Lynn L. Estes

Linezolid and Serotonergic Drug Interactions: A Retrospective Survey

BACKGROUND Linezolid is a reversible, nonselective monoamine oxidase inhibitor. There are currently 11 published case reports of serotonin syndrome being associated with linezolid and selective serotonin reuptake inhibitors (SSRIs). Controversy exists regarding whether linezolid and SSRIs can be given concomitantly. The purpose of this study was to report the incidence of serotonin syndrome in patients receiving linezolid and SSRIs. METHODS This study was a retrospective chart review of inpatients at the Mayo Clinic (Rochester, MN) with concomitant orders or therapy within 14 days for linezolid and an SSRI from 2000 to 2004. The Sternbach criteria and Boyer criteria for diagnosis of serotonin syndrome were used to identify clinical features of serotonin syndrome. RESULTS Seventy-two patients received linezolid and an SSRI or venlafaxine within 14 days of each other. Fifty-two patients (72%) received concomitant therapy with linezolid and an SSRI or venlafaxine, and 20 patients (28%) did not receive concomitant therapy but received linezolid and an SSRI within a 14-day period. Overall, only 2 patients (3%) had a high probability of serotonin syndrome. In both patients with high probability, symptoms reversed rapidly on discontinuation of serotonergic therapy. The Boyer criteria were much more specific than the Sternbach criteria for identification of serotonin syndrome. CONCLUSIONS On the basis of our experience, we suggest that, if the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRIs, without a 14-day washout period and with careful monitoring for signs and symptoms of serotonin syndrome. Serotonergic agents should be promptly discontinued if serotonin syndrome is suspected.

Reduction of Vancomycin Use in Orthopedic Patients With a History of Antibiotic Allergy

Objective To reduce prophylactic vancomycin use in patients with a history of penicillin or cephalosporin allergy undergoing elective orthopedic surgery by using a targeted allergy consultation and penicillin allergy skin testing. Patients and Methods The participants in this practice improvement study were patients with a history of penicillin or cephalosporin allergy who were scheduled for elective orthopedic surgery and referred by orthopedic surgeons for allergy consultation and penicillin allergy skin testing between September 22, 1998, and April 15, 1999. The primary outcome measure was the percentage of participants who received prophylactic cefazolin during the study period compared with historical controls. Results Of the 60 study patients, 59 received a penicillin allergy skin test, 58 underwent orthopedic surgery, and 55 received antibiotic prophylaxis. Fifty-five patients had a history of allergy to penicillin, a cephalosporin, or both, and 5 had a history of nonspecific antibiotic allergy. Of the 59 patients, 55 (93%) had negative penicillin allergy skin test results. Fifty-four (90%) of the 60 patients were given clearance by the allergist to receive cefazolin. Of the 55 study patients who received antibiotic prophylaxis, 6 (11%) received vancomycin compared with 38 (30%) of 127 historical controls ( P ≤05). None of the study patients had an immediate reaction to cefazolin or to vancomycin. Conclusion Prophylactic vancomycin use in patients with a history of penicillin or cephalosporin allergy undergoing elective orthopedic surgery can be reduced by a targeted allergy consultation and penicillin allergy skin testing.

Gastric Ulcer Perforation Associated with the Use of Injectable Ketorolac

OBJECTIVE: To report a case of a perforated gastric ulcer associated with the use of injectable ketorolac tromethamine. DATA SYNTHESIS: A 77-year-old woman with no previous history of peptic ulcer disease developed a perforated gastric ulcer after four days of treatment with ketorolac. To date, six other cases of gastrointestinal (GI) perforation associated with the use of ketorolac have been reported to the manufacturer. CONCLUSIONS: Although ketorolac is an effective analgesic, it is a nonsteroidal antiinflammatory agent and thus has the propensity for causing GI ulceration. Caution should be used when administering this drug and patients should be monitored for GI adverse effects.

Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed-Release Tablet versus the Oral Suspension

ABSTRACT While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection.

Review of Pharmacokinetics and Pharmacodynamics of Antimicrobial Agents

Pharmacokinetics is a science that has long been used in ascertaining the appropriate antimicrobial dose. It refers to the disposition of drugs in the body and includes absorption, bioavailability, distribution, protein binding, metabolism, and elimination. Pharmacodynamics is a newer science that relates to the interaction between the drug concentration at the site of action over time and the desired antimicrobial effect. This article reviews the principles of pharmacokinetics and pharmacodynamics as well as the clinical application of these two sciences to design antimicrobial dosing regimens for optimal results in individual patients.

Reduction in false-positive Aspergillus serum galactomannan enzyme immunoassay results associated with use of piperacillin-tazobactam in the United States.

ABSTRACT Piperacillin-tazobactam (PTZ) is known to cause false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA), due to contamination with galactomannan (GM). We tested 32 lots of PTZ and 27 serum specimens from patients receiving PTZ. GM was not detected in the lots of PTZ; one serum specimen (3.7%) was positive. PTZ formulations commonly used in the United States today appear to be a rare cause for false-positive GM results.

Effect of Combined Fluoroquinolone and Azole Use on QT Prolongation in Hematology Patients

ABSTRACT QTc prolongation is a risk factor for development of torsades de pointes (TdP). Combination therapy with fluoroquinolones and azoles is used in patients with hematologic malignancies for prophylaxis and treatment of infection. Both drug classes are implicated as risk factors for QTc prolongation. The cumulative effect on and incidence of QTc prolongation for this combination have not been previously described. A retrospective chart review was performed with hospitalized inpatients from 1 September 2008 to 31 January 2010 comparing QTc interval data from electrocardiogram (ECG) assessment at baseline and after the initiation of combination therapy. Ninety-four patients were eligible for inclusion. The majority, 88 patients (93.6%), received quinolone therapy with levofloxacin. Fifty-three patients (56.4%) received voriconazole; 40 (42.6%) received fluconazole. The overall mean QTc change from baseline was 6.1 (95% confidence interval [CI], 0.2 to 11.9) ms. Twenty-one (22.3%) of the studied patients had clinically significant changes in the QTc while receiving combination fluoroquinolone-azole therapy. Statistically significant risk factors for clinically significant changes in QTc were hypokalemia (P = 0.03) and a left-ventricular ejection fraction of <55% (P = 0.02). Low magnesium (P = 0.11), exposure to 2 or more drugs with the potential to prolong the QTc interval (P = 0.17), and female sex (P = 0.21) trended toward significance. Combination therapy with fluoroquinolone and azole antifungals is associated with increased QTc from baseline in hospitalized patients with hematologic malignancies. One in five patients had a clinically significant change in the QTc, warranting close monitoring and risk factor modification to prevent the possibility of further QTc prolongation and risk of TdP.

Non–anti-infective Effects of Antimicrobials and Their Clinical Applications: A Review

Antimicrobial agents are undoubtedly one of the key advances in the history of modern medicine and infectious diseases, improving the clinical outcomes of infection owing to their inhibitory effects on microbial growth. However, many antimicrobial agents also have biological activities stemming from their interactions with host receptors and effects on host inflammatory responses and other human or bacterial cellular biological pathways. These result in clinical uses of antimicrobial drugs that are distinct from their direct bacteriostatic or bactericidal properties. We reviewed the published literature regarding non-anti-infective therapeutic properties and proposed clinical applications of selected antimicrobials, specifically, macrolides, tetracyclines, sulfonamides, and ketoconazole. The clinical applications reviewed were varied, and we focused on uses that were clinically relevant (in terms of importance and burden of disease) and where published evidence exists. Such uses include chronic inflammatory pulmonary and skin disorders, chronic periodontitis, gastrointestinal dysmotility, rheumatoid arthritis, and cancer. Most of these potential therapeutic uses are not Food and Drug Administration approved. Clinicians need to weigh the use of antimicrobial agents for their non-anti-infective benefits, considering potential adverse effects and long-term effect on microbial resistance.

Evaluation of Impact of Statin Use on Development of CPK Elevation During Daptomycin Therapy

Background: Because both daptomycin and statins may increase creatine phosphokinase (CPK) levels, the manufacturer of daptomycin suggests considering holding statins during daptomycin therapy. Published evidence suggests potential detrimental effects of withdrawing statin therapy. Objectives: The objectives of this study were to determine the impact of concurrent statin therapy on peak CPK values, incidence of CPK elevation in patients receiving daptomycin therapy, and clinical factors associated with increased risk of developing CPK elevation. Methods: This was a single-center, retrospective cohort study of patients ≥18 years of age who received daptomycin for ≥72 hours and had ≥1 follow-up CPK during a 5-year period. A Kaplan-Meier curve was used to evaluate time to CPK elevation. Cox regression analyses were used to compare the risk of developing elevated CPK between 3 study groups: those receiving daptomycin alone, daptomycin with concurrent statin therapy, and statin therapy held while on daptomycin. Results: 498 patients were included in the study—384 received daptomycin alone, 63 received daptomycin concurrent with statin, and 51 with statin held during daptomycin therapy. Cumulative incidence of CPK elevation was 5.1% and 12% at 7 and 14 days. Those on daptomycin and statin concurrent therapy demonstrated an approximately 2-fold risk of CPK elevation compared with those having their statin therapy held, but the overall group effect was not statistically significant (P = .17). Conclusions: Our findings suggest that holding statin during daptomycin therapy may not be necessary, but may indicate need for increased frequency of CPK monitoring when these medications are used concurrently.

Effect of Telephoned Notification of Positive Clostridium difficile Test Results on the Time to the Ordering of Antimicrobial Therapy

The time between electronic-medical-record reporting of a positive result of a test for Clostridium difficile toxin in stool and the ordering of antimicrobial therapy was compared during consecutive periods when results were not telephoned (n = 274) and when results were telephoned (n = 90) to the clinical service. The mean times to the ordering of antimicrobial therapy were 11.9 and 3.6 hours, respectively (P < .001).