Ronald G. Hall

Vancomycin-Associated Nephrotoxicity: Grave Concern or Death by Character Assassination?

Vancomycin-associated nephrotoxicity was reported in 0% to 5% of patients in the 1980s. This has been confirmed by numerous clinical trials comparing novel anti-methicillin-resistant Staphylococcus aureus agents with vancomycin at the Food and Drug Administration-approved dosage of 1 g every 12 hours. Treatment failures of vancomycin in patients with methicillin-resistant S. aureus infections have been reported despite in vitro susceptibility. These failures have led to the use of vancomycin doses higher than those approved by the Food and Drug Administration. Higher doses are being administered to achieve goal vancomycin trough concentrations of 10 to 20 microg/mL recommended by several clinical practice guidelines endorsed by the Infectious Diseases Society of America. Recent studies suggest that increased rates of nephrotoxicity are associated with aggressive vancomycin dosing. These increased rates are confounded by concomitant nephrotoxins, renal insufficiency, or changing hemodynamics. These studies also have demonstrated that vancomycins nephrotoxicity risk is minimal in patients without risk factors for nephrotoxicity. Clinicians unwilling to dose vancomycin in accordance with clinical practice guidelines should use an alternative agent because inadequate dosing increases the likelihood of selecting heteroresistant methicillin-resistant S. aureus isolates.

Atazanavir for the Treatment of Human Immunodeficiency Virus Infection

Atazanavir is the first once‐daily protease inhibitor for the treatment of human immunodeficiency virus type 1 infection and should be used only in combination therapy, as part of a highly active antiretroviral therapy (HAART) regimen. In addition to being the most potent protease inhibitor in vitro, atazanavir has a distinct cross‐resistance profile that does not confer resistance to other protease inhibitors. However, resistance to other protease inhibitors often confers clinically relevant resistance to atazanavir. Currently, atazanavir is not a preferred protease inhibitor for initial HAART regimens. In treatment‐naïve patients, atazanavir can be given as 400 mg/day. However, atazanavir should be pharmacologically boosted with ritonavir in treatment‐experienced patients or when coadministered with either tenofovir or efavirenz. Patients who receive atazanavir experience similar rates of adverse events compared with patients receiving comparator regimens. An exception is an increased risk of asymptomatic hyperbilirubinemia, which is due to competitive inhibition of uridine diphosphate‐glucuronosyltransferase 1A1. Although hyperbilirubinemia is a common adverse drug reaction of atazanavir therapy (22–47%), fewer than 2% of patients discontinue atazanavir therapy because of this adverse effect. Common adverse effects reported with atazanavir include infection, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash. Of significance, fewer abnormalities have been observed in plasma lipid profiles in patients treated with atazanavir compared with other protease inhibitor–containing regimens. As with other protease inhibitors, atazanavir is also a substrate and moderate inhibitor of the cytochrome P450 (CYP) system, in particular CYP3A4 and CYP2C9. Clinically significant drug interactions include (but are not limited to) antacids, proton pump inhibitors, histamine type 2 receptor antagonists, tenofovir, diltiazem, irinotecan, simvastatin, lovastatin, St. Johns wort, and warfarin. We conclude that atazanavir is a distinctively characteristic protease inhibitor owing to its in vitro potency, once‐daily dosing, distinct initial resistance pattern, and infrequent association with metabolic abnormalities.

Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin.

Background: Rosuvastatin (RSV) is a potent statin with a lower potential for drug interactions. However, recent data have revealed unexpected increases in RSV concentrations with lopinavir/ritonavir. The objective is to study the pharmacokinetic interaction of RSV with atazanavir/ritonavir (ATV/RTV) or fosamprenavir/ritonavir (FPV/RTV). Methods: In a prospective pharmacokinetic drug interaction study, six HIV-seronegative, healthy adult volunteers received single 10-mg doses of RSV at baseline and after 6 days of ATV/RTV and FPV/RTV, with 6-day washout periods. Plasma concentrations of RSV and its metabolites, N-desmethyl-RSV and RSV-lactone, were measured by using a internally validated tandem mass spectrometric (LC-MS/MS) method over 24 hours. Results: Compared to baseline, the area under the plasma concentration-time curve (AUC0-24h) and maximum plasma concentration (Cmax) of RSV increased by 213% and 600%, respectively, and the time to reach Cmax was shorter (1.75 h vs. 2.91 h) when given with ATV/RTV (P < 0.05). However, coadministration with FPV/RTV did not significantly affect the pharmacokinetics of RSV. The AUC0-24h of N-desmethyl-RSV was not significantly affected by either combinations, but that of RSV-lactone increased (P < 0.05) by 61% and 76% after coadministration with ATV/RTV and FPV/RTV, respectively. Conclusion: ATV/RTV significantly increases the plasma concentrations of rosuvastatin, most likely by increasing rosuvastatins oral bioavailability. Dose limitations of RSV with ATV/RTV may be needed.

Pharmacologic Treatment Options for Nosocomial Pneumonia Involving Methicillin-Resistant Staphylococcus aureus

Objective: To discuss current and potential treatment options for nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). Data Sources: A MEDLINE search (1966–January 2007) was conducted to identify English-language literature on pharmacotherapy of nosocomial pneumonia and the bibliographies of pertinent articles. Programs and abstracts from infectious disease meetings were also searched. Search terms included MRSA, nosocomial pneumonia, pulmonary infections, vancomycin, quinupristin/dalfopristin, linezolid, daptomycin, tigecycline, dalbavancin, oritavancin, and ceftobiprole. Data Selection and Data Extraction: All articles were critically evaluated and all pertinent information was included in this review. Data Synthesis: Vancomycin has been the drug of choice for MRSA infections for many years. Recent data suggest that linezolid may be superior to vancomycin in the treatment of MRSA nosocomial pneumonia. However, there are limitations to the available data. Therefore, prospective, randomized studies are needed before linezolid is recommended as the preferred first-line therapy. Other approved agents for nosocomial MRSA infections, such as quinupristin/dalfopristin and daptomycin, should not be used in the treatment of MRSA pneumonia, as they were inferior in clinical trials. Tigecycline has excellent activity against MRSA in vitro, but should not be routinely used for the treatment of MRSA pneumonia, as clinical data are lacking. In a Phase III clinical trial, an anti-MRSA cephalosporin, ceftobiprole, is being evaluated for effectiveness against nosocomial pneumonia. Investigational glycopeptides may eventually have a role in the treatment of nosocomial pneumonia, but data are currently lacking. Conclusions: Vancomycin is still the drug of choice for treatment of MRSA pneumonia, and linezolid should be used as an alternative agent. Linezolid should carry strong consideration for patients with vancomycin-induced nephrotoxicity or a documented lack of response to vancomycin. Tigecycline and investigational agents with activity against MRSA may be future options for nosocomial pneumonia due to MRSA.

Multicenter Evaluation of Vancomycin Dosing – Emphasis on Obesity

BACKGROUND There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight. METHODS This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients >or=18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included. RESULTS Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%). Adequate initial dosing (>or=10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P < .0001). Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received >or=15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines. Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy. CONCLUSION In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.

Treatment of Active Pulmonary Tuberculosis in Adults: Current Standards and Recent Advances: Insights from the Society of Infectious Diseases Pharmacists

Tuberculosis is a global pandemic, with 9 million new cases of the disease and approximately 2 million deaths each year. More than 98% of patients treated for tuberculosis in the United States between 1993 and 2007 had drug‐susceptible strains. The standard treatment regimen for drug‐susceptible tuberculosis has not changed in decades and was developed on the basis of empiric observations of different treatment regimens. Only recently has the veracity of the scientific basis for standard therapy been examined. The backbone of therapy is still isoniazid, rifampin, and pyrazinamide, although fluoroquinolones are being investigated as a replacement for isoniazid. Recent population pharmacokinetic studies have demonstrated the importance of individualized dosing of isoniazid, pyrazinamide, and rifampin. Isoniazid serum clearance differs depending on the patients number of N‐acetyltransferase 2 gene *4 (NAT2*4) alleles. Pyrazinamide serum clearance has been shown to increase with increases in body weight. Rifampins volume of distribution, clearance, and absorption have wide between‐patient and within‐patient variability. Microbial pharmacokinetic‐pharmacodynamic (PK‐PD) indexes and targets to optimize microbial killing and minimize resistance have been identified for rifampin, isoniazid, pyrazinamide, and the fluoroquinolones. These PK‐PD indexes suggest that different doses and dosing schedules than those currently recommended could optimize therapy and perhaps shorten duration of therapy. Efflux pump inhibition is also being investigated to enhance first‐line antituberculosis drug therapy. Comorbid conditions such as diabetes mellitus and genetically determined iron overload syndromes have been associated with significantly worse patient outcomes. Therapy for these and other patient groups needs further improvement. These patient factors, the covariates for pharmacokinetic variability, and PK‐PD factors suggest the need to individualize therapy for patients with tuberculosis in order to optimize outcomes and reduce the duration of therapy.

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.

Fractal Geometry and the Pharmacometrics of Micafungin in Overweight, Obese, and Extremely Obese People

ABSTRACT The majority of Americans are overweight, and the incidence of obesity continues to increase. This trend predisposes people to a number of deleterious consequences, including the metabolic syndrome and other conditions that lead to a greater number of hospital admissions. Invasive candidiasis is an important nosocomial infection that results from these admissions. Echinocandins such as micafungin are indicated for treatment. We have previously demonstrated that overweight patients exhibit higher micafungin systemic clearance (SCL) than leaner patients. We hypothesized that obese and extremely obese people would show even higher SCL than merely overweight patients. To test this, we performed a prospective study of 36 adult volunteers randomized to receive a single dose of either 100 mg or 300 mg of micafungin whose body mass index fell within one of the following categories: <25, 25 to 40, and >40 kg/m2. The male-to-female ratio was 1:1. The minimum weight was 43 kg, the median 97 kg, and the maximum weight 155 kg. A two-compartment model was examined using the maximum likelihood solution via the expectation-maximization algorithm. Men had a higher median SCL of 1.53 liters/h versus 1.29 liters/h (P = 0.01) in the Mann-Whitney U-test. The typical SCL was 1.04 liters/h but increased by a factor of (weight/66)0.75 as weight increased above 66 kg. Thus, the relationship between micafungin SCL and weight in adults is best described by fractal-geometry-based laws. Furthermore, micafungin SCL continues to increase as weight increases, with no obvious plateau. This leads to a requirement for strategies to determine individualized dosing levels for obese and extremely obese patients.

Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures beyond Two-Thirds or Three-Fourths

ABSTRACT Echinocandins, such as caspofungin, are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that the microbial effect of these agents is concentration dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adults with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The central volume was typically 4.2 liters but increased by a factor of (weight/53.6)3/4. The peripheral compartment volume was typically 2.53 liters but increased by a factor of (weight/53.6)3/2, an unusual power law signature. Similarly, the 3/4 power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kg, whereas intercompartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area-under-the-concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling and warrants further study. Moreover, this suggests that use of a “floating” instead of a fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients. (This study protocol was registered at www.clinicaltrials.gov under registration number NCT01062165.)

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.