What Is the Evidence for Co-trimoxazole, Clindamycin, Doxycycline, and Minocycline in the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) Pneumonia?

Objective: To review the evidence for trimethoprim-sulfamethoxazole (TMP-SMX), clindamycin, doxycycline, and minocycline in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Data Source: MEDLINE, PubMed, EMBASE, Google, Google Scholar, Cochrane Central Register of Controlled Trials from 1946 to May 20, 2019. The search was performed with the keywords methicillin-resistant Staphylococcus aureus, MRSA, Staphylococcus aureus, pneumonia, trimethoprim, sulfamethoxazole drug combination, trimethoprim, sulfamethoxazole, TMP-SMX, co-trimoxazole, clindamycin, doxycycline, and minocycline. Data Extraction: Studies reporting the use of the above antibiotics for MRSA pneumonia treatment with clinical outcomes were included. Search parameters were limited to English language and human studies only. Data Synthesis: The search yielded 16 relevant articles: 6 TMP-SMX, 8 clindamycin, zero doxycycline, and 2 minocycline. For TMP-SMX, prospective randomized trials showed variable results; however, these studies were not specifically designed to assess MRSA pneumonia treatment. Retrospective studies with clindamycin suggested that it could be used as monotherapy or in combination with other anti-MRSA antibiotics. There was no evidence for doxycycline use, but 2 small retrospective reviews appeared to support minocycline as a treatment option. Relevance to Patient Care and Clinical Practice: These antibiotics are often used in clinical practice as potential treatment options for MRSA pneumonia. This article reviews the evidence for the clinical efficacy and safety of these agents. Conclusions: There are limited data to support use of TMP-SMX, clindamycin, doxycycline, or minocycline in MRSA pneumonia treatment. Randomized controlled trials are required to determine the effectiveness of these antibiotics. Clinicians should base their decision to use these agents on a case-by-case basis depending on clinical status and susceptibility results.

RELATE: Relationship of limited sampling strategy and adverse effects of mycophenolate mofetil in pediatric renal transplant patients.

MMF, a prodrug converted to the active form MPA, is an immunosuppressant used to prevent rejection in solid organ transplant recipients. MPA exposure, defined by AUC, can be estimated using limited sampling strategies (LSS). The relationship between MPA AUC and clinical outcomes has not been studied in pediatrics. The objectives were to describe the relationship of MPA AUC (estimated via LSS) with adverse effects and rates of rejection, and to compare clinical outcomes between different MPA monitoring practices. Descriptive statistics were used to summarize demographics, adverse effects, and rejection. Thirty-three patients (91 trough concentrations and 12 LSS sets) aged 2-20 years old were included. The estimated median MPA AUCs (David-Neto and Filler) were higher for those who did not have any adverse effects reported (65.85 and 85.05 mg*h/L, respectively) compared to those who had an adverse effect (60.75 and 54.2 mg*h/L, respectively). The median trough concentration when no adverse effects occurred was comparable to when adverse effects occurred. The median MPA AUC at which rejection occurred was lower than in those without rejection. The median trough concentration at which rejection occurred was higher than those without rejection (3.1 mg/L compared to 1.9 mg/L). The occurrence of adverse effects or rejection was not shown to be related to measured MPA trough or AUC outside of the target therapeutic range. The value of MPA concentration monitoring remains unclear; therefore, the practice of monitoring MPA AUC by LSS or trough concentrations should be reconsidered.

Combination of Ceftriaxone and Ampicillin for the Treatment of Enterococcal Endocarditis: A Qualitative Systematic Review.

OBJECTIVE: The aim of this systematic review is to review all human trials assessing the efficacy and safety of ampicillin and ceftriaxone for enterococcal endocarditis and to discuss the clinical implications of the findings. DATA SOURCES: MEDLINE (1946-), EMBASE (1974-), CENTRAL, Google Scholar, and the World Health Organization Clinical Trials Registry Platform were searched through January 2017 using the search terms ampicillin, penicillin, ceftriaxone, cephalosporin, enterococ*, and endocarditis. Unpublished studies were eligible for inclusion. Additional references were identified from literature citations. STUDY SELECTION AND DATA EXTRACTION: Clinical trials in humans that reported on clinical efficacy or adverse outcomes with ceftriaxone and ampicillin therapy in patients with enterococcal endocarditis were included. Case reports, nonhuman, and non-English studies were excluded. DATA SYNTHESIS: Four observational clinical studies were identified. One examined the effects of ceftriaxone and ampicillin alone, and 3 compared the therapy to the current standard of care, ampicillin and gentamicin. The studies had small sample sizes and were not adequately designed or powered to establish noninferiority or equivalence to the current standard of care. Rates of clinical cure with ampicillin 2 g every 4 hours and ceftriaxone 2 g every 12 hours were similar to those of ampicillin and gentamicin. Ampicillin and ceftriaxone therapy was well tolerated with low rates of renal failure (0%-33%). CONCLUSION: The evidence to support the use of ampicillin and ceftriaxone for enterococcal endocarditis is not definitive. In the absence of compelling evidence, clinicians may consider ampicillin and ceftriaxone in patients with Enterococcus faecalis infection at high risk for nephrotoxicity or those with aminoglycoside-resistant pathogens.

Evidence-Based Review of Pharmacotherapy Used for Parkinson's Disease Psychosis.

OBJECTIVE: To summarize and evaluate the existing literature regarding medications to treat Parkinson's disease (PD) psychosis. DATA SOURCES: MEDLINE (1946 to March 2017), EMBASE (1980 to March 2017), CINAHL (1982 to March 2017), and PsychInfo (1887 to March 2017) were searched using the following terms: Parkinson disease, Parkinson's disease, psychotic disorders, psychosis, delusions, and hallucinations. STUDY SELECTION AND DATA EXTRACTION: The search was limited to randomized controlled trials (RCTs) reporting human outcomes. Data extracted included the following: study design, population, setting, intervention, control, outcomes related to psychosis and safety, and potential biases assessed using Cochrane Collaboration's Risk of Bias Assessment Tool. DATA SYNTHESIS: After assessment, 16 of 235 studies were included; 11 articles reported comparisons between active drug and placebo, whereas 5 compared clozapine and an active comparator. Placebo-controlled trials demonstrated benefit for clozapine (n = 2) and pimavanserin (n = 2), with no firm benefits observed for quetiapine (n = 4) or olanzapine (n = 3). Comparative studies demonstrated improved efficacy in symptom scores when clozapine or comparator agent (n = 2, quetiapine; n = 1, olanzapine; n = 1, risperidone; and n = 1, ziprasidone) was assessed alone. However, no comparator data suggest that one agent is better than another, and none are yet available for pimavanserin. Overall risk of bias across all studies was moderate to high. CONCLUSIONS: Despite lack of rigor in study designs, published data to date suggest that clozapine and pimavanserin should be considered drugs of choice to treat PD psychosis.

A Comprehensive Review on the Predictive Performance of the Sheiner-Tozer and Derivative Equations for the Correction of Phenytoin Concentrations.

OBJECTIVE: In settings where free phenytoin concentrations are not available, the Sheiner-Tozer equation-Corrected total phenytoin concentration = Observed total phenytoin concentration/[(0.2 × Albumin) + 0.1]; phenytoin in µg/mL, albumin in g/dL-and its derivative equations are commonly used to correct for altered phenytoin binding to albumin. The objective of this article was to provide a comprehensive and updated review on the predictive performance of these equations in various patient populations. DATA SOURCES: A literature search of PubMed, EMBASE, and Google Scholar was conducted using combinations of the following terms: Sheiner-Tozer, Winter-Tozer, phenytoin, predictive equation, precision, bias, free fraction. STUDY SELECTION AND DATA EXTRACTION: All English-language articles up to November 2015 (excluding abstracts) were evaluated. DATA SYNTHESIS: This review shows the Sheiner-Tozer equation to be biased and imprecise in various critical care, head trauma, and general neurology patient populations. Factors contributing to bias and imprecision include the following: albumin concentration, free phenytoin assay temperature, experimental conditions (eg, timing of concentration sampling, steady-state dosing conditions), renal function, age, concomitant medications, and patient type. Although derivative equations using varying albumin coefficients have improved accuracy (without much improvement in precision) in intensive care and elderly patients, these equations still require further validation. CONCLUSIONS: Further experiments are also needed to yield derivative equations with good predictive performance in all populations as well as to validate the equations' impact on actual patient efficacy and toxicity outcomes. More complex, multivariate predictive equations may be required to capture all variables that can potentially affect phenytoin pharmacokinetics and clinical therapeutic outcomes.

Opioid Pharmacokinetics-Pharmacodynamics: Clinical Implications in Acute Pain Management in Trauma.

OBJECTIVE: To evaluate acute traumatic pain protocols and to suggest optimization by characterizing opioid pharmacokinetics and pharmacodynamics (PK-PD). DATA SOURCES: MEDLINE (1946 to November 2015), EMBASE (1974 to November 2015), International Pharmaceutical Abstracts (1970 to December 2014), and Cochrane Database of Systematic Reviews (2005 to November 2015). KEYWORDS: morphine, hydromorphone, fentanyl, trauma, acute pain, intravenous, opioid, pharmacokinetics, and pharmacodynamics. STUDY SELECTION AND DATA EXTRACTION: Literature characterizing opioid PK-PD was included. Additionally, studies evaluatingoutcomes of opioids for acute severe pain in adult trauma patients were selected. DATA SYNTHESIS: PK-PD literature suggests that morphine exhibits an effect delay of 1.6 to 4.8 hours; however, clinical significance is doubtful. The relative onset of morphine is approximately 6 minutes, and duration, 96 minutes. Morphine 0.1 mg/kg IV then 0.05 mg/kg every 5 minutes achieved pain control in 40% of patients at 10 minutes and 76% at 60 minutes. The effect delay of hydromorphone (orally) is 18 to 38 minutes; its relative onset (IV), 5 minutes; and duration, 120 minutes. Hydromorphone every 15 minutes achieved variable success in clinical trials. The effect delay of fentanyl IV is 16.4 minutes; relative onset, 2 minutes; and duration, 7 minutes. One randomized controlled trial used fentanyl 0.1 µg/kg IV every 5 minutes. CONCLUSIONS: Further integration of opioid PK-PD into acutepain protocols is possible. One opioid should not be deemed more effective but rather titrated to effect. Morphine and hydromorphone can be titrated IV every 5 minutes until adequate pain control. Fentanyl can be titrated every 3 minutes.

Magnocaine: Physical Compatibility and Chemical Stability of Magnesium Sulphate and Lidocaine Hydrochloride in Prefilled Syringes.

OBJECTIVE: To evaluate the physical compatibility and chemical stability of mixtures of magnesium sulphate and lidocaine in order to determine the feasibility of manufacturing a prefilled syringe combining these two drugs for use as an intramuscular (IM) loading dose for eclampsia prevention and/or treatment. This ready-to-use mixture will provide a more tolerable and accessible route of administration appropriate for widespread use. METHODS: Physical compatibility (pH, colour, and formation of precipitate) and chemical stability (maintaining > 90% of initial concentrations) of mixtures of MgSO4, using both commercially available MgSO4 (50%) and MgSO4 reconstituted from salt (61%), with lidocaine hydrochloride (2%) were evaluated every 14 days over six months. The concentration of lidocaine was determined by a stability indicating high performance liquid chromatographic method, while the concentration of magnesium was determined by an automated chemistry analyzer. RESULTS: No changes in pH, color or precipitates were observed for up to 6 months. The 95% confidence interval of the slope of the curve relating concentration to time, determined by linear regression, indicated that only the admixtures of commercially-available magnesium sulfate and lidocaine as well as the 61% magnesium sulfate solution (reconstituted from salt) maintained at least 90% of the initial concentration of both drugs at 25°C and 40°C at 6 months. CONCLUSIONS: Commercially available MgSO4 and lidocaine hydrochloride, when combined, are stable in a pre-filled syringe for at least six months in high heat and humidity conditions. This finding represents the first step in improving the administration of magnesium sulphate in the treatment and prevention of eclampsia in under-resourced settings.

Systematic Review of Efficacy, Pharmacokinetics, and Administration of Intraventricular Aminoglycosides in Adults.

Due to increasing prevalence of intracranial device use and multidrug-resistant and nosocomial organisms, central nervous system (CNS) infections requiring treatment with intraventricular (IVT) aminoglycosides are becoming increasingly common. This article systematically reviews IVT aminoglycoside literature in adults and integrates available evidence to serve as a practical reference for clinicians. Medline (1946 to December 2015), Embase (1974 to December 2015), PubMed (1966 to December 2015), Google, and Google Scholar were searched using the term aminoglycoside combined individually with the terms IVT, meningitis, shunt infection, ventriculitis, and cerebral spinal fluid. Eighteen articles were included. IVT aminoglycosides were assessed in meningitis, ventriculitis, intracranial device infections and neurosurgery prophylaxis. No serious adverse effects following IVT aminoglycoside were reported. Dosages ranged from IVT gentamicin 4-10 mg daily, IVT tobramycin 5-10 mg daily, and IVT amikacin 5-50 mg daily. Duration of therapy should be individualized; however, continuing IVT antibiotics for 3 days and up to 21 days after cerebrospinal fluid (CSF) sterilization has been reported in literature. Most studies included concomitant intravenous antibiotic use. Therapeutic drug monitoring (TDM) was reported in five studies, with varying timing of CSF concentrations obtained. No clear relationship between CSF levels and efficacy or toxicity was evident. Based on current literature, IVT aminoglycosides for the treatment of sensitive gram-negative meningitis, ventriculitis, and CNS device-associated infections appear safe and effective. Optimal dosing regimens are unclear. It is reasonable to initiate IVT aminoglycoside at lowest dose in combination with IV therapy and continuing post CSF sterilization. Preservative-free formulations should be utilized to minimize adverse drug reactions. TDM should not be routinely utilized but reserved for more complicated patients. Further pharmacokinetic and clinical trials of IVT aminoglycosides are necessary to fill current therapeutic gaps. Due to the relatively limited cases of IVT aminoglycoside utilization, prospective, randomized, controlled trials are likely not feasible, and clinicians will have to rely on data from non-randomized and/or retrospective studies.

Vancomycin loading doses: a systematic review.

OBJECTIVE: To systematically assess the literature to ascertain the pharmacokinetics, pharmacodynamics, and clinical efficacy and safety associated with administration of a vancomycin loading dose (LD). DATA SOURCES: MEDLINE (1948-December 31, 2014), EMBASE (1980-December 31, 2014), Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts (1970-December 31, 2014), Google and Google Scholar, and International Clinical Trials Registry Platform were searched using the following terms: vancomycin, glycopeptides, loading dose, dose-response relationship. STUDY SELECTION AND DATA EXTRACTION: Pharmacokinetic, pharmacodynamic, and clinical efficacy studies using vancomycin LDs to achieve trough concentrations of 15 to 20 mg/L were included. Nonhuman, non-English, oral vancomycin, and dialysis patient studies were excluded. Abstracts were included. Study quality was ranked using US Preventative Services Task Force 1996 classification system. Data on study design, baseline characteristics, exclusion criteria, dosing, study outcomes, and conclusions were extracted. DATA SYNTHESIS: A total of 8 studies (5 manuscripts [2 level I, 3 level II-3] and 3 abstracts) were cited. Of 6 adult studies, 4 concluded that administration of vancomycin LDs resulted in significantly more patients achieving troughs of 15 to 20 mg/L. Studies in children found that LDs did not lead to rapid attainment of vancomycin levels ≥15 mg/L. No studies assessed clinical or microbiological outcomes. Limitations included heterogeneity and inconsistent timing of concentration measurements. CONCLUSIONS: High-quality data to guide the use of vancomycin LDs are lacking. LDs may more rapidly attain vancomycin troughs of 15 to 20 mg/L in adults, but information in pediatrics, obesity, and renal impairment is limited. Further studies are required to determine benefit of LDs on clinical and microbiological outcomes.

Evaluating outcomes of alternative dosing strategies for cefepime: a qualitative systematic review.

OBJECTIVE: To perform a qualitative systematic review of the evidence comparing traditional with prolonged intermittent or continuous infusions of cefepime based on clinical and pharmacodynamic outcomes. DATA SOURCES: PubMed (1946 to October 2014), EMBASE (1980 to October 2014), CENTRAL, Cochrane Database of Systematic Reviews, Web of Science, and International Pharmaceutical Abstracts (1970 to October 2014) were searched using the terms cefepime, pharmacokinetics, pharmacodynamics, drug administration, intravenous infusions, intravenous drug administration, continuous infusion, extended infusion, and intermittent therapy. Reference lists from relevant materials were reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating administration regimens of cefepime, one of which included the traditional, manufacturer-recommended 0.5-hour infusion and the other a prolonged or continuous infusion were included. Prespecified clinical outcomes of interest included all-cause mortality, length of hospital stay, clinical cure, and adverse events. The primary pharmacodynamic outcome was percentage time of unbound drug concentration remaining above the minimum inhibitory concentration. DATA SYNTHESIS: In all, 18 studies were included; 6 studies assessed clinical outcomes, and 12 assessed pharmacodynamic outcomes. Prolonged or continuous infusions of cefepime achieved the pharmacodynamic targets more often than traditional infusions. The association of improved clinical outcomes with prolonged or continuous infusions is unclear. All-cause mortality was significantly decreased with the use of a prolonged cefepime infusion in a retrospective study. Two prospective, randomized studies demonstrated no statistically significant difference in mortality between prolonged and intermittent infusions. CONCLUSIONS: The available literature on prolonged and continuous infusions of cefepime demonstrated an improved achievement of pharmacodynamic targets; however, the effect on clinical outcomes is inconclusive. Well-designed prospective studies are required to determine optimal dosing and administration strategies.

Use of proton pump inhibitors in the management of gastroesophageal varices: a systematic review.

OBJECTIVE: To review the efficacy and safety of proton pump inhibitors (PPIs) in gastroesophageal varices (GEVs). DATA SOURCES: MEDLINE (1946 to September 2014), EMBASE (1974 to September 2014), International Pharmaceutical Abstracts (1970 to September 2014), Cochrane Central Register of Controlled Trials (1991 to September 2014), Google, and Google Scholar were searched using the following terms: esophageal varices, gastroesophageal varices, variceal hemorrhage, variceal bleeding, banding ligation, endoscopic variceal ligation, sclerotherapy, proton pump inhibitor, PPI, omeprazole, pantoprazole, lansoprazole, dexlansoprazole, rabeprazole, and esomeprazole. STUDY SELECTION AND DATA EXTRACTION: Published and unpublished studies evaluating the clinical outcomes of PPI use for GEVs were included regardless of study design. Non-English and nonhuman studies were excluded. DATA SYNTHESIS: Of 1156 studies, 20 were included after assessment. There was wide methodological heterogeneity and moderately high risk of bias among studies. Level I evidence suggests that PPIs reduce esophageal ulcer size post-elective esophageal ligation; the clinical importance of such findings is not known given the self-limiting nature of esophageal ulcer. Available evidence does not support a role of PPIs for long-term prophylaxis of portal hypertension-related bleeding and high-dose infusion for acute management of GEV hemorrhage. Retrospective data demonstrate a potential increase in the incidence of spontaneous bacterial peritonitis in patients with cirrhosis receiving PPIs. CONCLUSIONS: The best available evidence supports the use of short-course (10 days) PPI post-endoscopic variceal ligation to reduce ulcer size if ulcer healing is a concern. Practices such as high-dose infusion and prolonged use should be discouraged until evidence of benefit becomes available.

Gender, smoking and tobacco reduction and cessation: a scoping review.

Considerations of how gender-related factors influence smoking first appeared over 20 years ago in the work of critical and feminist scholars. This scholarship highlighted the need to consider the social and cultural context of women's tobacco use and the relationships between smoking and gender inequity. Parallel research on men's smoking and masculinities has only recently emerged with some attention being given to gender influences on men's tobacco use. Since that time, a multidisciplinary literature addressing women and men's tobacco use has spanned the social, psychological and medical sciences. To incorporate these gender-related factors into tobacco reduction and cessation interventions, our research team identified the need to clarify the current theoretical and methodological interpretations of gender within the context of tobacco research. To address this need a scoping review of the published literature was conducted focussing on tobacco reduction and cessation from the perspective of three aspects of gender: gender roles, gender identities, and gender relations. Findings of the review indicate that there is a need for greater clarity on how researchers define and conceptualize gender and its significance for tobacco control. Patterns and anomalies in the literature are described to guide the future development of interventions that are gender-sensitive and gender-specific. Three principles for including gender-related factors in tobacco reduction and cessation interventions were identified: a) the need to build upon solid conceptualizations of gender, b) the importance of including components that comprehensively address gender-related influences, and c) the importance of promoting gender equity and healthy gender norms, roles and relations.

Systematic review of efficacy, pharmacokinetics, and administration of intraventricular vancomycin in adults.

Central nervous system infections requiring treatment with intraventricular (IVT) vancomycin are becoming increasingly common with advent of intracranial devices and increasing prevalence of multi-drug resistant and nosocomial organisms. Administering vancomycin via IVT route bypasses the blood-brain barrier to allow localized and controlled delivery directly to the desired site of action, achieving high concentrations for more reliable bactericidal action. This article systematically reviews current literature on IVT vancomycin in adults, compiles current knowledge, and integrates available evidence to serve as a practical reference.Medline (1946-July 2012), Embase (1974-July 2012), and International Pharmaceutical Abstracts (1970-July 2012) were searched using terms vancomycin, intraventricular, shunt infection, cerebrospinal fluid, and intraventriculitis. Seventeen articles were included in this review. Indications for IVT vancomycin included meningitis unresponsive to intravenous antibiotics, ventriculitis, and intracranial device infections. No serious adverse effects following IVT vancomycin have been reported. Dosages reported in literature ranged from 0.075-50 mg/day, with the most evidence for dosages of 5 to 20 mg/day. Duration of therapy most commonly ranged from 7 to 21 days. Therapeutic drug monitoring was reported in 11 studies, with CSF vancomycin levels varying widely from 1.1 to 812.6 mg/L, without clear relationships between CSF levels and efficacy or toxicity. Using IVT vancomycin to treat meningitis, ventriculitis, and CNS device-associated infections appears safe and effective based on current evidence. Optimal regimens are still unclear, and dosing of IVT vancomycin requires intricate consideration of patient specific factors and their impact on CNS pathophysiology. Higher-quality clinical trials are necessary to characterize the disposition of vancomycin within CNS, and to determine models for various pathophysiological conditions to facilitate better understanding of effects on pharmacokinetic and pharmacodynamic parameters.

Multiple regression analysis of factors predicting mycophenolic acid free fraction in 91 adult organ transplant recipients.

BACKGROUND: Mycophenolic acid (MPA) is an antirejection drug used in various types of solid organ transplants. MPA is extensively bound to albumin, and free MPA is thought to be the primary immunosuppressive agent. Little is known of what contributes to the wide interindividual variability in the observed MPA free fraction (MPAf) in humans. The purpose of this study was to determine, using multiple regression analysis of demographic and laboratory variables that are routinely collected during clinic visits, patient factors that predict MPAf in a large sample (n = 91) of organ transplant recipients. METHODS: Age, weight, height, total daily MPA dose, albumin, serum creatinine (SrCr), and MPAf were obtained from islet (n = 16), kidney (n = 28), and heart/lung (n = 47) transplant recipients. Multiple linear regression analysis and the The Spearman rank correlation were conducted using SigmaStat (version 3.5 for Windows). Significance was set a priori at P = 0.05. RESULTS: The pooled data can be described as (mean ± SD) follows: age (52 ± 13 years), weight (72 ± 15 kg), height (169 ± 9 cm), total daily MPA dose (1632 ± 667 mg), albumin (42 ± 7 g/L), SrCr (112 ± 34 µmol/L), and MPAf (2.9% ± 3.5%). Multiple regression of all commonly acquired variables generated the following equation: MPAf = 1.865 + (0.0357 × age (yrs)) + (0.0125 × weight (kg)) - (0.0202 × height (cm)) - (0.000323 × total daily dose (mg)) + (0.0122 × albumin (g/L)) + (0.0160 × SrCr (µmol/L)) (r = 0.06), but none of the variables were significant predictors of MPAf (P > 0.05). The Spearman rank correlation of each individual variable confirmed lack of significant correlation with MPAf. CONCLUSIONS: To our knowledge, this is the first study attempting to describe factors predicting MPAf in adult organ transplant recipients involving a large sample size. The novel findings of lack of significant predictors warrant further investigations using additional patient factors.

Pharmacogenetics of risperidone: a systematic review of the clinical effects of CYP2D6 polymorphisms.

OBJECTIVE: To summarize and evaluate the pharmacogenetic literature pertaining to the effects of CYP2D6 polymorphism on clinical outcomes of risperidone therapy. DATA SOURCES: A systematic literature search was performed using the search terms risperidone, pharmacogenetics, cytochrome P-450 enzyme system, cytochrome P-450 CYP2D6, and polymorphism (genetic) in MEDLINE (1946-October 2012), EMBASE (1980-October 2012), PubMed (1947-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and Google Scholar. STUDY SELECTION AND DATA EXTRACTION: Identified articles were included if they measured the association between CYP2D6 genetic polymorphisms and clinical outcomes in at least 2 patients taking risperidone. The data elements extracted from these articles consisted of study design, number of subjects, indication for risperidone therapy, CYP2D6 phenotype status, mean daily dose of risperidone, and effects on clinical outcomes. DATA SYNTHESIS: The identified citations consisted of 10 prospective nonrandomized, uncontrolled cohort studies, 1 retrospective cohort study, 1 prospective case-control study, and 1 retrospective case series. Studies were of variable quality and none provided high-quality evidence; they included heterogeneous patient populations with varying clinical diagnoses and drug therapy regimens. Most studies reported nonsignificant trends but were limited by power to detect statistical significance and short trial duration. However, increased risk of adverse effects (including QT interval prolongation) was observed in patients with inactive alleles. CONCLUSIONS: While there were trends toward increased adverse effects in poor metabolizers, most outcomes were not significant. As such, routine genotyping should not be used for screening. Future usefulness cannot be ruled out, as many studies had significant limitations that preclude determination of clinical relevance. Adequately powered clinical and epidemiologic studies are warranted to clarify the role of CYP2D6 genotyping in practice.

Addition of rifampin to vancomycin for methicillin-resistant Staphylococcus aureus infections: what is the evidence?

OBJECTIVE: To evaluate evidence supporting efficacy and safety of the combination of vancomycin and rifampin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. DATA SOURCES: MEDLINE (1946-February 2013), EMBASE (1974-February 2013) and Cochrane Database of Systematic Reviews were searched. STUDY SELECTION: All human prospective trials and retrospective studies evaluating clinical outcomes of vancomycin-rifampin combinations were included. Case reports, case series, and in vitro or animal data were excluded. DATA EXTRACTION: Full-text articles were included and abstracts excluded; 43 of 421 references were reviewed. Five articles met inclusion and were evaluated. DATA SYNTHESIS: A nonrandomized prospective trial reported complete clearance of MRSA bacteremia at 24 hours in all 14 burn patients receiving vancomycin-rifampin therapy. In a case-control study of 42 patients with MRSA endocarditis, adding rifampin prolonged bacteremia (5.2 vs 2.1 days, p < 0.001), decreased survival rates (79% vs 95%, p = 0.048), resulted in drug interactions (52% of cases), and increased hepatic transaminases (21% vs 2%, p = 0.014). In a retrospective analysis of 28 patients with persistent MRSA bacteremia requiring salvage therapy, switching from vancomycin-based to linezolid-based treatment was associated with better salvage success than adding rifampin (88% vs 0%, p < 0.001). In a randomized open-label trial of 42 patients with MRSA endocarditis, addition of rifampin to vancomycin did not affect cure rates (90% combination vs 82% monotherapy, p > 0.20), but increased duration of bacteremia (9 vs 7 days, p > 0.20) compared with vancomycin monotherapy. Another randomized open-label trial of combination versus monotherapy for MRSA pneumonia in 93 intensive care unit patients reported higher clinical successes (53.7% vs 31.0%, p = 0.047), similar 30-day mortality rates, and more adverse events with combination therapy (11 vs 6). CONCLUSIONS: Limited evidence exists to support the adjunctive use of rifampin to treat MRSA infections. The combination may increase drug interactions, adverse effects, and rifampin resistance. Further studies are needed to define the role of rifampin adjunct therapy.

Effect of the UGT1A1*28 allele on unconjugated hyperbilirubinemia in HIV-positive patients receiving Atazanavir: a systematic review.

OBJECTIVE: To systematically examine the literature assessing the effect of uridine 5'-diphospho-glucuronosyltransferase (UGT)1A1*28 genetic polymorphisms on atazanavir-associated hyperbilirubinemia. DATA SOURCES: MEDLINE (1948-November 2012), EMBASE (1980-November 2012), International Pharmaceutical Abstracts (1970-November 2012), Google, and Google Scholar were searched using combinations of the following terms: glucuronosyltransferase, glucuronosyltransferase 1A1, atazanavir, atazanavir plus ritonavir, or polymorph$. The reference lists of all identified articles were manually searched. STUDY SELECTION AND DATA EXTRACTION: Studies were included if at least 1 group of patients received atazanavir therapy and assessed the effect of UGT1A1*28 variants on bilirubin concentrations or atazanavir discontinuation rates. The quality of each study was ranked according to the US Preventive Services Task Force 1996 classification system. Information extracted included study design, baseline characteristics, treatment regimens, UGT1A1*28 genotype frequencies, bilirubin concentrations, incidence of hyperbilirubinemia, and atazanavir discontinuation rates. DATA SYNTHESIS: Our search produced 12 studies, of which 9 were included (6 full manuscripts [level II-2], 2 abstracts, and 1 letter to the editor [level III]). Reported UGT1A1*28 homozygote genotype frequencies (0.8-23.8%) were in general agreement with the literature for the diverse ethnic population captured in the 9 studies. An association between the incidence of hyperbilirubinemia and UGT1A1*28 genotype (homozygotes > heterozygotes > wild-type) was demonstrated in all studies that reported such data (6 of 9 studies). However, the calculated positive predictive value for homozygosity and hyperbilirubinemia from pooled data was low (40.3%). Only 2 studies (levels II-2 and III) reported rates of atazanavir discontinuation due to hyperbilirubinemia and showed some positive correlation with presence of the UGT1A1*28 allele. CONCLUSIONS: Based on the available evidence, homozygosity of the UGT1A1*28 allele does not strongly predict the incidence of severe hyperbilirubinemia. Thus, until large, prospective trials demonstrate otherwise, UGT1A1*28 testing does not appear to provide additional information to aid clinical decision-making when initiating atazanavir treatment in HIV-infected patients.

The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors.

Imatinib mesylate is a tyrosine kinase inhibitor used as first-line treatment in Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and metastatic or unresectable gastrointestinal stromal tumors (GIST). Therapeutic drug monitoring (TDM) for imatinib has been suggested to improve efficacy, assess compliance, and evaluate drug-drug interactions. Imatinib has proven efficacy in improving treatment response and survival in patients with Ph+ CML and GIST. Several analytical methods are available to quantify total plasma imatinib concentrations. A good relationship exists between total imatinib plasma concentrations and pharmacologic response. Clinical evaluation of pharmacologic response to imatinib alone may be insufficient given the long duration of therapy before clinical response in patients with Ph+ CML and GIST. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of TDM for imatinib. The suggested trough concentrations for improved complete cytogenetic or major molecular response in patients with Ph+ CML and improved time to progression for patients with GIST are >1000 and >1100 ng/mL, respectively. Imatinib exhibits interindividual pharmacokinetic variability. Increased apparent clearance of imatinib has been observed in chronic phase chronic myeloid leukemia and increased body weight. Decreased apparent clearance has been observed in renal impairment and patients on concomitant medications with potent inhibition of cytochrome P450 3A4. Duration of therapy in patients with Ph+ CML and GIST is lifelong. Based on the available evidence, TDM for imatinib may provide additional information on efficacy, compliance, and safety than clinical evaluation alone. Patients with suboptimal response to treatment, treatment failure, rare adverse events, drug interactions, or suspected nonadherence will attain the greatest benefit from TDM.

Pharmacokinetic effects of bariatric surgery.

OBJECTIVE: To evaluate the effect of bariatric surgery on the pharmacokinetics of medications. DATA SOURCES: EMBASE (1980-September 2011), PubMed (1947-September 2011), MEDLINE (1948-September 2011), and International Pharmaceutical Abstracts (1970-September 2011) were searched for the following terms: gastric bypass or stomach bypass or bariatric surgery, and pharmacokinetic. STUDY SELECTION AND DATA EXTRACTION: All English-language primary literature that reported pharmacokinetic parameters for orally dosed medications in post-bariatric surgery patients was evaluated, with the exception of studies involving the jejunoileal bypass method. DATA SYNTHESIS: Worldwide, the incidence of obesity is increasing and so are options for managing it, including bariatric surgery. Major alterations to the physical structure of the gastrointestinal tract may cause changes in pharmacokinetic parameters of oral medications, which theoretically could lead to increased or decreased drug exposure. We reviewed 11 prospective trials, 5 of which were available only as abstracts and all of which were small with relatively low power (n = 6-36). The studies were split almost equally between using subjects as their own controls or using separate control subjects; 1 study used historical data as the control. Results were varied, highlighting the multifactorial nature of pharmacokinetics. Drugs such as atorvastatin, which undergo presystemic intestinal metabolism via CYP3A, may show increased bioavailability, whereas those such as amoxicillin, which rely on transport mediators, may be decreased. Most of the studies lacked sufficient power to show significant changes in post-bariatric surgery patients. CONCLUSIONS: Bariatric surgical procedures may result in altered pharmacokinetic parameters, but the literature is lacking in sufficient quantity and quality of studies to make solid conclusions and recommendations. Until more studies of sufficient power are completed, clinicians should closely monitor these patients in the immediate and distant postsurgical period for signs of both drug efficacy and toxicity and adjust their medications as required.

Mosquirix (RTS,S): a novel vaccine for the prevention of Plasmodium falciparum malaria.

OBJECTIVE: To summarize and evaluate the literature for Mosquirix (RTS,S) and provide insight into the therapeutic and economic controversies of this novel malaria vaccine candidate. DATA SOURCES: A systematic literature search was performed using the terms Mosquirix; RTS,S; malaria; vaccine; and Plasmodium in MEDLINE (1948-November 2011), EMBASE (1980-November 2011), International Pharmaceutical Abstracts (1970-November 2011), Google, and Google Scholar. STUDY SELECTION AND DATA EXTRACTION: Clinical trials describing vaccine development, pharmacology, pharmacokinetics, efficacy, and safety were reviewed. For efficacy, clinical trials were reviewed that reported acquisition of malarial disease. Information regarding study design, population, study period, baseline characteristics, clinical outcomes, results, and assessors of quality was extracted. DATA SYNTHESIS: Five randomized controlled trials and 4 follow-up extension studies were identified. In Phase 2 trials, vaccine efficacy rates were 33-65% in infants and 30-53% in children for preventing the first episode of clinical disease. In Phase 3 trials, vaccine efficacy was 56% in children aged 5-17 months. RTS,S reduced the number of clinical malaria episodes and prevented severe malaria in several studies. The follow-up period for vaccine efficacy ranged from 6 to 45 months. RTS,S 25 µg is administered intramuscularly as 3 injections given 1 month apart for infants and children. RTS,S appears to be generally well tolerated. A few cases of meningitis and seizures (within 7 days of vaccination) have been reported. CONCLUSIONS: RTS,S has demonstrated efficacy and safety in Phase 1, 2, and 3 trials, and has the potential to decrease morbidity and mortality from malaria worldwide. Major challenges include determination of the duration of immunity, assessment of its cost-effectiveness, its use in special populations, and its dissemination in endemic regions. Pending further studies, RTS,S has the potential to become the benchmark as the first effective vaccine against malaria.