Evaluation of a Capped Dosing Telavancin Regimen Compared to Standard Dosing at a Large Community Teaching Hospital

ABSTRACT

Telavancin, a lipoglycopeptide antibiotic, is traditionally dosed at 10 mg/kg based on total body weight but is associated with toxicities that limit its use. This study supports the use of a capped dosing regimen of 750 mg in obese patients, which is associated with equal efficacy and fewer adverse effects compared to traditional dosing.

INTRODUCTION

Telavancin is a lipoglycopeptide antibiotic that exhibits concentration-dependent, bactericidal activity against Gram-positive organisms (1, 2). The recommended dose in adult patients with a creatinine clearance greater than 50 mL/min is 10 mg/kg intravenously (i.v.) every 24 h based on total body weight (TBW) (2). Although generally well tolerated, this dosing has been associated with safety concerns, particularly nephrotoxicity (3–5) and QTc prolongation (6). Increased area-under-the-curve (AUC) exposure occurs in obese patients, increasing the risk of adverse drug effects (7, 8). Thus, traditional dosing may not be optimal in obese patients. Evidence exists to support the strategy of using capped doses of telavancin at 750 mg/dose to decrease adverse effects while preserving efficacy (9, 10). The primary objective of this study was to assess the safety and efficacy of the capped dosing regimen compared to the standard dosing regimen.

As part of routine clinical practice, some infectious disease physicians at our facility (Huntsville Hospital, Huntsville, Alabama) began utilizing capped doses of 750 mg telavancin for patients weighing 75 kg or more, resulting in some patients receiving the capped dose and others receiving the standard dose. This study, approved by the Huntsville Hospital institutional review board, is a single-center, retrospective chart review comparing clinical outcomes in overweight patients who received the 750-mg capped dosing regimen to those in patients who received telavancin based on TBW. Inclusion criteria included an age of ≥18 years, a weight of ≥75 kg, and receipt of ≥3 doses. Pregnant patients and all those not meeting the inclusion criteria were excluded. Data collection included dose and duration, indication, length of stay, laboratory and microbiological data, readmission rates, and case mix index (CMI).

Efficacy was assessed through four factors: leukocytosis resolution (defined as a decrease in white blood cell count to ≤12,200 cells/μL if elevated at admission), fever resolution (decrease in temperature to ≤100.4°F if elevated upon admission), need for additional Gram-positive antibiotics, and readmission rate at 30 days for any cause. The case mix index was used to evaluate acuity between the groups. Safety was assessed by comparing incidence of QTc prolongation, nephrotoxicity, and mortality between groups. Patients were evaluated for QTc prolongation if they received an electrocardiogram (EKG) before and after initiation of telavancin to determine if the QTc interval increased to >500 ms. Nephrotoxicity was measured using the RIFLE (risk, injury, failure, loss of kidney function, and end-stage kidney disease) classification of a 2-fold increase in serum creatinine from baseline or a 50% decrease in glomerular filtration rate after the initiation of telavancin. Chi-square tests were used for comparisons of categorical variables, and independent-sample t tests were used for comparisons of continuous variables. Separate logistic regression analyses were performed to determine the effect of the group (capped dosing versus standard dosing) on the following outcome variables: readmission, QTc prolongation, nephrotoxicity, and mortality.

A total of 333 patients were evaluated for inclusion; 169 did not meet inclusion criteria, so 164 patients were analyzed. Seventy-three patients (45%) received the capped regimen. The two groups were comparable in terms of weight, sex, and CMI (Table 1). The mean age of patients receiving capped dosing was significantly lower (P = 0.008) and baseline creatinine clearance (CR_CL) was significantly higher (P = 0.003) in the capped group than the standard group. Average weight was similar between groups (P = 0.683). Mean telavancin dose in the standard group was 1,060 mg (10 mg/kg); mean dosing in the capped group was 7.16 mg/kg/dose. There were 15 prescribed indications for telavancin. The primary indications in the capped group were bacteremia/sepsis (33%), skin and soft tissue infections (SSTIs) (26%), and pneumonia (5%), compared to SSTIs (29%), bacteremia/sepsis (26%), and pneumonia (23%) in the standard group.

TABLE 1.

Baseline characteristics and efficacy/safety parameters

Type	Characteristic or parameter	Result for group receiving:		P value
		Capped dose (n = 73)	Standard dose (n = 91)
Baseline characteristics	Avg wt (kg) (range)	100 (75–341)	108 (77–206)	0.683
	Age (yrs) (range)	53 (18–81)	59 (21–87)	0.008
	Male (%)	46 (63)	64 (70)	0.982
	Avg CRCL (mL/min) (range)	97 (10–120)	83 (28–120)	0.003
	Avg CMI	3.1998	3.4309	0.635
	Indications for telavancin	Bacteremia/sepsis (33%); skin/soft tissue infections (26%); pneumonia (5%); septic arthritis (4%); various other infections (32%)	Skin/soft tissue infections (29%); bacteremia/sepsis (26%); pneumonia (23%); septic arthritis (8%); various other infections (14%)	NAa
Efficacy parameters [no./total (%)]	Leukocytosis resolution	21/35 (60.0)	20/59 (33.9)	0.014
	Fever resolution	15/18 (83.3)	12/20 (60)	0.113
	Readmission	6/67 (9.0)	17/66 (25.8)	0.010
	Need for additional antibiotics	6/69 (8.7)	9/73 (12.3)	0.481
Safety parameters [no./total (%)]	QTc prolongation	4/20 (20)	5/32 (15.6)	0.685
	Nephrotoxicity	7/59 (11.9)	21/84 (25.0)	0.051
	Mortality	7 (9.6)	28 (30.8)	0.001

^aNA, not applicable.

Efficacy and safety parameters are reported in Table 1. Leukocytosis resolution was significantly higher in the capped group compared to the standard group (P = 0.014). Fever resolution and need for additional Gram-positive antibiotics were similar between groups (P = 0.113 and P = 0.481, respectively). However, readmission rate was significantly higher in the standard group than the capped group (P = 0.010).

QTc interval increase and nephrotoxicity were similar between groups (P = 0.685 and P = 0.051, respectively). However, mortality was significantly higher in the standard group than the capped group (P = 0.001).

When controlling for age and CMI, the capped group was significantly less likely to experience readmission (P = 0.008) and mortality (P = 0.004). Patients with a higher CMI score were more likely to experience nephrotoxicity (P = 0.003) and mortality (P < 0.001) but not readmission (P = 0.071).

Limited data suggest that a telavancin capped dosing regimen of 750 mg is as effective as standard dosing based on TBW in overweight/obese patients, with a more favorable adverse-effect profile (9, 10). This study supports these findings and significantly adds to the existing literature. In this study, patients who received the capped regimen were more likely to experience resolution of leukocytosis, less likely to be readmitted to the hospital within 30 days, and less likely to experience mortality. Capped dosing may also theoretically result in a decreased incidence of nephrotoxicity. Although this study did not find a significant difference in nephrotoxicity, this may be due to the relatively small sample size of this study population, and this should be further evaluated in larger clinical trials.

This study has several limitations. It is a single-center, retrospective review, with limitations inherent to this study design. The relatively small sample size may have limited the ability to detect differences between certain parameters, particularly nephrotoxicity. While both groups had a high percentage of telavancin use for SSTIs and bacteremia/sepsis, the incidence of use for the treatment of pneumonia and other disease states differed between groups. In particular, worse outcomes would be expected with pneumonia, which was more common in the standard group. However, given the limited number of patients in each group, the effect of this disparity between the groups is difficult to ascertain. While both groups were comparable in most baseline characteristics, the standard dose group were older and had lower creatinine clearances compared to the capped group, which might predispose to worse outcomes.

Overall, the utilization of a capped telavancin dosing regimen of 750 mg in patients weighing 75 kg or more appears to be equally effective as a standard dosing regimen but with fewer adverse effects. In the future, further studies should attempt to confirm the results of this study and include a larger sample size, ideally from multiple centers, which will also allow a further examination of the effect of capped dosing in individual disease states.