Incidence of Nephrotoxicity and Association With Vancomycin Use in Intensive Care Unit Patients With Pneumonia: Retrospective Analysis of the IMPACT-HAP Database

Abstract

Background

The 2005 guidelines from the American Thoracic Society and the Infectious Diseases Society of America recommend vancomycin trough levels of 15 to 20 mg/L for the therapy of hospital-acquired (HAP), ventilator-associated (VAP), and health care–associated (HCAP) pneumonia.

Objective

The goal of this article was to report the incidence of nephrotoxicity and associated risk factors in intensive care unit patients who received vancomycin for the treatment of HAP, VAP, and HCAP.

Methods

This was a retrospective analysis of data from a multicenter, observational study of pneumonia patients. Antibiotic-associated nephrotoxicity was defined as either an increase in serum creatinine ≥0.5 mg/dL or 50% above baseline, from initiation of vancomycin to 72 hours after completion of therapy. Univariate and multivariate logistic regression analyses were performed to identify risk factors for development of renal dysfunction.

Results

Of the 449 patients in the database, 240 received at least one dose of vancomycin and 188 had sufficient data for analysis. In these 188 patients, 63% were male. Mean (SD) age was 58.5 (17.2) years, and the mean Acute Physiology and Chronic Health Evaluation II score was 19.4 (6.4). Nephrotoxicity occurred in 29 of 188 (15.4%) vancomycin-treated patients. In multivariate analysis, initial vancomycin trough levels ≥15 mg/L (odds ratio [OR], 5.2 [95% CI, 1.9–13.9]; P = 0.001), concomitant aminoglycoside use (OR, 2.67 [95% CI, 1.09–6.54]; P = 0.03), and duration of vancomycin therapy (OR for each additional treatment day, 1.12 [95% CI, 1.02–1.23]; P = 0.02) were independently associated with nephrotoxicity. The incidence of nephrotoxicity increased as a function of the initial vancomycin trough level, rising from 7% at a trough <10 mg/L to 34% at >20 mg/L (P = 0.001). The mean time to nephrotoxicity decreased from 8.8 days at vancomycin trough levels <15 mg/L to 7.4 days at >20 mg/L (Kaplan-Meier analysis, P = 0.0003).

Conclusions

Nephrotoxicity may be common among intensive care unit patients with pneumonia treated with broad-spectrum antibiotic therapy that includes vancomycin. The finding that an initial vancomycin trough level ≥15 mg/L may be an independent risk factor for nephrotoxicity highlights the need for additional studies to assess current recommendations for vancomycin dosing for ICU patients with pneumonia.

Introduction

Hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), and health care–associated pneumonia (HCAP) are important causes of morbidity and mortality in intensive care units (ICUs), despite advances in antimicrobial therapy and the use of better supportive care modalities. The American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) published an updated guideline for the management of HAP, VAP, and HCAP in 2005,¹ which emphasized early, appropriate antibiotics in adequate doses. These guidelines recommend that patients with risk factors for infection with multidrug-resistant pathogens should receive broad-spectrum empiric therapy with activity against gram-negative pathogens, including Pseudomonas aeruginosa, and an antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). The guidelines indicate that vancomycin should be dosed to achieve target trough levels of 15 to 20 mg/L.¹ The same vancomycin trough levels are also recommended for serious infections due to S aureus and MRSA (including pneumonia) in a consensus review of therapeutic monitoring of vancomycin by the American Society of Health-System Pharmacists, the Society of Infectious Diseases Pharmacists, and the IDSA² and in the recently published IDSA Clinical Practice Guidelines for the treatment of MRSA infections.³

Nephrotoxicity is uncommon when vancomycin is used at conventional dosages (eg, 1 g every 12 hours).2, 4, 5, 6 The risk, however, may increase when vancomycin is administered concomitantly with other nephrotoxic drugs or at the higher dosages needed to achieve target trough levels for patients with HAP, VAP, and HCAP.⁷ In early studies, vancomycin nephrotoxicity was confined to patients receiving concomitant aminoglycoside therapy.2, 6 More recent studies indicate that vancomycin trough levels ≥15 mg/L8, 9, 10, 11, 12, 13 and high daily dosages (ie, ≥4 g)¹⁴ are independently associated with an increased risk of nephrotoxicity. ICU patients had a 3-fold higher risk than non-ICU patients in the latter study.¹⁴ Because of a greater emphasis on achieving higher vancomycin levels (target trough levels of 15–20 mg/L) in recent guidelines,1, 2, 3 we believe additional studies are warranted to assess the potential nephrotoxic risks of increased vancomycin exposure.

To evaluate the risk of nephrotoxicity in ICU patients with pneumonia treated with broad-spectrum empiric therapy including vancomycin, we performed a retrospective analysis of patients enrolled in IMPACT-HAP (Improving Medicine Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia). IMPACT-HAP is a multicenter performance improvement project initiated soon after publication of the ATS/IDSA guidelines and aimed at improving the management of ICU patients with nosocomial pneumonia, details of which have been recently published.¹⁵ In the current study, our primary objective was to report the incidence of nephrotoxicity and its associated risk factors in ICU patients who received vancomycin for the treatment of HAP, VAP, and HCAP.