Penulis Topik: Drug Fever (Dibaca 8041 kali)

syx · « **pada:** Pebruari 04, 2010, 07:00:21 AM »

sedikit artikel tentang demam karena obat...

Drug Fever
Ruchi A. Patel, Pharm.D.; Jason C. Gallagher, Pharm.D.

Abstract

Drug fever is a common condition that is frequently misdiagnosed. It is a febrile response that coincides temporally with the administration of a drug and disappears after discontinuation of the offending agent. Drug fever is usually suspected when no other cause for the fever can be elucidated, sometimes after antimicrobial therapy has already been started. In nonsensitized individuals receiving a drug for the first time, the onset of fever is highly variable and differs among drug classes, but most commonly appears after 7–10 days of drug administration and rapidly reverses after discontinuation of the drug. Early diagnosis may reduce inappropriate and potentially harmful and expensive diagnostic and therapeutic interventions. Rechallenge with the offending agent will usually cause recurrence of fever within a few hours, confirming the diagnosis. Rechallenge is controversial and should be performed with extreme caution, since there is a potential for a more severe drug reaction. We describe the mechanisms in the pathophysiology of drug fever and summarize the results of published case reports on the wide variety of agents that are implicated in causing drug fever. Special attention is paid to the role of antimicrobial agents in drug fever.

Introduction

Drug fever is a common condition that manifests with an often unclear diagnosis.[1, 2] It is important for clinicians to suspect drugs as a cause of fevers of unknown origin.[1] Since a common response among clinicians to a patient's fever is to suspect infection, drug fever can lead to overutilization of antiinfectives and other agents to treat infections that are not present, possibly increasing the risk of adverse effects and the further development of antimicrobial resistance.[1] Fever that is due to a drug is also significant in that it may precede or accompany more serious adverse drug reactions.[3, 4] Drug fever is particularly problematic when it occurs during the course of an infection, since it can mislead clinicians into believing that a successful course of therapy is failing.

To gain a better understanding of the diagnosis, mechanisms, and management of drug fever so that we could increase awareness among clinicians, we conducted a literature search using the MEDLINE database (1950–2009). Search terms were drug fever, hypersensitivity reactions, drug-induced fever, and drug reactions. References in review articles were also evaluated.

Definition

Drug fever is a disorder characterized by a febrile response coinciding temporally with the administration of a drug in the absence of underlying conditions that can be responsible for the fever.[1, 2, 4, 5] A key feature that differentiates drug fever from fever of other causes is that it disappears once the offending drug is discontinued.[2, 3] Drug fever tends to be a diagnosis of exclusion, often suspected in patients with otherwise unexplained fevers.[6]

It is important for clinicians to maintain an index of suspicion for the possibility of drug fever and be aware of the most common offending agents in order to avoid expensive diagnostic work-up for further evaluation, incorrect treatment with antibiotic therapy, possible adverse effects, and prolonged hospital stays.[2, 7, 8] A review of 97 patients with drug fever, whose cases had been reported in the literature between 1966 and 1986, revealed that 39 were admitted specifically for a work-up of drug fever.[9] The same review identified 51 patients with drug fever at two Dallas hospitals between 1959 and 1986. In hose cases, episodes of drug fever led to a mean prolongation of hospital stay of 8.7 days. In addition, each drug fever episode resulted in an average of 5 blood cultures, 2.85 radiologic studies, and 0.53 courses of antibiotics. Another review over a 2-year period of 36 patients with drug fever found that delaying the diagnosis of drug fever resulted in an average cost of $493 for diagnostic procedures for each case of drug fever.[7] It is clear that drug fever can be an expensive complication.

A wide variety of agents can cause drug fever (Table 1).[7, 9–71] However, the list of drugs that are most frequently implicated is rather short and includes antimicrobials, anticonvulsants, antiarrhythmic agents, and other cardiac agents.[6, 9] Tables 2, 3 and 4 summarize the number of cases reported in the literature for each incriminating agent, as well as clinical and laboratory findings associated with each case.

Epidemiology

Drugs have been estimated to cause 10–15% of adverse events in hospitalized patients in the United States.[1, 3, 6] However, drug fever as the sole manifestation or the most prominent clinical feature of an adverse reaction occurs in only an estimated 3–5% of cases.[2, 72] The actual frequency of drug fever is unknown due to underreporting and frequent misdiagnosis.[3, 6] Since conducting clinical trials to specifically evaluate drug fever is not practical, the estimated rate of drug fever with individual agents is largely based on the number of reports on the agent either in safety reports of other studies or as case series. As a result, the accuracy of characterizations of the epidemiology of this disorder is uncertain.[8]

Physiology of Fever

The thermoregulatory center in the preoptic area of the anterior hypothalamus is responsible for maintaining control of the temperature set point in humans.[4] During fever, there is an upward shift in the thermoregulatory set point.[4, 73] Various exogenous pyrogens activate phagocytic leukocytes to produce endogenous pyrogens, primarily interleukin-1.[4, 73] Interleukin-1 excites the neurons in the anterior hypothalamus and initiates thermoregulatory events by causing an increase in production of prostaglandins, cyclic adenosine monophosphate, and nervous system monoamines, all leading to elevation of the thermoregulatory set point.[4, 73, 74] The body compensates by minimizing heat loss by heat conservation and heat production.[73, 74] Blood and core temperatures will continue to rise until they match the thermoregulatory set point.[73, 74] Pathophysiologically, a drug might cause fever by five principal mechanisms: interference with peripheral heat dissipation, alteration of central temperature regulation, evocation of either a cellular or humoral immune response, exogenous pyrogenicity, and the direct damage of tissues.[74]

Diagnosis

The key to diagnosing drug fever is to consider it in any patient in whom no other cause for fever can be elucidated, particularly when fevers do not correspond with likely infection.[3] The diagnosis is often difficult, and it should be made after a careful review of a patient's clinical presentation, drug therapy, and laboratory values. Drugs should be considered in the differential diagnosis of fever in many patients, particularly for those who are taking agents that are highly implicated with causing drug fever.[4, 72] In practice, the first assumption of most clinicians is to search for or treat a suspected infection, a process that is logical but can lead to the frequent overuse of antibiotics. Fever can be a characteristic of many disease processes other than infection, including malignancy, thromboembolic disease, cerebrovascular accidents, collagen vascular diseases, acute gout, surgery, and trauma.[4] If fever is unexpected, particularly in a situation when a patient is otherwise clinically well or improving, then drug fever should be considered in the differential diagnosis.[4, 73] A definite diagnosis can be made only when the fever resolves after discontinuing the implicating agent. Recurrence of fever after rechallenge of the suspected agent solidifies a diagnosis of drug fever but is a dangerous practice that should generally be avoided.

syx · « **Jawab #1 pada:** Pebruari 04, 2010, 07:04:57 AM »

Clinical Features

Drug fever may occur at any point during a course of drug therapy, and there is significant variation among different drug classes. The median time between initiation of the offending agent and onset of fever is 7–10 days.[4, 72] In the previously discussed review article,[9] the lag time between the initiation of the offending agent and onset of fever was found to be highly variable and also dependent on the drug class. The shortest intervals between initiation of therapy and onset of fever were observed with antineoplastic agents (median 0.5 days, mean 6 days) and antimicrobials (median 6 days, mean 7.8 days). A longer time interval was seen with central nervous system agents (median 16 days, mean 18.5 days) and cardiovascular drugs (median 10 days, mean 44.7 days). The shorter median lag time with antineoplastic agents compared with any other agent was significant. Although variability among the different classes of agents was apparent, this may have been biased toward longer times to onset by the exclusion of cases of fever due to drug administration, which occur more rapidly.

Various patterns of fever occur in patients with drug fever.[9, 72, 75] Different patterns include the following: continuous fevers; remittent fevers, in which temperatures vary but are consistently elevated from normal; intermittent fevers, which are interrupted by daily normal temperatures; and hectic fevers, which manifest as a combination of intermittent and remittent fever patterns. Hectic fever is the most common pattern, particularly since the use of antipyretic drugs and cooling blankets can change a pattern of fever from its natural course.[1, 9] In addition, the degree of pyrexia can vary as well, ranging from a low-grade temperature of 99°F to temperatures as high as 109°F, but elevated temperatures of 102–104°F are most common.[3, 4, 6] No strong relationship has been noted with the severity of clinical features and maximum temperature except that higher temperatures have been noted in patients taking antineoplastic agents, which could also be attributable to the underlying disease.[6]

Patients with drug fever often appear "inappropriately well" for the degree of fever that they have.[4, 72] They are also frequently unaware of their fevers.[4] Another clue aiding in detection of drug fever is relative bradycardia, a condition that occurs when the heart rate does not increase to the extent that typically accompanies the temperature elevation.[3, 76] To determine the presence of relative bradycardia, a temperature of at least 102°F is required, and sinoatrial disease or drugs that affect heart rate must not be present.[3, 76] To compute the approximate expected pulse response for a given temperature, one uses the last digit of the temperature reading in Fahrenheit and decreases it by 1. This number is multiplied by 10, and then added to 100. For example, for a temperature of 103°F, the appropriate pulse response would be approximately 120 beats/minute. Any value less than this would be considered relative bradycardia and therefore may be indicative of drug fever.[3]

Cutaneous manifestations of hypersensitivity are observed in 18–29% of patients with drug fever.[6, 9, 75] A generalized maculopapular rash occurs in a minority of patients and may be urticarial with or without petechiae.[3] Since cutaneous manifestations are not universal, their absence does not rule out a diagnosis of drug fever. Drug fever may precede a more overt drug reaction and may be the first clinical sign of an impending severe drug reaction.[4, 76] If a hypersensitivity reaction causing the drug fever is allowed to continue without discontinuing the drug, the patient may develop a drug rash or other clinical manifestations.[4, 76]

Laboratory Findings

Laboratory findings can be helpful in supporting a diagnosis of drug fever, although they are highly variable and cannot be relied on for a definitive diagnosis.[72] A leukocyte count with a differential should be performed for all patients with suspected drug fever. Leukocytosis with or without a left shift may be present.[3] The finding of leukocytosis with fever should prompt clinicians to reevaluate the possibility of infection. Eosinophil levels are frequently elevated, but true eosinophilia is less common.[3, 4] The erythrocyte sedimentation rate may also be slightly elevated. Erythrocyte sedimentation rates can be 100 mm/hour or greater, but values of 40–60 mm/hour are more common.[3, 4, 76] Mild elevations of hepatic transaminase levels may also be observed; however, they are no more than 2 times the upper limit of normal in approximately 90% of patients.[3, 4, 76] Lactic dehydrogenase levels may also be elevated.[75] Normal values do not preclude the diagnosis of a druginduced fever. No other laboratory test is consistently useful in diagnosis. The demonstration of antibodies to a drug by serologic or skin test is not helpful since these often develop in asymptomatic patients lacking clinical hypersensitivity.[72]

Although abnormal laboratory values and other clinical findings may support the diagnosis of fever, they are not present in all drug fever cases. In the previously discussed review,[9] relative bradycardia occurred in 11% of patients, whereas leukocytosis, eosinophilia, and skin rash were noted in 22%, 22%, and 18% of the patients, respectively.

Risk Factors

There are disagreements in the literature about which populations are most vulnerable to drug fever. Some publications have found that women and older populations are at increased risk for developing drug fever, particularly due to drugs other than antibiotics.[2, 6, 72] However, younger patients may be at increased risk for developing drug fever due to antibiotics.[6] The previously discussed review did not support either of these suppositions.[9] That review suggested that women and elderly patients are no more likely to experience drug fever than are other patients. The authors also found that patients with a history of drug allergies and atopic disease are no more likely to experience drug fever than are other patients.[2, 9] Despite these disagreements, certain patients may be predisposed to developing drug-induced fever. As with other types of allergic reactions, the sensitivity of a patient to one drug is often associated with sensitivities to other agents.[4]

Mechanisms of Drug Fever

Five mechanisms of drug fever have been identified. Fevers may arise from a drug's effects on thermoregulation, administration-related reactions, the drug's pharmacologic action, idiosyncratic response, and hypersensitivity reactions; this latter is the most common mechanism of drug fever.[1, 4, 72] Table 5 categorizes the drugs believed to cause fever by these mechanism.

syx · « **Jawab #2 pada:** Pebruari 04, 2010, 07:05:34 AM »

Altered Thermoregulatory Mechanisms

A variety of drugs can disrupt thermoregulatory mechanisms by either increasing heat production or limiting heat dissipation.[1] Levothyroxine sodium is an example of a drug that increases metabolic rate, therefore directly increasing heat production.[4, 72] This is due to the direct effects of the drug and can occur regardless of the patient's underlying thyroid state. Sympathomimetic agents such as cocaine, 3,4-methylene dioxymethamphetamine (MDMA, or "Ecstasy"), and amphetamine act centrally on the hypothalamus to cause fever.[1, 72] Hyperthermia induced by MDMA is a result of increased serotonin release.

Serotonin appears to have temperature rising effects, and the typical clinical manifestation of MDMA-induced hyperthermia is similar to serotonin syndrome.[77] Epinephrine raises body temperature by promoting peripheral vasoconstriction.[72] Certain drugs possessing anticholinergic activity such as atropine, antihistamines, tricyclic antidepressants, phenothiazines, and butyrophenone tranquilizers all reduce heat loss through controlling sweat gland secretion, which can possibly lead to druginduced fever; however, it does not appear that drug fever occurs with all agents in each of these drug classes.[1, 2, 72] Marked hyperthermia can occur when phenothiazines and anticholinergics are taken in combination to decrease extrapyramidal effects, or when taken in increased doses.[3] Monoamine oxidase inhibitors can cause hyperthermia by increasing metabolism through elevating levels of tissue catecholamines and thereby increasing heat liberation.[3] Cimetidine blocks histamine2 receptors in the hypothalamus and has been reported to cause drug fever through this mechanism. Many of these agents that cause an alteration in thermoregulation result in clinically evident fever only in overdose situations.[4]

Drug Administration–Related Fever

The process of administering a drug can directly result in a febrile reaction. Fevers can be due to contamination or due to the intrinsic effect of the drug itself.[72] Pyrogens not removed during the manufacturing process may contaminate some antibiotics, chemotherapy agents, and streptokinase, although manufacturing processes have improved as they have progressed.[2] Vancomycin at one time used to contain impurities ("Mississippi mud") and was a wellknown source of drug fever; since then it has been reformulated and is now rarely a culprit of administration-related drug-induced fever.[2, 3] Drugs such as amphotericin B formulations and bleomycin sulfate have intrinsic pyrogenic activity that causes elevations in temperature purportedly by causing the release of endogenous pyrogens (interleukin-1) from granulocytes.[1, 72, 73] Administration-related fever may also occur with injection, as a result of phlebitis from the infusion of irritating solutions such as cephalosporins and vancomycin.[3, 4] Infusion-related phlebitis may lead to an inflammatory response resulting in the release of cellular pyrogens that can cause fever. A sterile abscess and fever can develop after intramuscular injection of pentazocine and paraldehyde.[1] Vaccines and allergenic extracts cause pyrexia through a similar mechanism because they contain bacterial or viral pyrogens.[3, 4] Fevers from administration-related reactions can occur during or within hours of the administration of a drug.[1, 3] Delayed reactions are uncommon.[1, 3]

Fever Related to Pharmacologic Action of the Drug

Sometimes the pharmacologic effect of a drug is itself the cause of drug fever. The Jarisch-Herxheimer reaction is a classic example that is seen during antibiotic therapy for spirochetal diseases such as syphilis, leptospirosis, and borreliosis.[1] The hypothesis is that the release of endotoxins from killed or dying organisms leads to a febrile reaction.[1] Endotoxin, also known as lipopolysaccharide, is an integral part of the cell wall of gram-negative bacteria and is released when neutrophils digest the organisms.[78] A febrile response usually occurs 6–8 hours after initiation of therapy.[4] Another example includes fever induced by antineoplastic agents.[3, 4] These agents can elicit fever when neoplastic cells damaged by the drugs release endogenous pyrogens that act on the hypothalamus and cause pyrexia.[1, 73, 74] Drug fever by this mechanism has been reported with cytosine arabinoside, bleomycin, chlorambucil, vincristine, asparaginase, streptozocin, and cisplatin.[2, 8, 17, 24, 25, 46, 66, 71] Case of drug fever occurring with 6-mercaptopurine and chlorambucil have been reported in patients with lymphoproliferative disease.[9, 21] It has been postulated that drug sensitivity reactions occur as part of an altered immunologic response by the lymphoproliferative disease.[21] Indirect pharmacologic actions of drugs can also result in development of fever, which has been suggested with the use of heparin and warfarin when excessive anticoagulation causes bleeding into enclosed spaces.[3]

Idiosyncratic Reactions

In certain patients, febrile idiosyncratic drug reactions can develop due to hereditable genetic predisposition.[8, 74] The most notable example of this is malignant hyperthermia, which is a disorder characterized by marked hyperthermia (temperature > 106°F), muscular rigidity, tachycardia, arrhythmias, and hypotension in patients undergoing treatment with inhaled anesthetic agents.[73, 74] The most commonly implicated agents include halothane (alone or in combination with succinylcholine), isoflurane, and enflurane. The mechanism is thought to be due to a genetic defect resulting in abnormal release of calcium ions into the muscle myoplasm, leading to catabolic reactions that produce a large amount of heat.[74] This type of hyperthermia is a medical emergency and must be reversed immediately by dantrolene to prevent tissue damage.[79]

Neuroleptic malignant syndrome (NMS) is more commonly encountered by clinicians and is characterized by hyperthermia, muscle rigidity, fluctuating consciousness, and autonomic disturbances.[4, 80] It is most commonly associated with highly potent dopamine2-receptor antagonists such as the phenothiazines, haloperidol, and thiothixene.[3, 4, 77, 80] Dopamine antagonists cause NMS in 0.02–2.4% of patients due to effects on hypothalamic heat-conserving mechanisms, which occur as a result of blockade of dopamine receptors.[77, 79] The onset is often related to an increase in dosage, and the reaction occurs over 1–6 days.[77] The NMS may respond to dantrolene, to dopamine agonists such as bromocriptine, and to a discontinuation or reduction in the dose of the responsible drug.[79]

Some drugs may cause a hemolytic reaction in patients with a deficiency of glucose-6-phosphate dehydrogenase, which can be accompanied by fever.[73] Numerous drugs, such as the sulfonamides, antimalarial agents (e.g., primaquine), nitrofurantoin, quinidine, and chloramphenicol, have been associated with this reaction.[1, 4] The mechanism is due to release of endogenous pyrogens by the hemolyzed red blood cells that cause an elevation in body temperature.[3]

syx · « **Jawab #3 pada:** Pebruari 04, 2010, 07:08:20 AM »

Hypersensitivity

The most common mechanism for drug fever is due to a hypersensitivity reaction.[1–3, 72, 73] Several types of hypersensitivity that lead to drug fever have been proposed. The most probable mechanism is mediated by a humoral response.[4] Drugs or degradation products may act as either a complete antigen or a hapten.[4] Haptens are small molecules that can elicit an immune response only when attached to large carrier proteins to form functional antigens.[78] The formation of circulating antibody-antigen complexes in combination with complement can stimulate the release of pyrogens from granulocytes, resulting in pyrexia.[3, 4] A second mechanism for the development of hypersensitivity that manifests as drug fever is through T-cell lymphocyte immune response or cellular immunity.[3, 4] The mechanism of pyrexia in cellular immunity appears to be due to production of nonpyrogenic soluble factors (lymphokines) that act on blood and tissue macrophages to produce and release endogenous pyrogen to result in fever.[3, 4, 72]

Most hypersensitivity reactions are not limited to drug fever.[72, 74] Since many other characteristics of an allergic response accompany the fever, the diagnosis of drug hypersensitivity can be made fairly easily when this is the case.[1, 4, 5, 72–74] Conversely, when drug fever without any evidence of obvious findings of hypersensitivity occurs, the diagnosis of drug hypersensitivity is considerably more difficult. There is no consensus on the frequency in which this occurs; estimates vary depending on the definition of drug fever that is used.[3, 73, 74] Drugs such as methyldopa, anticonvulsants (phenytoin, carbamazepine), antimicrobial agents, procainamide, quinidine, allopurinol, and others cause drug fever through this mechanism.[4, 18, 19, 73, 74]

The presence of antibodies in the serum does not prove a hypersensitivity reaction since they can be present in patients who demonstrate no signs of a drug reaction.[3, 4, 74] Also, the failure to detect the presence of antidrug antibodies does not rule out hypersensitivity-induced drug fever since the antibodies formed may not be directed against the drug itself.[4]

The timing of the onset of drug fever due to hypersensitivity can be an important diagnostic clue. Elevated temperatures can appear several days to weeks after starting drug therapy. This variability in the onset of drug fever can cloud the diagnosis, particularly in patients who begin several new drugs simultaneously. In contrast with the initial fever from hypersensitivity, fever recurs within hours of a rechallenge when the offending agent is readministered whether days, months, or even years later.[2, 4, 73] The diagnosis of drug fever can be confirmed with careful attention to the temporal relationship in response to the offending agent and resolution of fever after discontinuation of the agent.

Drug Fever from Antimicrobial Agents

Drug fever is not uncommon during antibiotic therapy, and it is particularly problematic since temperature is frequently monitored to gauge clinical response in patients with infections. Many antibiotics are associated with a relatively high frequency of drug fever, particularly the β-lactams.[75, 76] One group of authors conducted a review of drug fever induced by antibiotics at their institution.[75] In this study, drug fever was defined as a temperature of 99.5°F or above that lasted for more than 2 days during treatment with an antibiotic, the fever was associated with neither other clinical manifestations nor laboratory findings suggestive of an infectious etiology, the fever could not be ascribed to any other measures, and the fever subsided after cessation of a suspected antibiotic. This study evaluated 390 patients who received parenteral antibiotics for more than 7 days for the treatment of pulmonary infections. A total of 56 episodes of drug fever were noted in 51 (13%) of the 390 patients. The frequency was highest in patients who received piperacillin (17%) followed by the cephalosporins cefotaxime (15%), ceftizoxime (14%), cefapirin (10%), and cefuroxime (8%).

Drug fever induced by non–β-lactam antibacterials was rarely implicated. The frequency was significantly lower in patients older than 70 years (8.8%) than in patients aged 49 years or younger (18.7%). This finding contrasts with the findings of others who suggest that advanced age is a risk factor for developing drug fever.[2, 6, 72] The frequency was also lower in patients without cancer compared with those with cancer. The onset to drug-induced fever ranged from 1–5 weeks and was dependent on whether the patient received prior antibiotic therapy. The most common fever pattern was a low-grade fever at time of onset followed by high and remittent fever. The highest diurnal body temperature increased gradually on a daily basis and subsided when the drug was withdrawn. Eosinophilia developed in 25% of patients, and rash occurred in only 5% of patients with drug fever. Fifty-one percent of patients had a slight elevation in serum lactic dehydrogenase level that was found to be significant, whereas liver transaminase levels remained unchanged in most cases.

Patients with cystic fibrosis are more inclined to develop antibiotic-related drug fever and other manifestations of hypersensitivity because of their hyperimmune state.[81] One study evaluated the frequency and presentation of allergic reactions in adult patients with cystic fibrosis who received parenteral β-lactam antibiotics.[81] This study was conducted to determine the relative frequency of allergic reactions such as drug-induced fever and rash. Drug induced fever was defined as a temperature of more than 38°C, no new infection or other cause of fever detected, absence of underlying conditions that may cause a febrile state, development of fever coinciding temporally with the administration of the offending antibiotic, fever disappearing within 72 hours after discontinuation of the agent, and patient remaining afebrile for at least 72 hours after the temperature returned to normal. In this study, a total of 111 medical records were reviewed. Of 90 evaluable patients, 26 (28.9%) developed drug fever with or without rash to β-lactam antibiotics. The frequency was highest for piperacillin (35.5%), followed by imipenemcilastatin (25%), then mezlocillin (16.7%). The mean ± SD onset to drug-induced fever was 10.1 ± 5.4 days. As a group, patients receiving penicillins had a higher frequency of drug fever than those receiving cephalosporins. This study concluded that piperacillin, mezlocillin, and imipenem-cilastatin are associated with increased frequency of allergic reactions including drug fever in patients with cystic fibrosis.

Another group reviewed 25 cases of drug fever from antibiotic pharmacotherapy.[12] Nineteen of the 25 cases were surgical; in 10 of these treatments, the antibiotic was given for prophylaxis. Six of the 25 cases were medical; 3 were for the treatment of subacute bacterial endocarditis. Three types of temperature patterns were identified: in type 1, an antibiotic was administered for prophylaxis and fever developed; this was the most common reaction. The type 2 pattern was found in two cases when the initial infection and fever had responded to the antibiotic and the fever reappeared later caused by the drug. Type 3 occurred in two cases when the fever from the infection blended with that from the drug reaction. In six cases, fever appeared on the first day; in seven others, within the first week; and in four cases, fever appeared between days 10 and 18. The longest interval for onset of fever was at the conclusion of 60 days of treatment. Ten antibiotics were found to be responsible for causing fever; penicillin was responsible for 7 of 16 episodes when only one antibiotic was administered. When a combination of drugs was involved, penicillin and streptomycin were responsible in nine cases. Eleven patients received a second antibiotic for the fever that was caused by the first antibiotic. This last point is particularly significant, as it demonstrates one of the key problems with drug fever.

syx · « **Jawab #4 pada:** Pebruari 04, 2010, 07:20:53 AM »

Treatment

The most sensible approach to treating drug fever is to discontinue the offending agent, if appropriate. Determining the appropriate agent can be a challenge, and there is no standard approach. Depending on the severity of the accompanying reaction, it may be appropriate to stop all suspected drugs, those added recently or all nonessential drugs. In the setting of a fever without signs of hypersensitivity, discontinuing either a recently added agent or a drug with a high index of suspicion alone may be adequate. After discontinuation, the resolution of fever generally occurs within 48–72 hours, although it may persist for days to weeks if other manifestations of hypersensitivity accompany the fever, such as a maculopapular rash, or if the elimination rate of the agent is low.[2, 5] Discontinuation of the agent should be considered with caution, since the benefits of continued therapy may outweigh the risk of continued fever in some clinical scenarios. In the situation where continued treatment is required, switching to a chemically unrelated substitute may be performed if possible.[73] However, some drugs do not have an adequate substitute such as during the treatment of a particular type of cancer or a highly drug-resistant microorganism. In this situation, it may be possible to pretreat the patient with corticosteroids, antihistamines, and/or prostaglandin inhibitors while remaining vigilant for further signs of hypersensitivity.[1] Pretreatment with corticosteroids is generally not done unless necessary in a cutaneous reaction.[3] For patients receiving therapy in which multiple agents can be the culprits of fever, the discontinuation of all nonessential drugs should be considered.[73] Drugs may be reintroduced cautiously, one at a time, if necessary after fever abatement, with the most highly suspected drugs avoided if possible.

Rechallenge

Rechallenge in patients with drug fever is controversial and should be approached with extreme caution.[3] Rechallenge may be unwise, particularly in situations where the original febrile reaction was accompanied with severe adverse effects. In most of the cases we reviewed, rechallenge with a single therapeutic dose was performed very cautiously, often with the patient's consent, to confirm the diagnosis of drug-induced fever. The implicated drug was discontinued when the febrile reaction reoccurred after rechallenge. The risks and benefits of rechallenge should be weighed before reintroduction of the offending agent and discussed with the patient, if possible. Rechallenge should not be performed solely to solidify the diagnosis of drug fever.

Conclusion

The heterogeneity seen with cases of drug fever makes forming general conclusions difficult. The diversity of reports in the literature points to the wide variety of drugs that are implicated in causing fever. When drug fever is suspected, clinicians are often faced with weighing the risks and benefits of discontinuing suspected agents. In patients whose fever resolves after discontinuation of several agents that are not urgently necessary (such as those needed for stable chronic conditions), these agents should be restarted individually, only as required, and cautiously to help identify the causative agent of the fever. In this case, the drug with the highest index of suspicion for causing the fever should be omitted if possible. The management of each episode of suspected drug fever must be individualized for the patient's situation, taking into account the severity of illness that the suspected drug is treating, comorbid conditions, and other variables. A diagnosis of presumed drug fever should also not distract the clinician from pursing other diagnostic probabilities for fever, particularly in acutely ill patients. Pharmacists and other clinicians must remain vigilant in suspecting drugs as a cause of fever, knowledgeable about the agents reported to be responsible, and wary of the possibility of underprescribing when several needed agents are simultaneously discontinued.

syx · « **Jawab #5 pada:** Pebruari 04, 2010, 07:21:23 AM »

References

1. Hanson MA. Drug fever: remember to consider it in diagnosis. Postgrad Med 1991;89:167–73.
2. Roush MK, Nelson KM. Understanding drug-induced febrile reactions. Am Pharm 1993;NS33:39–42.
3. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 1996;10:85–91.
4. Tabor PA. Drug-induced fever. Drug Intell Clin Pharm 1986;20:413–20.
5. Cluff LE, Johnson J III. Drug fever. Prog Allergy 1964;8: 149–94.
6. Tisdale JE, Miller DA. Drug-induced diseases: prevention, detection, and management. Bethesda, MD: American Society of Health-Systems Pharmacists, 2005.
7. Harris LF, Holdsambeck HK. Drug fever: surprisingly common and costly. Ala Med 1986;56:19–22.
8. Mackowiak PA. Drug fever: mechanisms, maxims and misconceptions. Am J Med Sci 1987;294:275–86.
9. Mackowiak PA, LeMaistre CF. Drug fever: a critical appraisal of conventional concepts—an analysis of 51 episodes in two Dallas hospitals and 97 episodes reported in the English literature. Ann Intern Med 1987;106:728–33.
10. Shea BF, Harbison MA, Sesin GP, Benotti PN, Hammer SM. Acyclovir-associated fever: a case report. Pharmacotherapy 1987;7:54–5.
11. Caldwell JR, Cluff LE. Adverse reactions to antimicrobial agents. JAMA 1974;230:77–80.
12. Foster FP, Beard RW. Fever from antibiotics: some lessons drawn from 25 cases. Med Clin North Am 1963;47:532–9.
13. Sabeel A, Al Meshari K, Abutaleb N, Al Shaibani K. Drug fever induced by azathioprine in a haemodialysis patient. Nephrol Dial Transplant 1998;13:1004–5.
14. Saway PA, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity: case report and review of the literature. Am J Med 1988;84:960–4.
15. Smak Gregoor PJ, van Saase JL, Weimar W, Kramer P. Fever and rigors as sole symptoms of azathioprine hypersensitivity. Neth J Med 1995;47:288–90.
16. Jeurissen ME, Boerbooms AM, van de Putte LB, Kruijsen MW. Azathioprine-induced fever, chills, rash, and hepatotoxicity in rheumatoid arthritis. Ann Rheum Dis 1990;49:25–7.
17. Carter JJ, McLaughlin ML, Bern MM. Bleomycin-induced fatal hyperpyrexia. Am J Med 1983;74:523–5.
18. Sheridan WP, King RW, Gerstman M. Fever as an adverse reaction to carbamazepine. Aust N Z J Med 1982;12:520–2.
19. Stewart CR, Vengrow MI, Riley TL. Double quotidian fever caused by carbamazepine [case report]. N Engl J Med 1980;302:1262.
20. Lang R, Lishner M, Ravid M. Adverse reactions to prolonged treatment with high doses of carbenicillin and ureidopenicillins. Rev Infect Dis 1991;13:68–72.
21. Sawitsky A, Boklan BF, Benjamin Z. Drug fever produced by chlorambucil. N Y State J Med 1971;71:2434–6.
22. Corbett CL, Holdsworth CD. Fever, abdominal pain, and leucopenia during treatment with cimetidine. Br Med J 1978;1:753–4.
23. Hiraide A, Yoshioka T, Ohshima S. IgE-mediated drug fever due to histamine H2-receptor blockers. Drug Saf 1990;5:455–7.
24. Curtin JP, Hoskins WJ, Rubin SC, et al. Chemotherapyinduced neutropenia and fever in patients receiving cisplatinbased chemotherapy for ovarian malignancy. Gynecol Oncol 1991;40:17–20.
25. Ashford RF, McLachlan A, Nelson I, Mughal T, Pickering D. Pyrexia after cisplatin. Lancet 1980;2:691–2.
26. Beckner RR, Canada AT, Ockene IS. Fever due to clofibrate. N Engl J Med 1979;301:1345–6.
27. Portnoy J, Torchinsky A, Mendelson J, Kagan J. Febrile reactions after cloxacillin [letter]. Can Med Assoc J 1975;112:280.
28. Rose MS, Bateman DN. Pyrexia with cytosine arabinoside [case report]. Br Med J 1972;4:115.
29. Dominguez EA, Hamill RJ. Drug-induced fever due to diltiazem. Arch Intern Med 1991;151:1869–70.
30. Chapman SA, Stephan T, Lake KD, Sonnesyn SW, Emery RW. Fever induced by dobutamine infusion [case report]. Am J Cardiol 1994;74:517.
31. Robison-Strane SR, Bubik JS. Dobutamine-induced fever. Ann Pharmacother 1992;26:1523–4.
32. Zajecka J, Guy C, Solomon B. Antidepressant drug fever. J Clin Psychopharmacol 1991;11:73–4.
33. Dorschner L, Speich R, Ruschitzka F, Seebach JD, Gallino A. Everolimus-induced drug fever after heart transplantation. Transplantation 2004;78:303–4.
34. Clegg HW, Riopel DA. Furosemide-associated fever. J Pediatr 1995;126:817–18.
35. Forni AL, Murray HW. Drug fever induced by heparin [case report]. Am J Med 1992;92:107.
36. Jacobs P, Wood L, Foster J. Hydroxyurea hypersensitivity reaction [case report]. S Afr Med J 1989;75:506.
37. Lossos IS, Matzner Y. Hydroxyurea-induced fever: case report and review of the literature. Ann Pharmacother 1995;29:132–3.
38. Lannemyr O, Kutti J. Hydroxyurea as a cause of drug fever in essential thrombocythaemia. Eur J Haematol 1999;62:354–5.
39. Bauman JL, Shulruff S, Hasegawa GR, Roden R, Hartsough N, Bauernfeind RA. Fever caused by hydroxyurea. Arch Intern Med 1981;141:260–1.
40. van der Klooster JM, Sucec PM, Stiegelis WF, Hagenbeek A. Fever caused by hydroxyurea: a report of three cases and review of the literature. Neth J Med 1997;51:114–18.
41. Starmans-Kool MJ, Fickers MM, Pannebakker MA. An unwanted side effect of hydroxyurea in a patient with idiopathic myelofibrosis. Ann Hematol 1995;70:279–80.
42. Mandell B, Shen HS, Hepburn B. Fever from ibuprofen in a patient with lupus erythematosus [letter]. Ann Intern Med 1976;85:209–10.
43. Davis RS, Stoler BS. Febrile reactions to INH [case report]. N Engl J Med 1977;297:337.
44. Jacobs NF Jr, Thompson SE III. Spiking fever from isoniazid simulating a septic process. JAMA 1977;238:1759–60.
45. Dasta JF, Prior JA, Kurzrok S. Isoniazid-induced fever. Chest 1979;75:196–7.
46. Smithson WA, Gronert GA, Moss KK. Dantrolene and potentially fatal hyperthermia secondary to L-asparaginase. Cancer Treat Rep 1983;67:318–19.
47. Dar KJ, McBrien ME. MDMA-induced hyperthermia: report of a fatality and review of current therapy. Intensive Care Med 1996;22:995–6.
48. Harris A. Pyrexia and mebendazole [case report]. Br Med J 1979;2:1365.
49. Glontz GE, Saslaw S. Methyldopa fever. Arch Intern Med 1968;122:445–7.
50. Parker WA. Methyldopa hyperpyrexia [letter]. JAMA 1974;228:1097.
51. MacNeil M, Haase DA, Tremaine R, Marrie TJ. Fever, lymphadenopathy, eosinophilia, lymphocytosis, hepatitis, and dermatitis: a severe adverse reaction to minocycline. J Am Acad Dermatol 1997;36:347–50.
52. Gorard DA. Late-onset drug fever associated with minocycline. Postgrad Med J 1990;66:404–5.
53. Grim SA, Romanelli F, Jennings PR, Ofotokun I. Late-onset drug fever associated with minocycline: case report and review of the literature. Pharmacotherapy 2003;23:1659–62.
54. Chueh SC, Hong JC, Huang CY, Lai MK. Drug fever caused by mycophenolate mofetil in a renal transplant recipient: a case report. Transplant Proc 2000;32:1925–6.
55. Israel HL, Diamond P. Recurrent pulmonary infiltration and pleural effusion due to nitrofurantoin sensitivity. N Engl J Med 1962;266:1024–6.
56. Nielsen JL, Lund NO. Drug fever due to nomifensine treatment in patients with endogenous depression. Int Pharmacopsychiatry 1981;16:66–8.
57. Hasegawa K, Sakamoto Y, Mitsunaga K, Kashiwagi H. Drug fever due to oxprenolol. Br Med J 1980;281:27–8.
58. Miller RR. Hospital admissions due to adverse drug reactions: a report from the Boston collaborative drug surveillance program. Arch Intern Med 1974;134:219–23.
59. Pierach CA. Drug fever due to procainamide. Minn Med 1969;52:813–16.
60. Lysy J, Oren R. Drug fever with a shift to the left [case report]. DICP 1990;24:782.
61. Savran SV, Flamm MD Jr. Fever as a toxic reaction to quinidine [letter]. N Engl J Med 1975;292:427.
62. Schlutz M, Zinneman HH, Hall WH. Drug fever caused by quinine and quinidine. Minn Med 1973;56:668–70.
63. Abrams J. Quinidine fever: an unusual manifestation of quinidine allergy. Chest 1973;64:120–2.
64. Schacherer D, Zeitoun M, Buttner R, et al. Sirolimus-induced drug fever and ciclosporin-induced leukencephalopathia with seizures in one liver transplant recipient. World J Gastroenterol 2007;13:6090–3.
65. Feldbaum JS, Silverstein H. Streptomycin drug fever during treatment of bilateral Meniere's disease. Arch Otolaryngol 1984;110:538–9.
66. Garnick MB, Ernst T, Martinez F. Acute febrile reaction to streptozocin [case report]. N Engl J Med 1984;311:798.
67. Hearing SD, Playfor S, Bentley SJ. High fever induced by sulphasalazine [case report]. BMJ 1995;311:1204.
68. Brown JR, Weir AB. Drug fever from tolmetin administration [case report]. JAMA 1978;239:24.
69. Safdi MA. Fever secondary to triamterene therapy [case report]. N Engl J Med 1980;303:701.
70. Smith PF, Taylor CT. Vancomycin-induced neutropenia associated with fever: similarities between two immunemediated drug reactions. Pharmacotherapy 1999;19:240–4.
71. Ishii E, Hara T, Mizuno Y, Ueda K. Vincristine-induced fever in children with leukemia and lymphoma. Cancer 1988;61:660–2.
72. Lipsky BA, Hirschmann JV. Drug fever. JAMA 1981;245: 851–4.
73. Kumar KL, Reuler JB. Drug fever. West J Med 1986;144:753–5.
74. Tierney L. Drug fever. West J Med 1978;129:321–6.
75. Oizumi K, Onuma K, Watanabe A, Motomiya M. Clinical study of drug fever induced by parenteral administration of antibiotics. Tohoku J Exp Med 1989;159:45–56.
76. Cunha BA. Antibiotic side effects. Med Clin North Am 2001;85:149–85.
77. Nimmo SM, Kennedy BW, Tullett WM, Blyth AS, Dougall JR. Drug-induced hyperthermia. Anaesthesia 1993;48:892–5.
78. Talaro K, Talaro A. Foundations in microbiology, 3rd ed. Columbus, OH: McGraw Hill Science and Engineering, 2006.
79. Saper CB, Breder CD. The neurologic basis of fever. N Engl J Med 1994;330:1880–6.
80. Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant hyperthermia: important issues for the medical consultant. Med Clin North Am 1993;77:477–92.
81. Pleasants RA, Walker TR, Samuelson WM. Allergic reactions to parenteral beta-lactam antibiotics in patients with cystic fibrosis. Chest 1994;106:1124–8.

Astrawinata G · « **Jawab #6 pada:** Pebruari 04, 2010, 03:07:12 PM »

liatnya aja uda kenyang Mod

r.a.n · « **Jawab #7 pada:** Pebruari 04, 2010, 10:33:33 PM »

eh makasih mas...infonya..kira-kira obat jenis apa yah yang sering begitu..

User

Artikel Sains

Aku Cinta ForSa

Pranala Luar

ShoutBox!

exile_rstd

MonDay

lam_lavoisier09

semut-ireng

Farabi

semut-ireng

dzikripratama

yo anes

semut-ireng

exile_rstd

Penulis Topik: Drug Fever (Dibaca 8041 kali)

syx

Drug Fever

syx

Re: Drug Fever

syx

Re: Drug Fever

syx

Re: Drug Fever

syx

Re: Drug Fever

syx

Re: Drug Fever

Astrawinata G

Re: Drug Fever

r.a.n

Re: Drug Fever