Krystal K. Haase

Use of vancomycin pharmacokinetic–pharmacodynamic properties in the treatment of MRSA infections

Vancomycin is a commonly used antimicrobial in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Increasing vancomycin MIC values in MRSA clinical isolates makes the optimization of vancomycin dosing pivotal to its continued use. Unfortunately, limited data exist regarding the optimal pharmacokinetic–pharmacodynamic (PK–PD) goal to improve bacterial killing and clinical outcomes with vancomycin. The hallmark study in this area suggests that achieving an AUC to MIC ratio of over 400 improves the likelihood of achieving these outcomes. Challenges in the implementation of PK–PD-based dosing for vancomycin include current methodologies utilized in microbiology laboratories, as well as intra- and interpatient pharmacokinetic variability. Individualized dosing based on MIC and specific patient factors is important to achieve optimal outcomes from vancomycin therapy.

Gram-positive resistance: pathogens, implications, and treatment options: insights from the Society of Infectious Diseases Pharmacists.

Despite the advent of new antibiotics, resistance in gram‐positive pathogens, including staphylococci and enterococci, continues to increase. This is evident with the recent emergence of vancomycin‐resistant Staphylococcus aureus. Newer treatment agents are available, including quinupristin‐dalfopristin, linezolid, and daptomycin. In addition, investigational agents are being explored. Clinical trials have been conducted for various infections, such as skin and skin structure infections, pneumonia, and bloodstream infections. Antibacterial activity, site of infection, and potential for adverse effects must be taken into account when making decisions regarding therapy.

Potential Interaction between Celecoxib and Warfarin

TO THE EDITO R : Celecoxib is a recently marketed nonsteroidal antiinflammatory drug with no significant effects on platelet aggregation or serum thromboxane production.1,2 Although the product monograph3 states that there is no drug interaction between warfarin and celecoxib, we recently observed a case in which administration of celecoxib to a patient receiving warfarin resulted in a significant increase in the patient’s i n t e rnational normalized ratio (INR). Case Report . An 88y e a r-old white woman with atrial fibrillation, osteoarthritis, glaucoma, hypertension, gout, and hypothyroidism was diagnosed with deep venous thrombosis on June 7, 1999, and prescribed warfarin 5 mg/d. Other medications included furosemide 40 mg/d, levothyroxine 125 μg/d, potassium chloride 10 mEq/d, diclofenac 50 mg and misoprostol 200 μg bid, felodipine 10 mg bid, allopurinol 300 mg/d, digoxin 125 μg/d, metaxalone 400 mg bid, Caltrate-D bid, a multivitamin, and calcitonin nasal spray. The patient was stabilized on warfarin 40 mg/wk (INR 2.7–3.1). Celecoxib 200 mg/d was started on July 8, and diclofenac/misoprostol was stopped (Figure 1). INR prior to starting celecoxib was 3.1. On July 13, the INR was 4.4 and on July 15, the INR further increased to 5.8. The patient experienced no complications, described no changes in dietary habits, and no changes in medication; all other laboratory indices were normal. Wa r f a r i n was withheld for two days and the dosage was reduced to 37.5 mg/wk. The INR decreased to 3.1 on July 20, and increased to 4.1 one week later. At that time, the warfarin dosage was reduced to 32.5 mg/wk. One week later, INR was 3.9, and the dosage was further reduced to 30 mg/wk. INR decreased to 3.0 within one week of this dosage adjustment. The total weekly warfarin dosage was 25% lower than before celecoxib was initiated. D i s c u s s i o n . Celecoxib undergoes hepatic metabolism by CYP2C9, which also is the isoform through which the S-enantiomer of warfarin is m e t a b o l i z e d .3 Although celecoxib did not appear to alter the pharm acokinetics of Ror S-warfarin in volunteers, it may cause an interaction in elderly patients.3 Various factors must be considered when designing pharmacotherapeutic regimens for geriatric patients, since they often consume multiple drugs, suffer from multiple diseases, and exhibit agerelated changes in pharmacokinetics such as decrements in renal and hepatic function.4 Indeed, an age-related decrease in the content and function of CYP2C9/10 has been documented.5 Also germane is a study by Mungall et al.,6 in which warfarin clearance decreased 1% each year in patients 18–70 years old. As we could find no other obvious reason for INR elevation, these events emphasize the importance of close monitoring of patients receiving these drugs concomitantly. This is especially true in geriatric patients who are at high risk for drug interactions and who require more stringent INR monitoring. On the Naranjo7 probability scale the score indicated a probable likelihood that celecoxib caused the increase in INR. Although additional studies are needed to further delineate the mechanism and clinical significance of the proposed celecoxib–warfarin interaction, we advocate monitoring INR on two occasions three to seven days after the initiation of celecoxib to assess its effect on the patient’s INR. It should also be noted that similar cases8 , 9 have been reported to the manufacturer and the Food and Drug Administration, and that rofecoxib also has been noted to increased INR.8 , 9

Empiric guideline-recommended weight-based vancomycin dosing and nephrotoxicity rates in patients with methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study

BackgroundPrevious studies have established a correlation between vancomycin troughs and nephrotoxicity. However, data are currently lacking regarding the effect of guideline-recommended weight-based dosing on nephrotoxicity in methicillin-resistant Staphylococcus aureus bacteremia (MRSAB).MethodsAdults who were at least 18 years of age with methicillin-resistant Staphylococcus aureus bacteremia and received of empiric vancomycin therapy for at least 48 hours (01/07/2002 and 30/06/2008) were included in this multicenter, retrospective cohort study. The association between guideline-recommended, weight-based vancomycin dosing (at least 15 mg/kg/dose) and nephrotoxicity (increase in serum creatinine (SCr) by more than 0.5 mg/dl or at least a 50% increase from baseline on at least two consecutive laboratory tests) was evaluated. Potential independent associations were evaluated using a multivariable general linear mixed-effect model.ResultsOverall, 23% of patients developed nephrotoxicity. Thirty-four percent of the 337 patients who met study criteria received weight-based dosing. The cohort was composed of 69% males with a median age of 55 years. The most common sources of MRSAB included skin/soft tissue (32%), catheter-related bloodstream bacteremia (20%), pulmonary (18%). Eighty-six percent of patients received twice daily dosing. Similar rates of nephrotoxicity were observed regardless of the receipt of guideline-recommended dosing (22% vs. 24%, OR 0.91 [95% CI 0.53-1.56]). This finding was confirmed in the multivariable analysis (OR 1.52 [95% CI 0.75-3.08]). Independent predictors of nephrotoxicity were (OR, 95% CI) vancomycin duration of greater than 15 days (3.36, 1.79-6.34), weight over 100 kg (2.74, 1.27-5.91), Pitt bacteremia score of 4 or greater (2.73, 1.29-5.79), vancomycin trough higher than 20 mcg/ml (2.36, 1.07-5.20), and age over 52 years (2.10, 1.08-4.08).ConclusionsOver one out of five patients in this study developed nephrotoxicity while receiving vancomycin for MRSAB. The receipt of guideline-recommended, weight-based vancomycin was not an independent risk factor for the development of nephrotoxicity.

Empiric guideline-recommended weight-based vancomycin dosing and mortality in methicillin-resistant Staphylococcus aureus bacteremia: A retrospective cohort study

BackgroundNo studies have evaluated the effect of guideline-recommended weight-based dosing on in-hospital mortality of patients with methicillin-resistant Staphylococcus aureus bacteremia.MethodsThis was a multicenter, retrospective, cohort study of patients with methicillin-resistant Staphylococcus aureus bacteremia receiving at least 48 hours of empiric vancomycin therapy between 01/07/2002 and 30/06/2008. We compared in-hospital mortality for patients treated empirically with weight-based, guideline-recommended vancomycin doses (at least 15 mg/kg/dose) to those treated with less than 15 mg/kg/dose. We used a general linear mixed multivariable model analysis with variables identified a priori through a conceptual framework based on the literature.ResultsA total of 337 patients who were admitted to the three hospitals were included in the cohort. One-third of patients received vancomycin empirically at the guideline-recommended dose. Guideline-recommended dosing was not associated with in-hospital mortality in the univariable (16% vs. 13%, OR 1.26 [95%CI 0.67-2.39]) or multivariable (OR 0.71, 95%CI 0.33-1.55) analysis. Independent predictors of in-hospital mortality were ICU admission, Pitt bacteremia score of 4 or greater, age 53 years or greater, and nephrotoxicity.ConclusionsEmpiric use of weight-based, guideline-recommended empiric vancomycin dosing was not associated with reduced mortality in this multicenter study.

Utilization and prescribing patterns of direct oral anticoagulants

Background Scant literature exists evaluating utilization patterns for direct oral anticoagulants (DOACs). Objectives The primary objective was to assess DOAC prescribing in patients with venous thromboembolism (VTE) and nonvalvular atrial fibrillation (NVAF) in outpatient clinics. Secondary objectives were to compare utilization between family medicine (FM) and internal medicine (IM) clinics, characterize potentially inappropriate use, and identify factors associated with adverse events (AEs). Methods This was a retrospective cohort study of adults with NVAF or VTE who received a DOAC at FM or IM clinics between 10/19/2010 and 10/23/2014. Descriptive statistics were utilized for the primary aim. Fisher’s exact test was used to evaluate differences in prescribing using an adapted medication appropriateness index. Logistic regression evaluated factors associated with inappropriate use and AEs. Results One-hundred twenty patients were evaluated. At least 1 inappropriate criterion was met in 72 patients (60.0%). The most frequent inappropriate criteria were dosage (33.0%), duration of therapy (18.4%), and correct administration (18.0%). Apixaban was dosed inappropriately most frequently. There was no difference in dosing appropriateness between FM and IM clinics. The odds of inappropriate choice were lower with apixaban compared to other DOACs (odds ratio [OR]=0.088; 95% confidence interval [CI] 0.008–0.964; p=0.047). Twenty-seven patients (22.5%) experienced an AE while on a DOAC, and the odds of bleeding doubled with each inappropriate criterion met (OR=1.949; 95% CI 1.190–3.190; p=0.008). Conclusion Potentially inappropriate prescribing of DOACs is frequent with the most common errors being dosing, administration, and duration of therapy. These results underscore the importance of prescriber education regarding the appropriate use and management of DOACs.

Aseptic Meningitis after Intraventricular Administration of Gentamicin

Infection of the central nervous system (CNS) is a major cause of morbidity in patients with cerebrospinal fluid (CSF) shunts. Intraventricular administration of gentamicin, in combination with systemic antibiotics and shunt removal, may be beneficial in treating these infections. A young child was treated successfully for a ventriculoperitoneal shunt infection while receiving systemic nafcillin and intraventricular gentamicin. During treatment she developed CNS toxicity resembling aseptic meningitis. Based on CSF gentamicin levels and differential white blood cell counts, it was suspected that gentamicin was causing meningeal inflammation. Discontinuation of the drug relieved her symptoms. Rebound CSF leukocytosis associated with lymphocyte increase, despite a negative CSF culture, can indicate aseptic meningitis when drugs are administered intraventricularly. Clinicians should evaluate CSF cell count differentials before concluding treatment failure when administering antibiotics intraventricularly for meningitis.

Challenges with Diagnosing and Managing Sepsis in Older Adults

ABSTRACT Sepsis in older adults has many challenges that affect rate of septic diagnosis, treatment, and monitoring parameters. Numerous age-related changes and comorbidities contribute to increased risk of infections in older adults, but also atypical symptomatology that delays diagnosis. Due to various pharmacokinetic/pharmacodynamic changes in the older adult, medications are absorbed, metabolized, and eliminated at different rates as compared to younger adults, which increases risk of adverse drug reactions due to use of drug therapy needed for sepsis management. This review provides information to aid in diagnosis and offers recommendations for monitoring and treating sepsis in the older adult population.

Empiric weight-based vancomycin in intensive care unit patients with methicillin-resistant Staphylococcus aureus bacteremia

Background:Previous studies were conducted in all hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia to determine safety and effectiveness of guideline-recommended, weight-based dosing of vancomycin. In these studies, it was observed that severely ill patients (Pitt bacteremia score ≥4 or intensive care unit [ICU] patients) were at an increased risk of mortality and/or nephrotoxicity. Therefore, a subanalysis of the effect of guideline-recommended vancomycin dosing on in-hospital mortality and nephrotoxicity in ICU patients with MRSA bacteremia was conducted. Methods:This multicenter, retrospective, cohort study was conducted in a subset of ICU patients from a previous MRSA bacteremia study. Patients were ≥18 years old and received ≥48 hours of empiric vancomycin from July 1, 2002, to June 30, 2008. The incidence of nephrotoxicity and in-hospital mortality was compared in patients who received guideline-recommended dosing (at least 15 mg/kg per dose) to patients who received non–guideline-recommended dosing of vancomycin. Multivariable generalized linear mixed-effects models were constructed to determine independent risk factors for in-hospital mortality and nephrotoxicity. Results:Guideline-recommended dosing was received by 34% of patients (n = 137). Nephrotoxicity occurred in 35% of patients receiving guideline-recommended dosing and 39% receiving non–guideline-recommended dosing (P = 0.67). In-hospital mortality rate was 24% among patients who received guideline-recommended dosing compared with 31% for non–guideline-recommended dosing (P = 0.40). Guideline-recommended dosing was not associated with nephrotoxicity (odds ratio: 1.10; 95% confidence interval: 0.43–2.79) or in-hospital mortality (odds ratio: 0.54; 95% confidence interval: 0.22–1.36) in the multivariable analysis. Conclusions:Guideline-recommended dosing of vancomycin in ICU patients with MRSA bacteremia is not significantly associated with nephrotoxicity or in-hospital mortality. However, the 7% absolute difference for in-hospital mortality suggests that larger studies are needed.

Pharmacy Practice Model Initiative—It's All About Implementation

Keywords: clinical pharmacy; clinical pharmacy specialist; pharmacy practice; Pharmacy Practice Model Initiative