Continuation of High-Dose Vancomycin despite Nephrotoxicity

LETTER

In agreement with several other studies (3, 4), Bosso et al. reported that in treating serious methicillin-resistant Staphylococcus aureus (MRSA) infections, vancomycin trough concentrations of >15 mg/liter were independently associated with nephrotoxicity (1). However, how best to manage patients in whom nephrotoxicity developed was not adequately addressed. We have found that vancomycin may be continued safely after dose adjustment in such patients.

We describe here our experience with a vancomycin quality improvement program in a 465-bed hospital from August 2007 to April 2008 in which patients requiring at least 5 days of high-dose vancomycin (HDV) were dosed and closely monitored by clinical pharmacists. Patients with creatinine clearance (Crcl) of ≥50 ml/min and <50 ml/min received an initial vancomycin dose of 15 to 20 mg/kg of body weight every 12 and 24 h, respectively, and doses were subsequently titrated to achieve vancomycin trough concentrations (Vtrough) of 15 to 20 mg/liter. Patients were excluded if they were less than 18 years old, pregnant, or incarcerated, had a baseline serum creatinine (Scr) greater than 2 mg/dl, or had deteriorating renal function or if nephrotoxicity occurred less than 2 days from the start of vancomycin. We examined the rate of nephrotoxicity and the impact of continued dose-adjusted HDV in patients who developed nephrotoxicity. Nephrotoxicity was defined as an increase in Scr of 0.5 mg/dl or ≥50% in 2 consecutive results compared with baseline values.

Thirty-five patients were monitored, and data were collected prospectively. Nephrotoxicity developed in 10 (29%) of 35 patients, consistent with other studies (3, 4). The mean Vtrough among nephrotoxic patients before onset of nephrotoxicity was 16.8 ± 5.4 mg/liter (range, 11 to 20.1 mg/liter), and 9 of 10 received concurrent nephrotoxic agents.

Despite nephrotoxicity, 7 of 10 nephrotoxic patients successfully completed their intended course of HDV for an additional 8 to 37 days (median of 26 days). Although doses of vancomycin were reduced, Vtrough were maintained between 15 and 20 mg/liter (mean Vtrough, 17.8 ± 5.2 mg/liter; range, 13.5 to 30 mg/liter). In 4 of these 7 patients, Scr levels returned to less than 0.5 mg/dl above or 150% of the baseline at discharge, while Scr levels were trending down in the remaining 3 patients (Table 1). No patient required hemodialysis.

Table 1.

Details of patients who developed nephrotoxicity^a

Patient no.	Gender and age (yr)	Days to Nftx onset from HDV initiation	Indication for HDV	Baseline Scr (mg/dl)	Peak Scr (mg/dl)	Scr before discharge (mg/dl)	Days on HDV after Nftx	Outcome	Scr outcome
1	F, 61	3	Empirical, pneumonia	1.8	2.7	2.3	12	Completed HDV; discharged; Scr at follow-up was 1.7 mg/dl	Returned to less than 0.5 mg/dl above or 150% of baseline
2	M, 47	4	MRSA bacteremia, osteomyelitis, pneumonia	0.9	3.1	1.1	35	Transferred to nursing home for 7 more days of HDV	Returned to less than 0.5 mg/dl above or 150% of baseline
3	F, 46	6	MRSA bacteremia, osteomyelitis	0.8	1.4	1.3	37	Completed HDV; discharged	Trending down (from peak to baseline)
4	M, 74	7	Empirical, retroperitoneal abscess	1.5	2.2	1.5	0	Abscess grew VRE; HDV discontinued	Returned to less than 0.5 mg/dl above or 150% of baseline
5	F, 44	13	MRSA tenosynovitis	0.4	0.7	0.6	10	MRSA MIC = 2 mg/liter; patient switched to daptomycin	Trending down (from peak to baseline)
6	M, 33	14	Empirical, osteomyelitis	0.9	1.5	1.2	29	Completed HDV; discharged home	Returned to less than 0.5 mg/dl above or 150% of baseline
7	M, 50	15	MRSA bacteremia, pneumonia	1	1.5	1.5	0	Stopped HDV treatment 2 days earlier	No further documented Scr
8	F, 30	17	MRSA bacteremia, endocarditis	0.5	1.8	1.4	26	Completed HDV; discharged home	Trending down (from peak to baseline)
9	M, 51	18	MRSA bacteremia, osteomyelitis, bursitis	0.7	1.5	1.2	0	Switched to trial of co-trimoxazole; Scr at follow-up was 0.8 mg/dl	Returned to less than 0.5 mg/dl above or 150% of baseline
10	M, 41	26	MRSA osteomyelitis	0.6	2	1.1	8	Completed HDV; discharged home; Scr at follow-up was 0.7 mg/dl.	Returned to less than 0.5 mg/dl above or 150% of baseline

^aNftx, nephrotoxicity; HDV, high-dose vancomycin; VRE, vancomycin-resistant enterococcus; MRSA, methicillin-resistant Staphylococcus aureus; Scr, serum creatinine; M, male; F, female.

Reasons for discontinuation of vancomycin in the other 3 patients included isolation of vancomycin-resistant enterococcus, high vancomycin concentrations able to last 2 more days until the intended completion date, and a switch to a trial of oral co-trimoxazole due to the patient's request for an early discharge.

It should be noted that we excluded patients with deteriorating renal function before HDV initiation. These patients could deteriorate further if given and continued on HDV. As they were not studied and may represent an important subset of those treated in the hospital, the result of our study cannot be extrapolated to this population.

How best to manage antimicrobial therapy in patients with apparent nephrotoxicity has received little attention (2, 4). We report here that carefully selected and monitored patients can safely continue dose-adjusted vancomycin despite nephrotoxicity, suggesting that nephrotoxicity associated with vancomycin use is often mild to moderate and that it is not inexorably progressive. This is important information, as continuation of HDV may be needed in instances in which a lack of superior alternatives, intolerance, or drug interactions preclude the use of alternative antimicrobials for the treatment of severe MRSA infections.