medications with acetaminophen purchase 15mg primaquine free shipping,53) medications starting with p buy cheap primaquine 15 mg on line. The physician treating a patient with mul whereas gabapentin as adjunctive therapy produced a much tiple handicaps must appreciate this potential unwanted higher rate of negative behavior, especially in patients with effect. Bone health, contracture formation, etam, oxcarbazepine, zonisamide, and vigabatrin have pro weight regulation, gastrointestinal disturbances, gynecologic duced, at least in case reports, aberrant behavior in persons concerns, and drug interactions affect not only the treatment with behavioral comorbidity, including those with mental of epilepsy but also medications prescribed for other comor retardation (38). Careful changes in behavior may often be the only sign of significant titration and monotherapy are recommended whenever possi abnormality in this group. Increased acting out and belligerence may appear as part of the brightening the treatment of the multihandicapped child or adult with process that can occur with conversion to newer, less sedative epilepsy must be tailored to the individual patient. Thus, changes in therapy should be made slowly with assessment of all comorbid conditions must be part of the careful clinical monitoring (38). The comor occur in an individual patient, long-term studies suggest that bid treatment and the epilepsy treatment will each affect the polypharmacy can be reduced successfully, especially when a other. In one study of 244 mentally retarded patients Understanding the difficulties in diagnosis and treatment of with epilepsy who were followed up for 10 years, monother individuals with multiple handicaps and the inter-relationship apy could be increased in 36. Identification of the epilepsy syndrome may also aid in Definition, Classification and Systems of Support. Diagnostic and Statistical Manual of Therapy for the multihandicapped individual comprises Mental Disorders. Static long-term follow-up and links with electrical status epilepticus during sleep Encephalopathies of Infancy and Childhood. Initiating and discontinuing antiepileptic drugs in patients with multiple handicaps and epilepsy. In: Devinsky E, Westbrook American Academy of Neurology and the Child Neurology Society. Removal of sedative-hypnotic antiepileptic ders after infantile spasms: a population based study nested in a cohort drugs from the regimen of patients with intractable epilepsy. Notably, the incidence (new cases) of epilepsy is signifi detected a higher rate. Some retrospective studies have indi cantly higher in this population than in any other (2,3). Accordingly, the incidence of seizures after stroke Netherlands and Finland (5,6). Until recently, periods of increased confusion may be having unrecognized it has been accepted that persons should not be diagnosed partial complex seizures. Most problematic, though, is that in with epilepsy until an individual experienced two or more a large number of cases the precise cause cannot be deter seizures. However, in light of current diagnostic tools, brain mined and the etiology is termed cryptogenic (crypt hidden; pathologies can be more readily identified. This is of particular Because most seizures in the elderly are caused by a focal area importance to the geriatrician due to the fact that many per of damage to the brain, the most common seizure types are sons within this age group suffering from seizures possess an localization related. Complex partial seizures are the most com identifiable brain pathology that corresponds with a known mon seizure type, accounting for nearly 40% of all seizures in risk for future seizures. In a prospec such as cardiac insufficiency, metabolic conditions, convulsive tive study of 1897 patients suffering from stroke, seizures syncope (micturation syncope, cough syncope), be eliminated occurred in 168 (8. Of the 265 persons within the study who suffered a event was an epileptic seizure. Of the Evaluation after a single seizure must therefore be compre 1632 persons within the study who suffered an ischemic hensive. Thus, those who suf events of the previous day or days, in order to identify any fered a hemorrhagic stroke had an increased risk for a seizure precipitating or predisposing factors that may have led to the 458 Chapter 37: Epilepsy in the Elderly 459 onset. Osteoporosis and bone fractures are many natural products designed to simulate weight loss or commonly seen in the elderly population and thus an elderly improve memory may have proconvulsant properties. Large prospective studies in women and abuse of drugs is not absent in the elderly, and a drug screen men have associated use of both phenytoin and gabapentin should be considered. Not well studied is the possi brain tumor, and encephalomalacia, should be performed. Thus, broad statements about these persons may not be relevant to each individual patient. Detection of interictal patterns can this group into the young-old (65 to 74 years of age), the confirm the presence of physiologically abnormal brain, middle-old or old (75 to 84 years of age), and the old-old solidifying the diagnosis of an epileptic as opposed to a (85 years of age). However, because these persons develop nonepileptic seizure; additionally, these patterns can also health issues at different times, further subdivisions, such as provide information on the severity of the epilepsy. Persons who experience periodic lateralized epileptiform also been proposed (Table 37. Thus, studies should be designed to address specific 21,551 studied persons was 83. Also seen as significantly problematic is the selection of an this distribution is similar to the data provided by the U. Of the residents in increased susceptibility to adverse effects, use of other medica the Garrard et al. Of these epilepsy/seizure disorder as it relates to advancing age in the persons, 20,558 (1. A similar pattern Phenytoin was used as monotherapy by almost 70% of the was reported from a study in Italy (25). Levetiracetam was not available at the time of the 10,318); while the second represented a follow-up cohort (n survey. Interestingly, genetic deter in nursing home residents: effect of age, gender, and comedication on minants of hepatic isoenzymes may be more important than patterns of use. However, there exists a substantial amount of or four to six times that reported for community-dwelling individual variability because clearance is also highly depen elderly. Compared to the young-old, those in the middle involve single-dose evaluations in small samples of the young old or old age group were 33% less likely to have been pre old. Another issue is that many elderly persons are taking other potentially interfering drugs (Table 37. Within the same study, compliant clinic the theoretical basis for expecting age-related changes in drug patients experienced variability of approximately 20% (37). Drug concentration at the site interlaboratory variability in measurement of drug concentra of action determines the magnitude of both desired and toxic tions, although laboratories not following rigid quality control responses. The unbound drug concentration in serum is in standards may experience even larger amounts of variability. The variability for carbamazepine is on the when the drug is not highly protein-bound (less than 75%), or order of 25%, possibly due to its shorter half-life, which may when the ratio of unbound to total drug concentration increase sample time variability (38). This was confirmed in an analysis of ser tein-bound, and protein binding is frequently altered. Interestingly, some had very little fluctuation and were protein) concentrations in the elderly may alter protein binding similar to that of the younger adults previously mentioned. Factors that contribute to this variabil goes saturable metabolism, which has the effect of producing ity in concentration must be identified and strategies should nonlinear changes in serum concentrations when the dose is be developed in order to minimize this phenomenon. Clinical studies in elderly patients have shown decreases in phenytoin binding to albu min and increases in free fraction. However, years of age) persons, 32 middle-aged (40 to 59 years of age) there is little data relating specifically to these drugs in the persons, and 26 younger adult (20 to 39 years of age) per elderly, and those that are available have been limited to the sons with epilepsy (45). Notably, these declined with age, and significantly lower values of Vmax elderly patients also experienced side effects at lower levels were seen in the elderly group compared to the younger compared with the levels in younger subjects (42). Other earlier and smaller studies have also A multicenter, double-blind, randomized comparison shown that phenytoin metabolism is reduced in the elderly. United Kingdom showed that the main difference between the Relatively small changes in dose (10%) are recommended two groups was the rate of dropout due to adverse events, when making dosing adjustments. Thus, in the elderly a with lamotrigine incurring an 18% dropout rate compared to starting daily dose of 3 mg/kg appears to be appropriate, that of carbamazepine which incurred a 42% dropout rate rather than the 5 mg/kg/day used in younger adults (46). Coumadin also has a very complicated interaction with phenytoin and often doses of both need to be manipulated (46). Carbamazepine Phenytoin has some effects on cognitive functioning, espe cially at higher phenytoin serum concentrations (48). However, Carbamazepine is effective for localization-related epilepsies, it is not known if the elderly will be more sensitive to this and thus has an efficacy profile appropriate for the elderly. Two studies In a study involving elderly persons, among the various of new-onset epilepsy in the community-dwelling elderly lifestyle, demographic, and health factors which contributed found carbamazepine to be as effective as lamotrigine, but to an increased risk, phenytoin was the only drug which was noted that it had a higher incidence of side effects (11,43). The apparent clearance of carbamazepine has been However, this study could not determine if this was due to reported to be 20% to 40% lower in the elderly as compared falls from ataxia or seizures, or was an effect due to bone to adults (52,53). These changes in carbamazepine phar effects profile, which may worsen cognition and depression, macokinetics indicate that lower and less frequent dosing in make it an undesirable drug for the elderly, especially in the elderly patients may be appropriate. Observed carbamazepine concen trations in the Birnbaum study were lower or below the sug Only a few studies have compared the pharmacokinetics of gested therapeutic range used in treating younger adults. As a result, and should be instructed to inform the physician whenever the desired clinical response may be achieved with a lower they are beginning a new medication, including any over-the dose. Because the and may significantly lower the concentration of carba serum elimination half-life may be prolonged, the dosing mazepine. However, it is not known if the total drug concentration, measurement of the unbound drug elderly will be more sensitive to this problem. Because of its effects on mood stabiliza bamazepine may cause imbalance and ataxia. One of the major con cerns with carbamazepine is its effect on sodium levels (54). Hyponatremia is a well-known phenomenon seen with carba Felbamate mazepine use, and may cause significant problems in younger adults, especially if there is polydypsia. The hyponatremia Felbamate is effective for localization-related epilepsies and associated with carbamazepine is more pronounced as a per appears to have a broader spectrum of effectiveness than some son becomes older (55). Elderly subjects had a lower mean clear a person is on a salt restriction diet or a diuretic. Felbamate is primarily metabolized by the liver and meters in the elderly will need to be studied. In the elderly, however, the half-life may be longer, and Gabapentin slow-release formulations may overcome the need to dose multiple times each day and may overcome some of the side Gabapentin is effective for localization-related epilepsies, effect problems associated with a rapid time to a high peak and has an efficacy profile appropriate for the elderly. Chapter 37: Epilepsy in the Elderly 465 Gabapentin has a short half-life that requires it to be given body clearance and an increased half-life up to 2. In the elderly, however, the half-life may longer in elderly subjects (age 61 to 88 years) who exhibited be longer due to a reduction in renal elimination. Levetiracetam also appears to withdrawal related to side effects was highest for carba have a favorable safety profile. Analysis of 3252 elderly per sons involved in studies of levetiracetam for epilepsy and Lamotrigine other conditions demonstrated that levetiracetam was well tolerated by the elderly (68). Lamotrigine is effective for localization-related epilepsies, and has an efficacy profile appropriate for the elderly. However, very few studies regarding lamotrigine and its effects on the Oxcarbazepine elderly have been published. Lamotrigine is primarily metabo lized by the liver using the glucuronidation pathway, which Oxcarbazepine is rapidly metabolized by first-pass meta unlike the P450 system, is thought to be less affected by age (61). The most extensive elderly oxcarbazepine study jects from the old-old age group showed that age did not affect involved low doses of oxcarbazepine given to 12 young and lamotrigine apparent clearance (62). Based on a study of 150 12 elderly healthy male volunteers and 12 young and 12 elderly subjects, the drop out rate due to adverse events was elderly female volunteers. At low doses of oxcarbazepine lower with lamotrigine (18%) than with carbamazepine (42%). Clinicians may want to consider other Oxcarbazepine can affect the cytochrome P450 system by factors when dosing elderly lamotrigine patients. However, oxcarbazepine appears to have a more creatinine ratio, weight, and phenytoin use (63). However, these drug inter Pregabalin action studies included very few elderly subjects. Levetiracetam has been approved as adjunctive therapy for partial-onset seizures in adults. Levetiracetam is extremely Tiagabine water soluble, which allows for rapid and complete absorp tion after oral administration.

Routine susceptibility testing of this species is macrolide-containing regimens for patients with dissemin not recommended (43) medications 247 order primaquine 15mg with visa. Until further data are available medications post mi order primaquine 15 mg online, the isolate is found on subsequent testing to be macrolide resistant treatment eczema buy discount primaquine on-line. If the isolate proves to be rifampin resistant symptoms 9f anxiety purchase generic primaquine, suscepti species that are macrolide resistant treatment 2011 buy cheap primaquine 7.5mg. Susceptibility testing of these species is difficult even with multiple cultures of the same strain (43) brazilian keratin treatment purchase online primaquine. There are no current recommendations for one specic clude sputum production, fatigue, malaise, dyspnea, fever, he method of in vitro susceptibility testing for fastidious moptysis, chest pain, and weight loss. Evaluation is often complicated by symptoms caused by coexisting lung diseases, such as bronchiectasis, chronic obstruc 7. Physical ndings are nonspecic and reect underlying pul monary pathology, such as bronchiectasis and chronic obstruc tive lung disease. Pulsed-eld gel electrophore sis (nodular/bronchiectatic disease) (see the online supplement). These biopsies are performed because of the small size of the tissue ndings correspond histopathologically to bronchiectasis, bron sample) but demonstrates mycobacterial histopathology features chiolar and peribronchiolar inammation, and granuloma for (without a history of other granulomatous or mycobacterial dis mation (94). Unfortunately, A plain chest radiograph may be adequate for evaluating many antigenic epitopes are shared by different mycobacterial patients with brocavitary disease. A single positive sputum culture, especially with a small number of organisms, is generally regarded as indetermi 1. Overly rigorous criteria might delay or tive, subsequently developed new chest radiographic abnormali prevent the diagnosis, with the subsequent risk for progressive tites. If a tissue times be made on the basis of smear and culture positivity or sample from a transbronchial, percutaneous, or open-lung biopsy negativity without quantitation. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules (A, I)* and 2. No pathologic studies have been done to demon be helpful for making this decision. The signicance of a single sputum specimen culture posi absence of radiographic evidence of pulmonary disease, respira tive for a nontuberculous mycobacterium is more uncertain. Given these considerations, the diagnosis of lung disease apy before species identication of the mycobacterial isolate. There have been with these clinical scenarios must be evaluated carefully, on an numerous reports of clinical deterioration and death temporally individual basis, and may require expert consultation. Smear results were cede any initiation of macrolide monotherapy, and cultures for positive in 26% of culture-positive specimens. Surgical airway disease and altered mucociliary clearance may be predis resection, lobectomy or pneumonectomy, should be reserved for posing factors. Poor control of the mycobac of patients on hospital wards for prolonged periods of time terial infection with medical management and, particularly, isola raise questions about person-to-person transfer or nosocomial tion of M. During tential sources of concern as was noted in a recent study of periods of clinical decline while unresponsive to treatment an M. Occasionally, hypoxemic respiratory failure requires hospitalization or intensive care unit Hypersensitivity-like Disease admission. The water sources, this syndrome has been reported in at least one histopathology is that of nonnecrotizing granulomas although case associated with a household shower (137). Because of the necrotizing granulomas, organizing pneumonia, or interstitial potential for acquiring this disorder from multiple sources, it pneumonia may also be described in some patients (149). Even if nonspecic, identifying characteristic histopathol bacteria are relatively resistant to disinfectants and may be able ogy on biopsy may be sufficient to raise suspicion for diagnosis. In addition, mycobacteria are also quite resistant to cases (see online supplement). Findings include diffuse inltrates agents used for disinfection, including quaternary ammonium with prominent nodularity throughout all lung elds. Pulmonary function testing demon chlorine would be expected to kill nonmycobacterial ora and strates mixed abnormalities. Blood tests are not sufficiently spe therefore could permit the growth of mycobacteria in the absence cic to be of diagnostic value. Key elements to a diagnosis are a compatible clinical tients often enter the hot tub before bathing, adding contamina history (including a hot-tub exposure), microbiology, radiographic tion. Interestingly, patients will often spend additional time in studies, and histopathology, when available. Mycobact cess, infectious process, or a combination of inammation and eria are also resistant to the heavy metals in metalworking uids infection. Exposure to these aerosols leads to hypersensitivity-like treatment recommendations; therefore, recommendations are pneumonitis similar to that seen with hot-tub exposure but asso based on expert opinion. Despite disinfection with multiple source (contaminated hot tub), the use of antimycobacterial ther agents, M. Similarly, for metal grinders, avoidance of mycobacterial Patients who have colonization of their respiratory and gastrointes (M. Corticosteroid tinal tracts are at higher risk of developing disseminated disease administration may also be associated with clinical improvement. For indoor pools and hot tubs, manufacturers universally recommend following regular maintenance procedures usually been less than 25 cells/ l (156, 157). Labora to occur late in the post-transplantation course and has been tory abnormalities may include severe anemia, with a hematocrit of frequently associated with preexistent chronic rejection (130). In the United gans, even if localizing signs and symptoms are not apparent States and Australia, the remaining cases are caused by (171). In one series of 200 patients with documented dis and other areas of northern Europe, M. The involved lymph none had active pulmonary disease, although a high percentage nodes are generally unilateral (95%) and not tender. Other nodal groups sample should alert the clinician to investigate for disseminated outside of the head and neck may be involved occasionally, disease and to consider preventive therapy. Suppurative lymphadenopathy, with swollen in adults, more than 90% of the culture-proven mycobacterial and painful cervical, axillary, or inguinal nodes, is the most lymphadenitis is due to M. For symptomatic patients with two negative culin have a range of reactions from negative to positive; up to blood cultures, biopsy and culture of bone marrow or liver are one-third in one series showed reactions of 10 mm or more sometimes indicated. However, granulomata or retroperitoneal adenopathy may require ne needle aspiration other compatible cytopathology, such as a mixture of degenerating of the involved lymph nodes for diagnosis. Failure of the lymph between 1 and 5 years old is the most common presentation of node culture to yield M. Even with excised nodes showing compatible histopathol adenitis in children have been identied, but children with bacille ogy, only 50 to 82% will yield positive cultures (188, 189). Localized drainage or abscess were recovered from 42 of 108 (32%) tested locations, which formation at the site of puncture wounds (such as occurs after included homes, hospitals, commercial buildings, and reservoirs stepping on a nail) or open traumatic injuries or fractures are (224). Nosocomial skin and soft tissue infections from other environmental sources (225). These spe catheters, postinjection abscesses, infections after liposuction, cies are capable of growing in hospital water kept at tempera or surgical wound infections of the skin after augmentation mam tures as high as 55 C. Diagnosis is made by culture of the specic patho and are generally found only in cold-water systems. Tissue biopsy is the Biolms, which are the lmy layer at the solid (pipe) and most sensitive means of obtaining a specimen for culture. These mycobacterial species as well as others without apparent trauma, presumably due to hematogenous in are incredibly hardy, and resist the activity of organomercurials, fection. After open heart surgery, osteomyelitis of the sternum chlorine, 2% concentrations of formaldehyde and alkaline glutaral caused by M. An expansive or all-encompassing discussion of Recently, mycobacterial outbreaks of M. The whirlpool isolates were subsequently molecularly American Thoracic Society Documents 385 identied as the same strains as those recovered from patients. However, they have also been reported after insertions of prosthetic devices such as (but not. Recognition of outbreaks: Be familiar with the settings water is not acceptable, especially for a terminal rinse. A similar outbreak has been raises the question, Can environmental shielding protect patients described in San Antonio, Texas (108). A consensus among experts has not been reached events, unnecessary expense incurred by the hospital and pa on these important questions. This issue is yet to be assessed or addressed by public Recommendations: health personnel. The instruments should the rst clue to the identity of a nontuberculous mycobacte have a terminal alcohol rinse. Less as a result of specimen contamination than as a result of than 15% of cases, however, can be traced to this source, sug disease. However, even these species can, under some gesting that other environmental reservoirs are also important. The clinician should use sion than cavitary disease, such that long-term follow-up (months in vitro susceptibility data with an appreciation for its to years) may be necessary to demonstrate clinical or radio limitations. The major limitations for effective therapy were the sputum conversion rates at 6 months were comparable between absence of antimicrobial agents with low toxicity and good azithromycin and clarithromycin-containing regimens (67 vs. Patients received rifampin and ethambu and azithromycin, and presumably all other macrolides. Another similar study, however, failed to show clarithromycin and azithromycin, which have substantial in vitro a similar benet of clarithromycin-containing regimens (277). In a second trial, azithromycin and all compan able and inconsistent drug combinations, this study demon ion medications were given on a three-times-weekly basis. The choice of therapeutic regimen for a specic patient de Some of the important unresolved controversies in the management pends to some degree on the goals of therapy for that patient. Rifabutin also affects clarithromycin metabo on the clinical presentation and needs of an individual patient. Some beneficial effect of macrolide-containing treatment regimens for patients with bronchiectasis could be due to immune-modulating effects of the macrolide (296). American Thoracic Society Documents 389 the tolerance of the patient to specic drugs and drug combina attenuated doses, then gradually increasing the desired therapeu tions. The collective clinical experience also supports the use 10 mg/kg day (maximum, 600 mg/d). For many patients, the of the parenteral aminoglycoside therapy in extensive or drug doses of clarithromycin may need to be split. Although streptomycin has been used daily) because of gastrointestinal intolerance. Also, for patients more in this clinical setting than amikacin, there are no data with small body mass (50 kg) or older than 70 years, reducing demonstrating superiority of one agent over the other. Recent data suggest patients who do not tolerate daily medications, even with dosage that patients tolerate amikacin or streptomycin at 25 mg/kg three adjustment, should be tried on an intermittent treatment regi times weekly during the initial 3 months of therapy (297). Parenteral drugs are an option based on disease severity dosage would, however, be impractical for intramuscular admin and treatment response. For A more aggressive and less well tolerated treatment regimen older patients with nodular/bronchiectatic disease or patients for patients with severe and extensive (multilobar), especially who require long-term parenteral therapy. For extensive disease, day), ethambutol (15 mg/kg/d), and consideration of inclusion at least 2 months of intermittent (twice or three times weekly) of either amikacin or streptomycin for the rst 2 or 3 months streptomycin or amikacin is recommended, although longer par of therapy (see below). Selected patients in this disease category enteral aminoglycoside therapy may be desirable in patients with might be considered for surgery as well. Patients receiving very extensive disease or for those who do not tolerate other clarithromycin and rifabutin should be carefully monitored for agents. Some experts prefer amikacin to lar/bronchiectatic patient on all drugs at once on full doses of streptomycin due to a perceived difference in the severity of each medicine frequently results in adverse drug reactions re vestibular toxicity between the two drugs. Expert consultation should be sought for patients who within 12 months on macrolide-containing regimens (266). The optimal drug regimen for treating macrolide-resistant strains is a major Context: issue to be addressed in future studies as resistant strains become the following recommendations are for patients with macrolide more prevalent.

If appro priate methods and technical skill are not available to work up mixed cultures medications major depression 15mg primaquine otc, the culture should be sent to a reference laboratory or public health laboratory medications quotes order 15mg primaquine with amex. If a laboratory is performing culture facial treatment discount 7.5mg primaquine visa, having probes for identication may be useful medicine advertisements 15mg primaquine for sale, as they can provide a fast result for the most common species medications grapefruit interacts with generic 7.5 mg primaquine mastercard. If identication methods are not available medications you can crush generic 7.5mg primaquine, laboratories should refer isolates to an appropriate reference laboratory or public health laboratory. Because there is no a priori method of knowing which specimens may contain mycobacteria and which do not, all steps in specimen acqui sition, processing, and disposal must be designed to protect providers and laboratory personnel from exposure to infectious droplet nuclei (116). Performing risk assessment and stratication allows laboratory directors to design risk mitigation programs appropriate for each laboratory. As the use of molecular diagnostic assays increases, particularly self-contained systems with little or no need for specimen processing. The risk assessment may determine if agged positive vials may need to be transported using a leakproof container from room to room. Several aspects particular to the Xpert assay suggest that it might present a very low risk to testing personnel (121). After a 15-min incubation, the sputum sample treatment reagent mixture is transferred to a plastic assay cartridge, the cartridge lid is closed, and the cartridge is placed into an Xpert instrument. Adhere to the scheduled quality control and maintenance procedures for the autoclave. Package waste so that the outside of the container can be disinfected before it leaves the laboratory. Disposal of laboratory and other hospital/clinic waste poses unique challenges due to the presence of many types of labels attached to a wide variety of products. The most common approach is to use labels that darken during autoclaving, thereby obscuring the wording and numbering on labels. The intent of this section is not to delineate specic protocols for processing but rather to provide overall principles regarding various aspects of laboratory diagnosis as well as other details to aid in protocol development. Most specimens will be obtained from the respiratory tract, especially expectorated and induced sputum (the optimal volume is 5 to 10 ml), bronchial aspirates, and bronchoalveolar lavage uids. Designed to detect sputum contaminated with upper respiratory ora, the two criteria commonly used to assess sputum quality for bacterial culture, i. Processing of inappropriate clinical specimens for mycobacterial detection is a waste of both nancial and personnel resources. In cases where the specimen is less common, involves an invasive procedure, or could not otherwise be easily re-collected, an exception to the rejection criteria may be justied. Processing of Specimens for Mycobacterial Stains and Culture Due to the lengthy incubation times required for the growth of most Mycobacterium spp. Sterile tissues and body uids may not need decontamination; however, sputum, bronchoalveolar lavage uid, stool, urine, skin, and many other specimens that usually contain contaminating microbes need to be decontaminated to allow the growth of mycobacteria. The chosen decontamination process should not seriously affect the viability of mycobacteria. All samples, sterile and nonsterile, should also be concentrated to maximize the recovery of mycobacteria. However, the inclusion of a positive control in the processing of patient specimens is controversial and is discouraged in the United States due to the risk of cross-contamination (1). Sterile specimens should be transported to and processed in the laboratory as soon as possible. Liquefaction of the specimen and decon tamination are essential for sputum and other respiratory tract specimens, stool, skin scrapings, and urine. It is important to mix the solution vigorously until it is liqueed (about 5 to 20 s on a test tube mixer) and to invert each tube to ensure that the solution contacts all inside surfaces of the tube and cap. Nonsterile specimens should be transported to the laboratory and processed as soon as possible. Urine can be distributed in up to four 50-ml conical tubes, and the sediments can be combined; up to1gofformed stool samples should be emulsied in saline and thoroughly vortexed, and the particles should be allowed to settle out before processing the top portion of the liquid (1). Chlorhexidine, which is potentially toxic to mycobacteria, must be inactivated by incorporation with egg lecithin in the culture medium. There are many types of broth media, many of which are included with automated mycobacterial detection systems; most are based on Middlebrook 7H9 broth. Table 6 lists the various types of media that are available, while Table 7 summarizes salient features of automated broth-based culture systems. Of signicance, some decontamination/concentration procedures are known to be compatible with egg-based media only and may not be used with any other media not containing egg yolk. Tubed media should be incubated in a slanted position with screw caps loose for at least 1 week to ensure an even distribution of the inoculum (75). For the isolation of mycobacteria, the use of a liquid medium in combination with at least one solid medium is essential for good laboratory practice (141). Table 8 summarizes the claims and performance characteristics of these two commer cial assays. For this reason, amplication technologies should not be used on specimens collected from patients who have received antituberculosis drugs for more than 7 days or have received such therapy in the last 12 months prior to collection (148, 149). Therefore, the positive predictive value is likely to be lower in the United States. The duration of the continuation phase regimen hinges on the microbiological status at the end of the intensive phase of treatment; thus, obtaining a sputum specimen at the time of completion of 2 months of treatment is critical if sputum culture conversion to a negative result has not already been documented. The culture result of a sputum specimen obtained at the comple tion of the intensive phase of treatment (2 months) has been shown to correlate with April 2018 Volume 31 Issue 2 e00038-17 cmr. A comparison of prestained Ziehl-Neelsen versus prestained Kinyoun smears for the evaluation of differences in reading capabilities of participants revealed a signicantly better performance of the Ziehl-Neelsen staining method (P 0. These organisms may not always be acid fast with carbol fuchsin (1), auramine O (175), or auramine-rhodamine stain (175). Recommended interpreta tions of and ways to report results are shown in Table 11. Since many mycobacteria are slowly growing organisms, cultures can be examined for colony formation less frequently than routine bacterial cultures. All solid media should be examined within 3 to 5 days after inoculation to determine if there is contamination. Also, it is advisable to subculture the broth on a blood or chocolate agar plate to rule out contamination. In many larger laboratories, sequence-based identication has become a primary method to rapidly identify mycobacteria. The entire gene is 1,550 bp, including the conserved and variable regions, but a discriminatory sequence can generally be obtained by using 500 bp (185). Further differentiation may be required for some of these groups for epidemiological or clinical reasons. When possible, additional language should be included in the report regarding the M. The spectral data are then compared to a database to determine the likely identity of the organism. A preextraction step must occur, usually involving bead beating or vortexing in ethanol, formic acid, and acetonitrile; the extracted proteins are then spotted onto the plate (194, 195). Unfortunately, this delay increases the time to reporting compared to what can be achieved with sequencing. The mycobacteria may be identied to the species or to the species-complex group level. Conventional Biochemicals Identication of mycobacteria has traditionally relied on phenotypic characteristics such as the growth rate, colony morphology and pigmentation, optimal growth temperature, and reactions in a battery of biochemical tests. In addition, variability in phenotypic characteristics can be seen within strains of a species. Many of these new species have not been characterized biochemically and cannot be reliably identied by using biochemical methods. In programs using ooxacin or levooxacin and moxioxacin, possible testing is for moxioxacin only at both concentrations (0. For programs using only moxioxacin, testing is performed with the higher concentration (2. Essentially, the critical concentration differentiates antimicrobial susceptible from antimicrobial-resistant strains and is based on international con vention (215, 216). In cases where cultures are mixed, agar plates are useful for identifying and separating M. Some laboratories may use EpiCenter software in order to monitor growth dynamics (220). A summary of the most commonly used growth-based methods in the United States is provided in Table 13. If molecular methods for the detection of resistance are not performed, the specimen/isolate may be referred to a laboratory that has the capability to perform this testing, such as a reference laboratory or a local or state public health laboratory. Sequencing methods can be used to target a variety of genes to determine mutations associated with resistance. This section discusses several quality assurance features that laboratories should consider integrating into their quality management program in the mycobacteriology labora tory. Within the quality plan, several parameters should be addressed, including general laboratory systems and preanalytical, analytical, and postanalytical phases of testing. A clear process that addresses the development and use of quality indicators is effectively described in this document, along with other meaningful tools related to process improvement. It is incumbent on the laboratory to appropriately communicate specimen requirements to the health care provider to ensure the best-quality outcome for the patient. Provider instructions are a crucial component to ensure that adequate specimens are collected, labeled, and transported appropriately for processing. If specimens that are 5 ml are routinely submitted, there should be a mechanism in the laboratory to monitor appropriate specimen collection (see Acceptable Specimens and Rejection Criteria, above), and the laboratory should consider a quality monitor to assess specimen volume and have a mechanism for provider feedback if specimen requirements are not being followed (103). It is recom mended that the provider be notied of unsatisfactory specimens as soon as possible or within 24 h. Instructions to the provider should clearly state that sputum from deep in the respiratory tract is the optimal specimen, as opposed to saliva. Monitoring the number of specimens per patient can also be part of a robust quality assurance program. In larger systems, tracking the numbers of specimens per patient could be onerous unless an electronic mechanism to do so is readily available. Specimen delivery can also be broken down into many segments to monitor how effectively specimens are being transported to the laboratory for processing, especially if the laboratory is in a remote location compared to either the hospital or outpatient facilities. Specimen Processing and Decontamination Specimen management is very important across all clinical laboratory disciplines. If these numbers cannot be met, laboratories should consider referring specimens to a reference laboratory for testing. After an extensive review performed in 2000, it was determined that the median false-positive rate due to cross-contamination in the mycobacteriology labo ratory was approximately 3. The laboratory understanding of a root-cause analysis can be crucial to investigations related to contamination events (132). However, the inclusion of a positive control in the processing of patient specimens is discouraged due to the risk of cross-contamination (1). To resolve whether a cross-contamination event has occurred, laboratories can send out the isolates from the single-positive patient and the sentinel (possible source specimen from a known positive patient) for genotyping. If a contamination rate of 5 to 8% is observed, monitoring the time of transport of the specimen to the laboratory may be prudent, as delays in specimen submission may be occurring. However, if the positivity rate decreases compared to anticipated percentages, this might mean that the decontamination procedure is too stringent, resulting in false-negative cul tures. All these quality monitors are important for assessing the robustness of the processes and procedures in the mycobacteriology laboratory (103). Consultation with other colleagues is also prudent when looking for new avenues for continuous quality improvement, in addi tion to many of the references in this section. Table 15 lists several quality monitors that may be appropriate for laboratories that test specimens for mycobacteria, and bench marks can be found in Table 4. T-Cell Xtend contains antibodies that cross-link granulocytes to red blood cells and separate the granulocytes, which may reduce the viability of mononuclear cells and reduce their ability to release interferon gamma, from the mononuclear cells during centrifugation (265). A conjugated secondary antibody is then added, which April 2018 Volume 31 Issue 2 e00038-17 cmr. As for all tests, the results should be interpreted in conjunction with results of other diag nostic tests and epidemiological information to help determine the M. Reporting the quantitative value is important, especially when interpreting results from serial testing. The T-Spot Xtend reagent can be used to extend the time from collection to sample processing in the laboratory to 30 h, as noted above.

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