Kyle Vance-Bryan

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.

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.

Assessment of effects of protein binding on daptomycin and vancomycin killing of Staphylococcus aureus by using an in vitro pharmacodynamic model.

Initial clinical trials with daptomycin (2 mg/kg per day) were prematurely suspended because of unexplained treatment failures in patients with bacteremia who were treated with daptomycin, despite in vitro data indicating that the gram-positive cocci causing the infection were susceptible to daptomycin. One explanation for these clinical failures may relate to the relatively high degree of daptomycin protein binding (94%). To evaluate the impact of protein on daptomycin activity, a two-chamber in vitro pharmacodynamic model was used to study and compare the interaction between Staphylococcus aureus (clinical isolate) and either daptomycin or vancomycin, each in the presence and absence of physiologic human albumin concentrations. Low-dose (2 mg/kg) daptomycin, high-dose (6 mg/kg) daptomycin, and 10 mg of vancomycin per kg beta-phase elimination serum-concentration-versus-time curves were simulated by using this in vitro pharmacodynamic model. The bacterial kill rates by all three regimens were decreased in the presence of albumin (P less than 0.0002). The average times required for a 99% kill of the initial S. aureus inocula (approximately 5 x 10(7) CFU/ml) without albumin were 0.81 (low-dose daptomycin), 0.33 (high-dose daptomycin), and 6.18 (vancomycin) h. The average times required for a 99% kill of S. aureus with albumin were 7.66 (low-dose daptomycin), 0.95 (high-dose daptomycin), and 10.52 (vancomycin) h. These data demonstrate that, depending on the concentration of daptomycin, the presence of albumin can profoundly diminish the bactericidal activity of daptomycin.

QTc-interval prolongation associated with slow intravenous erythromycin lactobionate infusions in critically ill patients: a prospective evaluation and review of the literature.

Intravenous erythromycin has recently been associated with significant QTc interval prolongation, torsades de pointes, and sudden cardiac death. The prolonged the QTc interval attributed to erythromycin typically is associated with rapid infusion rates in excess of 10 mg/minute. We prospectively assessed the relationship between QTc interval prolongation and erythromycin administration by slow intravenous infusion (mean rate 8.9 ± 3.5 mg/minute, range 3.9–16.7 mg/minute). Electrocardiographic (ECG) rhythm strips were prospectively obtained in 44 critically ill patients receiving intravenous antibiotics (22 received erythromycin and 22 ceftazidime, cefuroxime, cefotaxime, ceftriaxone, or ampicillin‐sulbactam as controls). The ECG recordings were obtained immediately before and within 15 minutes after drug infusions. Only the first available set of ECG strips were evaluated. Two controls had evidence of hepatic dysfunction; no patients receiving erythromycin did. The QTc interval was calculated using Bazetts formula by two blinded investigators. For controls, mean ± 1 SD (range) QTc intervals were 423 ± 96 (300–550) msec at baseline and 419 ± 96 (280–610) msec after infusion (p=0.712). In contrast, in the erythromycin group, the interval was significantly prolonged from 524 ± 105 (360–810) msec at baseline to 555 ± 134 (400–980) msec after infusion (p=0.034). No patients experienced a dysrhythmia as a consequence of erythromycin infusion. Despite slow rates of infusion, QTc interval prolongation was significant. The clinical importance of this finding remains to be determined.

Comparison of vancomycin pharmacokinetics in hospitalized elderly and young patients using a Bayesian forecaster

Limited data have been published that compare the pharmacokinetic parameters of vancomycin in elderly versus young patients. This study was designed to assess vancomycin pharmacokinetics in 148 elderly (≥60 years of age) and 140 young (18–59 years of age) hospitalized infected patients. Serum vancomycin concentrations were determined using fluorescence polarization immunoassay. Serum concentration‐versus‐time data were fitted to a two‐compartment Bayesian forecasting program. Elderly versus young vancomycin pharmacokinetic parameters derived were as follows (patients with serum creatinine ≤.1.5 mg/dL): mean ± standard deviation terminal disposition half‐life (t1/2) of 17.8 ± 11.8 versus 7.5 ± 6.7 hours, respectively, P < .05; volume of distribution (Vz) of 74.2 ± 32.3 versus 67.0 ± 30.7 L, respectively, P = .16; and total body clearance (CL) of 0.71 ± 0.41 versus 1.22 ± 0.50 mL/min/kg, respectively, P < .05. Comparing subjects with normal serum creatinine values (≤1.5 mg/dL), the elderly required smaller daily doses as compared with the young group to maintain target peak and trough vancomycin serum concentrations (18.2 ± 5.8 versus 25.2 ± 7.8 mg/kg/day, P < .05). Stepwise multiple regression models for the pharmacokinetic parameters were developed to assess the predictive power of age, controlling for the effects of gender, total body weight, serum creatinine, and creatinine clearance. Age was consistently an independent and significant predictor of t1/2, Vz, and CL. These data demonstrate that elderly patients exhibit significant differences in vancomycin pharmacokinetic parameters compared with young patients and constitute a patient population in need of individualized vancomycin dosing due to substantial heterogeneity in physiologic and pharmacokinetic parameters.

Wide variation in single, daily-dose aminoglycoside pharmacokinetics in patients with burn injuries.

Five to seven mg/kg single, daily-dose aminoglycoside regimens have been recently advocated as effective alternatives to traditional aminoglycoside regimens. The rationale for single, daily-dose aminoglycoside therapy is to produce an optimal ratio between aminoglycoside peak concentrations (Cmax) and pathogen minimal inhibitory concentration to maximize bacterial killing and to produce an aminoglycoside-free period during the 24-hour dosing interval. Single, daily-dose aminoglycoside therapy has not been recommended to date for use in the population of patients with burn injuries. The purpose of this study was to determine the magnitude and variability of aminoglycoside Cmax and the duration of the aminoglycoside-free period after simulated single, daily-dose regimens in patients with burn injuries. Fifty-two patients receiving gentamicin or tobramycin in the burn unit were studied retrospectively to determine the individualized pharmacokinetic parameters and the simulated Cmax and 24-hour after the dose trough minimum concentrations for 5 and 7 mg/kg single, daily-dose aminoglycoside regimens. Patients were only included in the final analysis if they had been treated for burn wound infections and exhibited a calculated creatinine clearance exceeding 60 ml/min (N = 40). Mean [percentage coefficient of variation] Cmax/minimum concentrations were 15.4[30.5]/0.03[200.0] and 21.6[30.6]/0.04[200.0] mg/L for 5 and 7 mg/kg daily doses, respectively. The mean coefficient of variation time to reach an extrapolated concentration of 0.1 mg/L was 15.9[30.8] hours and 17.0[30.6] hours for the 5 and 7 mg/kg daily doses, respectively. Substantial variability in aminoglycoside Cmax and duration of the aminoglycoside-free period was observed. These data suggest that many patients with burn injuries are not candidates for single, daily-dose aminoglycoside therapy because of restrictive creatinine clearance criteria and pronounced variability in length of the aminoglycoside-free interval. If single, daily-dose aminoglycoside therapy is to be used in this patient population, therapeutic drug monitoring is recommended to screen for appropriate candidates and to optimize Cmax and minimal inhibitory concentration ratios and duration of the aminoglycoside-free interval.

Evaluation of activity of temafloxacin against Bacteroides fragilis by an in vitro pharmacodynamic system.

An in vitro pharmacodynamic system has been successfully adapted to simulate in vivo antimicrobial pharmacokinetics under anaerobic conditions. This system was used to perform time-kill kinetic studies which were designed to compare the activity of temafloxacin to ciprofloxacin and cefotetan against two strains of Bacteroides fragilis (ATCC 25285 and ATCC 23745). All experiments were performed as single-dose, 24-h, duplicate runs. Starting bacterial inocula of 10(7) CFU/ml were exposed to starting antimicrobial concentrations of 5 micrograms of temafloxacin per ml, 5 micrograms of ciprofloxacin per ml, and 100 micrograms of cefotetan per ml. Terminal half-lives of 8, 4, and 4 h were simulated for each antimicrobial agent. Temafloxacin was rapidly bactericidal against B. fragilis. Ciprofloxacin was not bactericidal (< 3 log10 unit decline in bacterial numbers) to either strain of B. fragilis. Cefotetan was bactericidal (> or = 3 log10 unit decline in bacterial numbers) to each strain but killed at a slower rate than temafloxacin. Times to 3 log10 unit declines of strain ATCC 25285 were 2, 4, and > 24 h, whereas those of strain ATCC 23745 were 4, 4, and > 24 h for temafloxacin, cefotetan, and ciprofloxacin, respectively. Total logarithmic declines of strain ATCC 25285 were > 4.5, > 4.5, and 2.9 log10 CFU/ml, whereas those of strain ATCC 23745 were 4.1, > 4.5, and 1.2 log10 CFU/ml for each drug, respectively. These and other studies demonstrated that temafloxacin showed potential as an agent that could have been further developed for use in the treatment of anaerobic infections. However, the drug was removed from the market by its manufacturer because of toxicity issues. Although the release of newer fluoroquinolones that possess significant activity against anaerobic bacteria does not appear imminent, the time-kill studies performed in this study demonstrate that further research is warranted in the development of fluoroquinolones which possess significant antianaerobic activity.

Investigation of the early killing of Staphylococcus aureus by daptomycin by using an in vitro pharmacodynamic model

The purpose of this study was to develop a pharmacodynamic model to describe the dependency of the rate of Staphylococcus aureus killing upon the concentration of daptomycin. A range of free (unbound) daptomycin concentrations ranging from 0.12 to 27 times the MIC were simulated in the peripheral compartment of a two-compartment pharmacokinetic model. Log-linear regression of free daptomycin concentrations versus growth or kill rate constants showed a significant correlation (r = -0.90; P less than 0.001). A Lineweaver-Burk plot of the reciprocal transformation of these data yielded a poor fit (r = -0.38; P greater than 0.05). When a Lineweaver-Burk-type regression analysis was performed on the reciprocal of the change in the rate constant rather than the rate constant itself, the result demonstrated good correlation (r = 0.90; P less than 0.0001). The observations were also well described by a sigmoidal maximum plateau pharmacologic effect model, in which the pharmacologic effect of daptomycin is a reduction in the bacterial exponential growth rate constant from the baseline in the absence of antibiotic to a lower (positive) growth or (negative) death rate constant observed in the presence of antibiotic. These data confirm that daptomycin exhibits concentration-dependent killing over a wide range of free daptomycin concentrations relative to the MIC and suggest that this is a saturable process similar to the Michaelis-Menten pharmacokinetic elimination of certain drugs.

Prolonged Neuromuscular Blockade in Two Critically Ill Patients Treated With Atracurium

Recent literature suggests that the risk of prolonged neuromuscular blockade associated with atracurium compared with other nondepolarizing neuromuscular blocking agents may be minimal. Two patients experienced prolonged weakness associated with the administration of atracurium. Both received atracurium 0.5–0.7 mg/kg/hour in combination with methylprednisolone 500–600 mg/day. Electromyographic results and creatine kinase levels were suggestive of muscular weakness in both patients. Despite high‐dose corticosteroid therapy, the electromyographic evidence supporting prolonged weakness did not suggest typical corticosteroid myopathy. Although some clinicians advocate routine administration of atracurium in critically ill patients due to the relative lack of reports of prolonged weakness, this may be premature. Although there are fewer reports of atracurium‐associated prolonged weakness compared with pancuronium and vecuronium, the patients we describe suggest that it may occur.