Linezolid for the treatment of resistant gram-positive cocci.

OBJECTIVE: To provide a comprehensive review of linezolid, the first of a new class of antibiotics, the oxazolidinones. Therapeutic issues regarding the emergence of multidrug-resistant bacteria and a brief history of the oxazolidinones are also discussed. DATA SOURCES: A MEDLINE search (1966-March 2001) was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Unpublished clinical data, adverse effects, and dosing information were abstracted from product labeling. STUDY SELECTION: Clinical efficacy data were extracted from clinical trials, case reports, and abstracts that mentioned linezolid. Additional information concerning antibiotic resistance, the oxazolidinones, in vitro susceptibility and the pharmacokinetic profile of linezolid also was reviewed. DATA SYNTHESIS: Linezolid exhibits activity against many gram-positive organisms, including vancomycin-resistant Enterococcus faecium, methicillin-resistant Staphylococcus aureus, and penicillin-resistant Streptococcus pneumoniae. Linezolid inhibits bacterial protein synthesis at an early step in translation and is rapidly and completely absorbed from the gastrointestinal tract following oral administration. Efficacy has been demonstrated in a number of unpublished clinical trials in adults with pneumonia, skin and skin structure infections, and vancomycin-resistant E. faecium infections. The adverse effect profile is similar to that of comparator agents (beta-lactams, clarithrornycin, vancomycin). CONCLUSIONS: Linezolid is the first oral antimicrobial agent approved for the treatment of vancomycin-resistant enterococci. Since the oxazoildinones have a unique mechanism of action and expanded spectrum of activity against virulent and highly resistant gram positive pathogens, linezolid is a valuable alternative to currently available treatment options. Clinical trials evaluating linezolid and other oxazolidinones for antibiotic-resistant gram-positive infections, as well as comparator studies comparing linezolid with other candidate drugs, such as quinupristin/dalfopristin and choramphenicol, will further define the role of linezolid.

Analysis of pharmacoeconomics of sedation and analgesia.

Intravenous sedation and analgesia are cornerstones of the pharmacologic management of the critically ill, mechanically ventilated adult patient. No conclusive evidence exists to support any single optimal sedative or analgesic regimen in this heterogeneous population. The role of cost effectiveness in the process of selecting a regimen is explored with a review of the literature, followed by proposed cost-effectiveness models and recommendations for the clinical practitioner.

The use of oral vasopressors in the management of autonomic dysfunction and orthostatic hypotension.

OBJECTIVE: To describe a patient with hypotension secondary to autonomic dysfunction who was successfully treated with oral vasopressors. CASE SUMMARY: A 76-year-old African-American man with a history of cerebrovascular accident with right hemiparesis 30 years prior to admission was admitted from another hospital four days after a new posterior inferior cerebellar artery occlusion and poor distal flow as manifested by weakness and hypotension. This was treated with intravenous fluids and dopamine. The dopamine was weaned and changed to phenylephrine to maintain systolic blood pressure >80 mm Hg. Fludrocortisone 0.3 mg orally once daily was initiated; pressure support garments were used for the management of orthostatic hypotension. Ephedrine 25 mg po tid was added and titrated up to 50 mg p.o. tid. Yohimbine 5.4 mg po every eight hours was added due to continued dependence on phenylephrine to maintain adequate blood pressure. Yohimbine was titrated up to 10.8 mg p.o. tid in an unsuccessful effort to wean the patient from phenylephrine. Fludrocortisone was decreased to 0.1 mg po tid and the phenylephrine was tapered off. The patient developed a pan-sensitive Escherichia coli urinary tract infection that was treated with oral trimethoprim/sulfamethoxazole. Over the subsequent days, an 80% left subclavian stenosis was detected; yohimbine and pressure support garments were discontinued. Subsequently, oral ephedrine was tapered off over two days, and fludrocortisone was tapered to 0.1 mg p.o. bid. The patient was transferred in a stable normotensive condition to an inpatient rehabilitation unit. The fludrocortisone was later discontinued with no further hypotension or orthostatic symptoms. DISCUSSION: In this case, orthostatic hypotension associated with autonomic dysfunction was successfully managed with a combination of intravenous vasopressors and hydration, pressure support garments, oral mineralocorticoids, and oral vasopressors. Oral vasopressors and mineralocorticoids are effective treatment options in the management of the vasopressor-dependent patient. In our patient the adverse effects were tolerable. After continued therapy, the oral vasopressors were withdrawn without a return of orthostatic symptoms. CONCLUSIONS: Orthostatic hypotension due to autonomic dysfunction may be successfully managed with combination oral therapy after initial treatment with intravenous vasopressors as evidenced by the absence of orthostasis.

Potential risk factors associated with thrombocytopenia in a surgical intensive care unit.

We conducted a retrospective chart review of 193 patients admitted during a 3-month period to determine the frequency of and potential risk factors associated with thrombocytopenia, and the association of acquired thrombocytopenia with length of stay in a surgical-trauma intensive care unit (SICU) and mortality. All records were reviewed beginning 24 hours after admission. Patients were followed for the duration of SICU stay or until death. Data collected and analyzed as potential risk factors for thrombocytopenia were age, gender, admitting diagnosis, classification (trauma, surgical, medical), APACHE II score, medical history, all scheduled drugs with start and stop dates, select laboratory values, arterial or central line placement, and complications. Thrombocytopenia occurred in 25 (13%) patients. These patients were more likely (p<0.05) than those without thrombocytopenia to have the following potential risk factors: presence of a central or arterial line (76% vs 46%, p<0.025), nonsurgical diagnosis (60% vs 37%, p<0.05), diagnosis of sepsis (p<0.001), and administration of phenytoin (p<0.01), piperacillin (p<0.005), imipenem-cilastatin (p<0.001), and vancomycin (p<0.005). A longer SICU stay (mean 21 vs 4.5 days, p<0.05) and increased mortality (16% vs 4%, p<0.05) were significantly associated with thrombocytopenia. Cefazolin administration was significantly associated with nonthrombocytopenia (p<0.05). Factors not associated with thrombocytopenia were age, gender, and administration of histamine2-receptor antagonists, heparin, enoxaparin, penicillins, ceftazidime, ceftriaxone, chloramphenicol, and amphotericin B. A central or arterial line was the only factor associated with the development of thrombocytopenia in a multiple linear regression analysis (p=0.0003, multiple r=0.2580). Thrombocytopenia is not a common occurrence in the SICU, but is associated with a longer SICU stay and increased mortality.

Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically ill surgery patients.

We compared pharmacokinetic parameters derived from three aminoglycoside serum concentration sampling methods and evaluated their effects on recommended aminoglycoside dosing regimens in 60 critically ill surgery patients. Patients had presumed or documented gram-negative sepsis, and had at least 4 aminoglycoside serum concentrations measured. We used a one-compartment model for peak and trough, 3-point series, and 4-point series sampling methods. Dosing regimens were calculated for each patient based on values derived from each method. We found differences in regimens for nearly 50% of patients if either 4- or 3-point series sampling was used to calculate the recommended dosage rather than peak and trough sampling. However, the 3-point method required a clinically significant change in regimen in only 12% of patients compared with 4-point sampling. The variability of all values derived from 3-point sampling were well accounted for by the 4-point method (r2 > 0.80). In addition, we noted significantly greater relative precision for 3-point sampling than peak and trough sampling for estimates of clearance, elimination rate, recommended daily dosage, and recommended dosing frequency. We recommend three optimally timed samples be drawn instead of peak and trough levels in dosing aminoglycosides in critically ill surgery patients.

Drugs and myasthenia gravis. An update.

Myasthenia gravis is a disease of the neuromuscular junction in which normal transmission of the neuron-to-muscle impulse is impaired or prevented by acetylcholine receptor antibodies. Several classes of drugs have been associated with clinical worsening of existing myasthenia gravis, and a small subset of drugs, most notably the antirheumatic agent penicillamine, have been implicated in the pathogenesis of a variant of the disease. Recent case reports and other documented evidence link a number of specific agents with clinical worsening of myasthenia gravis.

Prevention of anaphylactoid reactions in high-risk patients receiving radiographic contrast media.

OBJECTIVE: To review various pretreatment regimens for the prophylaxis of anaphylactoid reactions to radiographic contrast media (RCM) in high-risk patients. The proposed etiologies and risk factors for such reactions are also reviewed. DATA SOURCES: A MEDLINE search of the English-language literature was used to identify pertinent human studies and reviews. STUDY SELECTION: All studies comparing pretreatment regimens for anaphylactoid reactions to RCM were reviewed as well as studies comparing the incidence of anaphylactoid reactions between lower and higher osmolar RCM. DATA SYNTHESIS: The two types of reactions to RCM are dose-independent, unpredictable anaphylactoid (pseudoallergic or idiosyncratic) reactions and the dose-dependent, predictable physicochemical (intrinsic, nonidiosyncratic) reactions. Prophylaxis of the former type is targeted at stemming the effects of certain chemical mediators, primarily histamine. The use of lower osmolar RCM is associated with a lower incidence of anaphylactoid reactions compared with higher osmolar RCM, but is significantly more expensive. Risk factors for such reactions are a history of previous anaphylactoid reaction to RCM, asthma, and reaction to skin allergens or penicillin. Discontinuation of any beta-blockers before the procedure is suggested. Pretesting patients with a small amount of RCM has little predictive value for an anaphylactoid reaction. Various pretreatment prophylactic regimens have been studied. Almost all included a corticosteroid to target the inflammatory response and a histamine1 (H1)-antagonist to blunt the effects of histamine. In some clinical trials, ephedrine was added for bronchodilation and cimetidine for its antagonism at the histamine2-receptor. The few controlled clinical trials that have been performed show the combination of prednisone and diphenhydramine to be most beneficial in preventing anaphylactoid reactions to RCM. The addition of ephedrine or cimetidine to a pretreatment regimen remains controversial. CONCLUSIONS: More controlled clinical studies comparing various pretreatment regimens for high-risk patients need to be performed, especially in patients receiving lower osmolar RCM. Recommendations for high-risk patients who must receive RCM include use of a lower osmolar agent, pretreatment with a corticosteroid and an H1-antagonist, discontinuation of beta-blockers if the patient is taking any, and bedside availability of appropriate medications and equipment to treat anaphylaxis.