David R.P. Guay

Clinical Pharmacokinetics of Vancomycin

SummaryVancomycin utilisation has increased dramatically in the last 10 years due to the increasing clinical significance of infections with methicillin-resistant staphylococci. Recent studies have focused on characterising the disposition of vancomycin in patients and assessing the relationship between serum concentrations and therapeutic as well as adverse effects.Although vancomycin is not appreciably absorbed from the intact gastrointestinal tract, several recent case reports have documented the attainment of therapeutic and potentially toxic vancomycin serum concentrations following oral administration to patients with pseudomembranous colitis. The disposition of parenterally administered vancomycin has been best characterised by a triexponential model. The half-life of the initial phase (t½π) is approximately 7 minutes, that of the second phase (t½α) is approximately 0.5 to 1 hour, while the terminal elimination half-life (t½β) ranges from 3 to 9 hours in subjects with normal renal function. The volume of the central compartment (Vc) in adults is approximately 0.15 L/kg while the steady-state volume of distribution (Vdss) ranges from 0.39 to 0.97 L/kg. More than 80% of a vancomycin dose is excreted unchanged in the urine within 24 hours after administration, and the concentration of vancomycin in liver tissue and bile has been reported to be at or below detection limits. Vancomycin renal clearance approximates 0.5 to 0.8 of simultaneously determined creatinine or 125I-iothalamate clearances, suggesting that the primary route of renal excretion is glomerular filtration. Recently, non-renal factors such as hepatic conjugation have been proposed as an important route of vancomycin elimination. However, these data are difficult to reconcile with other studies showing minimal non-renal clearance of vancomycin in subjects with end-stage renal disease. As yet, the disposition of vancomycin in patients with hepatic disease has not been adequately defined.Only limited data are available regarding the concentrations of vancomycin in biological fluids other than plasma. The penetration of vancomycin into cerebrospinal fluid (CSF) in patients with and without meningitis has been quite variable. Although early studies suggested that adequate CSF concentrations may not be achieved in subjects with uninflamed meninges, more recent investigations have reported contradictory results. Therapeutic concentrations of vancomycin, i.e. greater than 2.5 mg/L, have, however, been reported in ascitic, pericardial, pleural and synovial fluids. Tissue concentrations of vancomycin have exceeded simultaneous serum concentrations in heart, kidney, liver and lung specimens.The disposition of vancomycin in paediatric and geriatric patients appears to be primarily related to the degree of renal function. However, there is some evidence of altered tissue binding and/or tissue distribution in geriatric patients. Since significant interpatient variability has been reported, further investigation will be required to substantiate dosing recommendations for these patient populations. Vancomycin clearance is decreased and the elimination half-life progressively prolonged in association with declining glomerular filtration rate, but the volume of distribution at steady-state is not significantly correlated with declining renal function. Although marked variability in vancomycin clearance within a defined range of renal function has been observed, highly significant relationships between vancomycin clearance and creatinine clearance have been reported and may be utilised for the adjustment of dosage in this patient population. Haemodialysis provides no significant contribution to total body clearance of vancomycin, while haemoperfusion has produced prompt and sharp declines in vancomycin serum concentrations. Peritoneal dialysis clearances of vancomycin are markedly lower than those observed during haemodialysis or haemoperfusion. However, due to the longer course of this mode of dialysis, contribution to total body clearance may be significant for some patients.Although early reports suggested that vancomycin therapy was frequently associated with adverse events, several recent reports have indicated that vancomycin is extremely safe. Nephrotoxicity has been observed in approximately 5% of patients and is associated with trough serum vancomycin concentrations of 30 mg/L or greater. The combination of an aminoglycoside and vancomycin may significantly increase the risk of nephrotoxicity. A causal relationship between attainment of peak vancomycin serum concentrations of 25 to 50 mg/L and/or trough concentrations of 13 to 32 mg/L and ototoxicity has been reported. Ototoxicity may be reversed, if not prevented, by close monitoring of vancomycin serum concentrations. The remaining adverse reactions which have been reported do not appear to be related to vancomycin dosage or serum concentrations.The prospective design of vancomycin dosage regimens would appear to be warranted in adults with impaired renal function, elderly patients, morbidly obese patients, and paediatric patients. Although the pharmacokinetic profile of vancomycin is best described by a 2- or 3-compartment model, the collection of a sufficient number of serum concentrations to perform these characterisations in individual patients is not practical or cost-justified in routine clinical practice. Therefore an approach similar to that used for the aminoglycoside antibiotics would appear to be most practical.

Clinical pharmacokinetics of ciprofloxacin.

SummaryCompared with nalidixic acid, ciprofloxacin is representative of a newer, more potent class of quinolones, termed the fluoroquinolones. It is available in both oral and parenteral dosage forms.The primary target of quinolone activity appears to be the bacterial DNA gyrase enzyme, which is a member of the class of type II topoisomerases. Bacteria do not acquire resistance to fluoroquinolones through mechanisms that are plasmid or R-factor mediated and, additionally, the quinolones do not appear to be vulnerable to degradatin by bacterial inactivating mechanisms. Rather, bacterial resistance to ciprofloxacin occurs either through chromosomal mutation in the target enzyme DNA gyrase or through mutations that alter drug permeability into the bacterial cell. Ciprofloxacin and the fluoroquinolones in general are no more likely to select resistant mutants than are aminoglycosides or β-lactam antibiotics.Ciprofloxacin displays in vitro activity against most Gram-negative and many Grampositive pathogenic bacteria, many of which are resistant to a wide range of antibiotics. This finding is of considerable potential clinical significance.High pressure liquid chromatography (HPLC) and microbiological agar diffusion assays have been routinely used to quantify ciprofloxacin concentrations in biological fluids. Both methods are reproducible and accurate for serum but HPLC is recommended for other specimens because of the presence of microbiologically active metabolites.Absorption after oral administration is rapid and can be satisfactorily described as a zero-order process; peak serum ciprofloxacin concentrations (Cmax) are reached in approximately I to 2 hours. Concomitant administration of food does not cause clinically significant impairment of absorption and may be helpful in minimising gastric distress caused by the drug. A linear relationship between serum ciprofloxacin concentrations and the dose administered either orally or intravenously has been reported. The absolute bioavailability of ciprofloxacin is approximately 70%. The volume of distribution is large with a steady-state range after oral or intravenous dosing of 1.74 to 5.0 L/kg reflecting penetration of the drug into most tissues.Nonrenal clearance accounts for approximately 33% of the elimination of ciprofloxacin; to date, 4 metabolites have been identified. A first-pass effect has been reported but is thought to be clinically unimportant. Faecal recovery of ciprofloxacin accounts for approximately 15% of an intravenous dose. Nonrenal elimination includes metabolic degradation, biliary excretion and transluminal secretion across the enteric mucosa.Glomerular filtration and tubular secretion account for approximately 66% of the total serum clearance. The terminal disposition half-life (ty,) is about 3 to 4 hours. Pharmacokinetic studies after multiple intravenous doses of ciprofloxacin have not reported significant differences in terminal disposition half-lives or systemic clearances between the first and the last dose.The pharmacokinetics of ciprofloxacin in the elderly are significantly different from those observed in the young: the elderly have a reduced renal clearance, a significantly greater area under the concentration-time curve (AUC). a larger Commax, and a prolonged t1/2. Several investigators have suggested that dosage intervals shorter than 12 hours be avoided in the elderly. The pharmacokinetics of ciprofloxacin in patients with cystic fibrosis do not differ significantly from those of healthy control populations and as a result, dosing regimen alterations are not required in patients with cystic fibrosis.In patients with varying degrees of renal dysfunction, the pharmacokinetics of ciprofloxacin are significantly altered; the ty, in end-stage renal disease is approximately twice that of healthy controls (### 8h). The observed AUC and Cmax may also be elevated in these patients. A wide variability in the ty, of ciprofloxacin has been observed among patients with severe renal failure, resulting in the recommendation that changes be made in the daily dose rather than the dosing interval in order to achieve drug concentrations comparable with those observed in normal renal function. The clinical impact of chronic ambulatory peritoneal dialysis or haemodialysis over a 4-hour period on the pharmacokinetics of ciprofloxacin is not significant, and therefore dosage supplementation after or during these procedures is not necessary. Liver dysfunction also appears to exert little effect on ciprofloxacin pharmacokinetics and dosage adjustments are not recommended.The concomitant oral administration of magnesium-, aluminium-, or calcium-containing antacids, sucralfate, iron preparations and multivitamins containing zinc significantly reduces the absorption of ciprofloxacin. Ciprofloxacin reduces the metabolism of theophylline by approximately 15 to 30%; caution is therefore advised when using any fluoroquinolone in combination with xanthine compounds. Case reports have documented increases in prothrombin times among patients receiving warfarin and ciprofloxacin concomitantly.Adverse reactions associated with ciprofloxacin administration are generally mild to moderate and usually do not result in termination of therapy; the worldwide incidence is in the range of 4 to 8%, which is similar to that reported for other fluoroquinolones. The most commonly reported adverse reactions involve either the gastrointestinal tract (nausea, vomiting and diarrhoea), metabolic or nutritional disorders, or the CNS.

Cranberry and Urinary Tract Infections

Urinary tract infection (UTI) refers to the presence of clinical signs and symptoms arising from the genitourinary tract plus the presence of one or more micro-organisms in the urine exceeding a threshold value for significance (ranges from 102 to 103 colony-forming units/mL). Infections are localized to the bladder (cystitis), renal parenchyma (pyelonephritis) or prostate (acute or chronic bacterial prostatitis). Single UTI episodes are very common, especially in adult women where there is a 50-fold predominance compared with adult men. In addition, recurrent UTIs are also common, occurring in up to one-third of women after first-episode UTIs. Recurrences requiring intervention are usually defined as two or more episodes over 6 months or three or more episodes over 1 year (this definition applies only to young women with acute uncomplicated UTIs).A cornerstone of prevention of UTI recurrence has been the use of low-dose once-daily or post-coital antimicrobials; however, much interest has surrounded non-antimicrobial-based approaches undergoing investigation such as use of probiotics, vaccines, oligosaccharide inhibitors of bacterial adherence and colonization, and bacterial interference with immunoreactive extracts of Escherichia coli. Local (intravaginal) estrogen therapy has had mixed results to date.Cranberry products in a variety of formulations have also undergone extensive evaluation over several decades in the management of UTIs. At present, there is no evidence that cranberry can be used to treat UTIs. Hence, the focus has been on its use as a preventative strategy. Cranberry has been effective in vitro and in vivo in animals for the prevention of UTI. Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uro-pathogens (e.g. uropathogenic E. coli) to the uroepithelium, thus impairing colonization and subsequent infection. The isolation of the component(s) of cranberry with this activity has been a daunting task, considering the hundreds of compounds found in the fruit and its juice derivatives. Reasonable evidence suggests that the anthocyanidin/proanthocyanidin moieties are potent antiadhesion compounds. However, problems still exist with standardization of cranberry products, which makes it extremely difficult to compare products or extrapolate results. Unfortunately, most clinical trials have had design deficiencies and none have evaluated specific key cranberry-derived compounds considered likely to be active moieties (e.g. proantho-cyanidins). In general, the preventive efficacy of cranberry has been variable and modest at best. Meta-analyses have established that recurrence rates over 1 year are reduced approximately 35% in young to middle-aged women. The efficacy of cranberry in other groups (i.e. elderly, paediatric patients, those with neurogenic bladder, those with chronic indwelling urinary catheters) is questionable. Withdrawal rates have been quite high (up to 55%), suggesting that these products may not be acceptable over long periods. Adverse events include gastrointestinal intolerance, weight gain (due to the excessive calorie load) and drug-cranberry interactions (due to the inhibitory effect of flavo-noids on cytochrome P450-mediated drug metabolism). The findings of the Cochrane Collaboration support the potential use of cranberry products in the prophylaxis of recurrent UTIs in young and middle-aged women. However, in light of the heterogeneity of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTIs at this time.

An Update on the Role of Nitrofurans in the Management of Urinary Tract Infections

There have been few recent reviews of the nitrofurans in the literature, and none include recently available data on the use of nitrofurazone (nitrofural) in the prevention of catheter-associated urinary tract infection (CAUTI). Nitrofurazone and nitrofurantoin are the only nitrofurans that have become established in clinical use in the 20th century. These 2 nitrofurans have remained clinically useful against a wide spectrum of Gram-positive and Gram-negative bacteria, including many strains of common urinary tract pathogens. Today, the primary use of nitrofurantoin is as an oral antibacterial treatment for genitourinary infections. Nitrofurazone is primarily used as a topical antibacterial agent in burns and skin grafts and recently was approved for the prophylaxis of CAUTI. The recent development of a nitrofurazone-impregnated catheter as a novel modality in the prevention of CAUTI reflects a renewed interest in the effectiveness of nitrofurans. In an era when concern about bacterial resistance to many anti-infective agents is growing, the nitrofurans have continued to be active against organisms that have developed resistance to antibacterials. The presence of multiple mechanisms of action for the nitrofurans might be expected to reduce the ability of bacteria to develop resistance. Considering that an emergence of resistance to the nitrofurans has not appreciably occurred after several decades of clinical use, the nitrofurans may be unique among common antibacterial agents in this regard.

Clinical pharmacokinetics of drugs used to treat urge incontinence.

Urge incontinence (also known as overactive bladder) is a common form of urinary incontinence, occurring alone or as a component of mixed urinary incontinence, frequently together with stress incontinence. Because of the pathophysiology of urge incontinence, anticholinergic/antispasmodic agents form the cornerstone of therapy. Unfortunately, the pharmacological activity of these agents is not limited to the urinary tract, leading to systemic adverse effects that often promote nonadherence. Although the pharmacokinetics of flavoxate, propantheline, scopolamine, imipramine/desipramine, trospium chloride and propiverine are also reviewed here, only for oxybutynin and tolterodine are there adequate efficacy/tolerability data to support their use in urge incontinence.Oxybutynin is poorly absorbed orally (2–11% for the immediate-release tablet formulation). Controlled-release oral formulations significantly prolong the time to peak plasma concentration and reduce the degree of fluctuation around the average concentration. Significant absorption occurs after intravesical (bladder) and transdermal administration, although concentrations of the active.N-desethyl metabolite are lower after transdermal compared with oral administration, possibly improving tolerability. Food has been found to significantly affect the absorption of one of the controlled-release formulations of oxybutynin, enhancing the rate of drug release. Oxybutynin is extensively metabolised, principally via N-demethylation mediated by the cytochrome P450 (CYP) 3A isozyme.The pharmacokinetics of tolterodine are dependent in large part on the pharmacogenomics of the CYP2D6 and 3A4 isozymes. In an unselected population, oral bioavailability of tolterodine ranges from 10% to 74% (mean 33%) whereas in CYP2D6 extensive metabolisers and poor metabolisers mean bioavailabilities are 26% and 91%, respectively. Tolterodine is metabolised via CYP2D6 to the active metabolite 5-hydroxymethyl-tolterodine and via CYP3A to N-dealkylated metabolites. Urinary excretion of parent compound plays a minor role in drug disposition. Drug effect is based upon the unbound concentration of the so-called ‘active moiety’ (sum of tolterodine + 5-hydroxymethyl-tolterodine). Terminal disposition half-lives of tolterodine and 5-hydroxymethyl-tolterodine (in CYP2D6 extensive metabolisers) are 2–3 and 3–4 hours, respectively. Coadministration of antacid essentially converts the extended-release formulation into an immediate-release formulation.Knowledge of the pharmacokinetics of these agents may improve the treatment of urge incontinence by allowing the identification of individuals at high risk for toxicity with ‘usual’ dosages. In addition, the use of alternative formulations (controlled-release oral, transdermal) may also facilitate adherence, not only by reducing the frequency of drug administration but also by enhancing tolerability by altering the proportions of parent compound and active metabolite in the blood.

Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders

BACKGROUND Few drugs are available for the management of hyperkinetic movement disorders such as the dystonias, choreas, dyskinesias, and tics. Those that are available (primarily neuroleptics) are associated with a wide range of potentially serious adverse effects, including induction of tardive movement disorders. Tetrabenazine (TBZ) is a monoamine-depleting agent initially studied in the 1950s and currently approved by the US Food and Drug Administration for the treatment of chorea in Huntingtons disease. OBJECTIVE This article reviews the chemistry, pharmacology, pharmacokinetics, therapeutic use, tolerability, drug-interaction potential, and dosing and administration of TBZ. METHODS MEDLINE was searched (1950-February 2010) for English-language articles investigating any aspect of TBZ. Search terms included tetrabenazine, Ro 1-9569, Nitoman, benzoquinolizines, and reserpine. The reference lists of the identified articles were searched for other pertinent publications, particularly those that were not indexed in the 1950s and 1960s. RESULTS In the search for a chemical compound that was simpler than reserpine while preserving reserpine-like psychotropic activity, TBZ was identified in the 1950s as one member of a large group of benzoquinolizine derivatives. TBZ acts by depletion of the monoamines serotonin, norepinephrine, and dopamine in the central nervous system (CNS). It does this by reversibly inhibiting vesicle monoamine transporter type 2 and thus preventing monoamine uptake into presynaptic neurons. Clinical studies suggest that TBZ may have therapeutic applications in a wide range of hyperkinetic movement disorders. TBZ has been associated with numerous adverse effects, some of them serious and potentially fatal; these include parkinsonism, other extrapyramidal symptoms (particularly akathisia), depression and suicidality, neuroleptic malignant syndrome, and sedation. TBZ is subject to important drug-drug interactions with inhibitors and inducers of cytochrome P450 (CYP) 2D6, reserpine, and lithium. It is one of very few drugs whose dosing is based, in part, on the results of genotyping (in its case, genotyping for CYP2D6 metabolizer status). CONCLUSIONS TBZ is a complicated drug in terms of its mechanism of action and its activities against the 3 major monoamines in the CNS, making it difficult to predict its efficacy and tolerability in patients with hyperkinetic movement disorders. It is associated with numerous adverse effects and several important drug-drug interactions. Much work remains to be done to determine the therapeutic potential of TBZ in the treatment of hyperkinetic movement disorders.

Clostridium difficile Colonization in Residents of Long-Term Care Facilities: Prevalence and Risk Factors

Objective: To determine the period prevalence of Clostridium difficile disease and asymptomatic carriage in the residents of long‐term care facilities (LTCF) and to characterize the risk factors for colonization or associated disease.

Effect of obesity on vancomycin pharmacokinetic parameters as determined by using a Bayesian forecasting technique.

Few data exist concerning the effect of obesity on the pharmacokinetic parameters of vancomycin. The purpose of this investigation was to assess the effect of obesity on vancomycin pharmacokinetic parameters in 95 nonobese and 135 obese adult patients (age range, 18 to 92 years) receiving vancomycin. All subjects had normal renal function as defined by a creatinine concentration in serum of < or = 1.5 mg/dl (mean estimated creatinine clearance +/- 1 standard deviation, 76 +/- 34; range, 23 to 215 ml/min). Vancomycin concentrations in serum were determined by the fluorescence polarization immunoassay. All data for vancomycin concentration in serum versus time for each course of therapy were fitted by using a two-compartment Bayesian forecasting program. Subjects were stratified into nine groups on the basis of the percent difference between actual body weight (ABW) and lean body weight (LBW) (> -10%, -10 to 0%, > 0 to 10%, > 10 to 20%, > 20 to 30%, > 30 to 40%, > 40 to 50%, > 50 to 60%, > 60%). Analysis of variance with post hoc Scheffes testing revealed that statistically significant differences occurred in terminal disposition half-life (t1/2 beta) between the extremes of modestly obese (group 4) and morbidly obese (group 9, P < 0.05) patients. Similar analysis with distribution volume (V) identified significant differences in patients at or near their LBW (groups 2 to 4) and patients who were morbidly obese (groups 8 and 9, P < 0.05). Multiple regression models for the pharmacokinetic parameters V, t1/2beta, and vancomycin total body clearance were developed to assess the joint predictive power of LBW, ABW, and percent over LBW, controlling for the effects of age, initial creatinine concentration in serum, initial creatinine clearance, and gender. In the final model for V, both ABW and percent over LBW were independent and significant predictors. For total body clearance, only ABW was significant and predictive. Percent over LBW was a significant and independent predictor of t1/2beta. LBW is not predictive of these pharmacokinetic parameters and should not be used for initial dosing. On the basis of these data, ABW appears to be superior to LBW for calculating initial dose requirements for vancomycin.

Prospective study of lower respiratory tract infections in an extended-care nursing home program: potential role of oral ciprofloxacin.

PURPOSE Infections of the lower respiratory tract pose an important problem in nursing homes. Despite the magnitude of this problem, few, if any, antibiotic studies have been targeted specifically at nursing home-acquired bronchopulmonary infections. Following the establishment of a teaching Extended-Care Nursing Home Program, which facilitated the early diagnosis and therapy of bronchopulmonary infections, a comparative trial of oral ciprofloxacin and intramuscular cefamandole was initiated in elderly patients with lower respiratory tract infections. In addition to assessing the relative efficacy and safety of ciprofloxacin and cefamandole, our goals were to identify problems and pitfalls associated with conducting clinical research in this nursing home setting, evaluate selected clinical and laboratory features of lower respiratory tract infection in this patient population, and measure outcomes in all study groups. PATIENTS AND METHODS During a 20-month period, 40 patients with pneumonia and 20 patients with acute bronchitis were enrolled in this randomized study. Sixty-three patients with pneumonia who were ineligible for the randomized study were also followed prospectively. The mean age of the 111 participants (123 cases) was 80.8 years; all patients had at least one chronic medical condition. RESULTS Although Streptococcus pneumoniae was the single most common isolate, gram-negative bacteria were cultured from 81 percent of the cases that yielded pathogens from a satisfactory sputum specimen. The in-hospital mortality rate was strikingly low (6.5 percent), and a large majority of patients in all study groups were discharged safely back to their nursing homes well within the Diagnosis-Related Group length of stay. CONCLUSION Ciprofloxacin appeared to be as safe and effective as cefamandole in this nursing home program; however, additional studies are needed to determine its role in the treatment of elderly patients with bronchopulmonary infections.

Immediate-release oxybutynin versus tolterodine in detrusor overactivity: a population analysis.

We evaluated adherence to treatment with immediate‐release (IR) oxybutynin (515 patients) and tolterodine (505 patients) for detrusor overactivity through retrospective analysis of a pharmacy claims database. Outcomes included percentage of patients continuing therapy for 6 months, medication possession ratios, and time to discontinuation of therapy. The proportion of patients continuing therapy for 6 months was statistically superior for tolterodine (32%) compared with IR oxybutynin (22%, p<0.001). Medication possession ratios were also superior for patients in the tolterodine group (medians 0.83 and 0.64, ranges 0.11–1.15 and 0.07–1.13, respectively, p<0.001). Oxybutynin was discontinued significantly earlier (mean 45 days) than tolterodine (mean 59 days, p<0.001) and was switched to another therapy more commonly than tolterodine (19% and 14%, respectively). Tolterodine was favored over oxybutynin for several measurements of patient adherence. However, less than one‐third of patients continued therapy with either agent for 6 months. The clinical relevance of these differences is unknown.